Age-related changes in amygdala-frontal connectivity during emotional face processing from childhood into young adulthood.

The ability to process and respond to emotional facial expressions is a critical skill for healthy social and emotional development. There has been growing interest in understanding the neural circuitry underlying development of emotional processing, with previous research implicating functional connectivity between amygdala and frontal regions. However, existing work has focused on threatening emotional faces, raising questions regarding the extent to which these developmental patterns are specific to threat or to emotional face processing more broadly. In the current study, we examined age-related changes in brain activity and amygdala functional connectivity during an fMRI emotional face matching task (including angry, fearful, and happy faces) in 61 healthy subjects aged 7-25 years. We found age-related decreases in ventral medial prefrontal cortex activity in response to happy faces but not to angry or fearful faces, and an age-related change (shifting from positive to negative correlation) in amygdala-anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) functional connectivity to all emotional faces. Specifically, positive correlations between amygdala and ACC/mPFC in children changed to negative correlations in adults, which may suggest early emergence of bottom-up amygdala excitatory signaling to ACC/mPFC in children and later development of top-down inhibitory control of ACC/mPFC over amygdala in adults. Age-related changes in amygdala-ACC/mPFC connectivity did not vary for processing of different facial emotions, suggesting changes in amygdala-ACC/mPFC connectivity may underlie development of broad emotional processing, rather than threat-specific processing. Hum Brain Mapp 37:1684-1695, 2016. © 2016 Wiley Periodicals, Inc.

Crack cocaine use impairs anterior cingulate and prefrontal cortex function in women with HIV infection.

Crack cocaine use is associated with impaired verbal memory in HIV-infected women more than uninfected women. To understand the neural basis for this impairment, this study examined the effects of crack cocaine use on activation of the prefrontal cortex (PFC) and strategic encoding during a verbal memory task in HIV-infected women. Three groups of HIV-infected women from the Chicago Consortium of the Women's Interagency HIV Study were compared: current users of crack cocaine (n = 10), former users of cocaine (n = 11), and women who had never used cocaine (n = 9). Participants underwent functional magnetic resonance imaging during a verbal memory task and completed a neuropsychological test of verbal memory. On the neuropsychological test, current crack users performed significantly worse than other groups on semantic clustering, a measure of strategic encoding, p < 0.05. During encoding, activation in left anterior cingulate cortex (ACC) was lower in current and former cocaine users compared to never users. During recognition, activation in bilateral PFC, specifically left dorsal medial PFC and bilateral dorsolateral PFC, was lower in current and former users compared to women who had never used cocaine. Lower activation in left dorsolateral PFC was correlated with worse performance on the recognition task, p < 0.05. The verbal learning and memory deficits associated with cocaine use in women with HIV may be partially accounted for by alterations in ACC and PFC function.

Cannabinoid modulation of amygdala subregion functional connectivity to social signals of threat.

BACKGROUND: Δ(9)-Tetrahydrocannabinol has been shown to modulate anxiety and facilitate the extinction of fear by inhibiting amygdala reactivity. Since functional coupling between the amygdala and prefrontal cortex is implicated in affective processes, it is possible that Δ(9)-tetrahydrocannabinol affects amygdala-prefrontal cortex functional connectivity in ways that differ across amygdala subregions: basolateral, centromedial, and superficial. METHODS: The aim of the study was to examine the effects of Δ(9)-tetrahydrocannabinol on functional connectivity between amygdala subregions and the prefrontal cortex during socio-emotional threat in healthy adults using a double-blind, placebo-controlled, within-subjects design. Sixteen subjects completed a functional magnetic resonance imaging task designed to probe amygdala responses to social threat. Amygdala subregion-prefrontal cortex functional connectivity was compared between Δ(9)-tetrahydrocannabinol and placebo using generalized psychophysiological interaction analyses. RESULTS: Findings indicated that Δ(9)-tetrahydrocannabinol enhanced basolateral and superficial amygdala connectivity to the rostral anterior cingulate/medial prefrontal cortex. CONCLUSION: These effects, including Δ(9)-tetrahydrocannabinol's potential ability to reduce threat perception or enhance socio-emotional regulation, may help understand the neurocircuitry of affect.

How mood challenges emotional memory formation: an fMRI investigation.

Experimental mood manipulations and functional magnetic resonance imaging (fMRI) provide a unique opportunity for examining the neural correlates of mood-congruent memory formation. While prior studies in mood-disorder patients point to the medial temporal lobe in the genesis of mood-congruent memory (MCM) bias, the interaction between mood and emotional memory formation has not been investigated in healthy participants. In particular it remains unclear how regulatory structures in the pre-frontal cortex may be involved in mediating this phenomenon. In this study, event-related fMRI was performed on 20 healthy participants using a full-factorial, within-subjects repeated-measures design to examine how happy and sad moods impact memory for valenced stimuli (positive, negative and neutral words). Main effects of mood, stimulus valence and memory were examined as was activity related to successful memory formation during congruent and in-congruent moods. Behavioral results confirm an MCM bias while imaging results show amygdala and hippocampal engagement in a global mood and successful recall, respectively. MCM formation was characterized by increased activity during mood-congruent encoding of negative words in the orbito-frontal cortex (OFC) and for mood-incongruent processing of negative words in medial- and inferior-frontal gyri (MFG/IFG). These findings indicate that different pre-frontal regions facilitate mood-congruent and incongruent encoding of successfully recalled negative words at the time of learning, with OFC enhancing congruency and the left IFG and MFG helping overcome semantic incongruities between mood and stimulus valence.

Amygdala and orbitofrontal reactivity to social threat in individuals with impulsive aggression.

BACKGROUND: Converging evidence from animal and human lesion studies implicates the amygdala and orbitofrontal cortex (OFC) in emotional regulation and aggressive behavior. However, it remains unknown if functional deficits exist in these specific brain regions in clinical populations in which the cardinal symptom is impulsive aggression. We have previously shown that subjects diagnosed with intermittent explosive disorder (IED), a psychiatric disorder characterized by reactive aggressive behavior, perform poorly on facial emotion recognition tasks. In this study we employed a social-emotional probe of amygdala-OFC function in individuals with impulsive aggression. METHODS: Ten unmedicated subjects with IED and 10 healthy, matched comparison subjects (HC) underwent functional magnetic resonance imaging while viewing blocks of emotionally salient faces. We compared amygdala and OFC reactivity to faces between IED and HC subjects, and examined the relationship between the extent of activation in these regions and extent of prior history of aggressive behavior. RESULTS: Relative to controls, individuals with IED exhibited exaggerated amygdala reactivity and diminished OFC activation to faces expressing anger. Extent of amygdala and OFC activation to angry faces were differentially related to prior aggressive behavior across subjects. Unlike controls, aggressive subjects failed to demonstrate amygdala-OFC coupling during responses to angry faces. CONCLUSIONS: These findings provide evidence of amygdala-OFC dysfunction in response to an ecologically-valid social threat signal (processing angry faces) in individuals with a history of impulsive aggressive behavior, and further substantiate a link between a dysfunctional cortico-limbic network and aggression.

Amygdala reactivity to emotional faces at high and low intensity in generalized social phobia: a 4-Tesla functional MRI study.

Using functional magnetic resonance imaging, we measured amygdala reactivity to faces varying on emotional intensity in subjects with generalized social phobia (GSP) and matched healthy controls, and observed greater bilateral activation to high (vs. low) intensity expressions in the phobic group, suggesting that more arousing social-emotional cues contribute to limbic hyperactivity in GSP.

Association between amygdala hyperactivity to harsh faces and severity of social anxiety in generalized social phobia.

BACKGROUND: Previous functional brain imaging studies of social anxiety have implicated amygdala hyperactivity in response to social threat, though its relationship to quantitative measures of clinical symptomatology remains unknown. The primary aim of this study was to examine the association between response to emotionally harsh faces in the amygdala, a region implicated in social and threat-related processing, and severity of social anxiety symptoms in patients with generalized social phobia (GSP). METHODS: Ten subjects with GSP naive to psychotropic medications and without psychiatric comorbidity and ten healthy comparison subjects matched on age, gender, ethnicity, and education completed the Liebowitz Social Anxiety Scale and underwent high-field (4Tesla) functional magnetic resonance imaging while viewing blocks of emotionally salient faces. RESULTS: Relative to happy faces, activation of the amygdala in response to harsh (angry, disgusted, fearful) faces was greater in GSP patients than in controls, and the extent of amygdala activation was positively correlated with severity of social anxiety symptoms, but not general state or trait anxiety levels. CONCLUSIONS: Our findings suggest that amygdala activation to interpersonal threat can be specifically linked to the severity of social anxiety symptoms of individual GSP patients, and thus, may serve as a useful functional marker of disease severity.

Prefrontal control and predictors of cognitive behavioral therapy response in social anxiety disorder.

Generalized social anxiety disorder (gSAD) is associated with aberrant anterior cingulate cortex (ACC) response to threat distractors. Perceptual load has been shown to modulate ACC activity such that under high load, when demands on processing capacity is restricted, individuals with gSAD exhibit compensatory activation to threat distractors yet under low load, there is evidence of reduced activation. It is not known if neural predictors of response to cognitive behavioral therapy (CBT), based on such emotional conflict resolution, interact with demands on controlled processes. Prior to CBT, 32 patients with gSAD completed an fMRI task involving a target letter in a string of identical targets (low perceptual load) or a target letter in a mixed letter string (high perceptual load) superimposed on fearful, angry and neutral face distractors. Whole-brain voxel-wise analyses revealed better CBT outcome was predicted by more frontopartial activity that included dorsal ACC (dACC) and insula to threat (vs neutral) distractors during high, but not low, perceptual load. Psychophysiological interaction analysis with dACC as the seed region revealed less connectivity with dorsolateral prefrontal cortex to threat distractors during high load. Results indicate patients with less regulatory capability when demands on higher-order control are great may benefit more from CBT.

Frontolimbic Morphometric Abnormalities in Intermittent Explosive Disorder and Aggression.

BACKGROUND: Converging evidence from neuroimaging studies suggests that impulsive aggression, the core behavior in the DSM-5 diagnosis intermittent explosive disorder (IED), is regulated by frontolimbic brain structures, particularly orbitofrontal cortex, ventral medial prefrontal cortex, anterior cingulate cortex, amygdala, insula, and uncus. Despite this evidence, no brain volumetric studies of IED have been reported as yet. This study was conducted to test the hypothesis that gray matter volume in frontolimbic brain structures of subjects with IED is lower than in healthy subjects and subjects with other psychiatric conditions. METHODS: High-resolution magnetic resonance imaging scans using a three-dimensional magnetization-prepared rapid acquisition gradient-echo sequence were performed in 168 subjects (n = 53 healthy control subjects, n = 58 psychiatric controls, n = 57 subjects with IED). Imaging data were analyzed by voxel-based morphometry methods employing Statistical Parametric Mapping (SPM8) software. RESULTS: Gray matter volume was found to be significantly lower in subjects with IED compared with healthy control subjects and psychiatric controls in orbitofrontal cortex, ventral medial prefrontal cortex, anterior cingulate cortex, amygdala, insula, and uncus. These differences were not due to various confounding factors or to comorbidity with other disorders previously reported to have reduced gray matter volume. Gray matter volume in these areas was significantly and inversely correlated with measures of aggression. CONCLUSIONS: Reductions in the gray matter volume of frontolimbic structures may be a neuronal characteristic of impulsively aggressive individuals with DSM-5 IED. These data suggest an anatomic correlate accounting for functional deficits in social-emotional information processing in these individuals.

Emotion Regulatory Brain Function and SSRI Treatment in PTSD: Neural Correlates and Predictors of Change.

Posttraumatic stress disorder (PTSD)-a chronic, debilitating condition, broadly characterized by emotion dysregulation-is prevalent among US military personnel who have returned from Operations Enduring Freedom (OEF) and Iraqi Freedom (OIF). Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for PTSD, but treatment mechanisms are unknown and patient response varies. SSRIs may exert their effects by remediating emotion regulatory brain activity and individual differences in patient response might be explained, in part, by pre-treatment differences in neural systems supporting the downregulation of negative affect. Thirty-four OEF/OIF veterans, 17 with PTSD and 17 without PTSD underwent 2 functional magnetic resonance imaging scans 12 weeks apart. At each scan, they performed an emotion regulation task; in the interim, veterans with PTSD were treated with the SSRI, paroxetine. SSRI treatment increased activation in both the left dorsolateral prefrontal cortex (PFC) and supplementary motor area (SMA) during emotion regulation, although only change in the SMA over time occurred in veterans with PTSD and not those without PTSD. Less activation of the right ventrolateral PFC/inferior frontal gyrus during pre-treatment emotion regulation was associated with greater reduction in PTSD symptoms with SSRI treatment, irrespective of pre-treatment severity. Patients with the least recruitment of prefrontal emotion regulatory brain regions may benefit most from treatment with SSRIs, which appear to augment activity in these regions.

Reduced default mode network connectivity following combat trauma.

Recent studies show decreased functional connectivity in the default mode network (DMN) in PTSD; however, few have directly examined combat trauma specifically. There is limited understanding of how combat itself may affect the DMN. Some literature suggests that trauma exposure, rather than PTSD, can disrupt the DMN. To further elucidate the effect of trauma and PTSD on the DMN, we investigated DMN functional connectivity during the resting-state in veterans with PTSD, combat-exposed controls, and never-traumatized healthy controls. Results revealed that DMN connectivity was reduced in veterans exposed to combat trauma with and without PTSD compared to healthy civilian controls. Specifically, both groups of veterans demonstrated weaker connectivity within a network involving the precuneus, medial prefrontal cortex (mPFC) and right superior parietal lobule regardless of whether the mPFC or precuneus was chosen as a seed region. Findings suggest that the experience of trauma, rather than the pathology of PTSD, may be related to DMN changes.

Neural substrates for voluntary suppression of negative affect: a functional magnetic resonance imaging study.

BACKGROUND: Successful control of affect partly depends on the capacity to modulate negative emotional responses through the use of cognitive strategies. Although the capacity to regulate emotions is critical to mental well-being, its neural substrates remain unclear. METHODS: We used functional magnetic resonance imaging to ascertain brain regions involved in the voluntary regulation of emotion and whether dynamic changes in negative emotional experience can modulate their activation. Fourteen healthy subjects were scanned while they either maintained the negative affect evoked by highly arousing and aversive pictures (e.g., experience naturally) or suppressed their affect using cognitive reappraisal. In addition to a condition-based analysis, online subjective ratings of intensity of negative affect were used as covariates of brain activity. RESULTS: Inhibition of negative affect was associated with activation of dorsal anterior cingulate, dorsal medial prefrontal, and lateral prefrontal cortices, and attenuation of brain activity within limbic regions (e.g., nucleus accumbens/extended amygdala). Furthermore, activity within dorsal anterior cingulate was inversely related to intensity of negative affect, whereas activation of the amygdala was positively covaried with increasing negative affect. CONCLUSIONS: These findings highlight a functional dissociation of corticolimbic brain responses, involving enhanced activation of prefrontal cortex and attenuation of limbic areas, during volitional suppression of negative emotion.

Anterior cingulate neurochemistry in social anxiety disorder: 1H-MRS at 4 Tesla.

Recent studies suggest exaggerated responses in the limbic system of patients with generalized social anxiety disorder in response to threat/anxiety-related social situations and aversive conditioning, processes mediated by the glutamatergic system. This single-voxel, high-field 1H-magnetic resonance spectroscopy study examined concentrations of glutamate, and other metabolites, in the anterior cingulate cortex and occipital cortex (control region) of 10 medication-naive patients with generalized social anxiety and 10 matched healthy comparison subjects. Glutamate (relative to creatine) levels were significantly higher in patients than controls in the anterior cingulate, but not occipital, cortex. Anterior cingulate glutamate/creatine levels were also correlated with intensity of social anxiety symptoms. These findings provide new evidence of glutamate's involvement in the neural mechanism underlying social phobia.

Neural correlates of telling lies: a functional magnetic resonance imaging study at 4 Tesla.

RATIONALE AND OBJECTIVE: Intentional deception (ie, lying) is a complex cognitive act, with important legal, moral, political, and economic implications. Prior studies have identified activation of discrete anterior frontal regions, such as the ventrolateral prefrontal cortex (VLPFC), dorsolateral prefrontal cortex (DLPFC), dorsal medial prefrontal cortex (DMPFC), and anterior cingulate cortex (ACC) during deception. To extend these findings, we used novel real-time functional magnetic resonance imaging (fMRI) technology to simulate a polygraph experience in order to evoke performance anxiety about generating lies, and sought to ascertain the neural correlates of deception. MATERIALS AND METHODS: In this investigational fMRI study done with a 4-T scanner, we examined the neural correlates of lying in 14 healthy adult volunteers while they performed a modified card version of the Guilty Knowledge Test (GKT), with the understanding that their brain activity was being monitored in real time by the investigators conducting the study. The volunteers were instructed to attempt to generate Lies that would not evoke changes in their brain activity, and were told that their performance and brain responses were being closely monitored. RESULTS: Subjects reported performance anxiety during the task. Deceptive responses were specifically associated with activation of the VLPFC, DLPFC, DMPFC, and superior temporal sulcus. DISCUSSION: These findings suggest the involvement of discrete regions of the frontal cortex during lying, and that the neural substrates responsible for cognitive control of behavior may also be engaged during deception.

Prefrontal engagement by cognitive reappraisal of negative faces.

Cognitive reappraisal has been associated with increased activation in prefrontal cortex (PFC) and cingulate regions implicated in cognitive control and affect regulation. To date, neuroimaging studies of reappraisal have primarily used emotionally evocative scenes, and it remains unclear whether the same cognitive strategy applied to emotional facial expressions would involve similar or different neural underpinnings. The present study used fMRI to examine brain activation during cognitive reappraisal of negatively valenced facial expressions relative to passive viewing of negative and neutral facial expressions. Twenty-two healthy adults completed a cognitive reappraisal task comprised of three different conditions (Look-Neutral, Maintain-Negative, Reappraise-Negative). Results indicated that reappraisal was associated with a decrease in negative affect and engagement of PFC brain regions implicated in cognitive control and affect regulation (DLPFC, mPFC, and VLPFC). Furthermore, individual differences in habitual reappraisal use were associated with greater DLPFC and mPFC activation, while suppression use was associated with greater amygdala activation. The present study provides preliminary evidence that facial expressions are effective alternative 'targets' of prefrontal engagement during cognitive reappraisal. These findings are particularly relevant for future research probing the neural bases of emotion regulation in populations for whom aversive scenes may be less appropriate (e.g., children) and illnesses in which aberrant responses to social signals of threat and negative feedback are cardinal phenotypes.

Neural correlates of individual differences in fear learning.

Variability in fear conditionability is common, and clarity regarding the neural regions responsible for individual differences in fear conditionability could uncover brain-based biomarkers of resilience or vulnerability to trauma-based psychopathologies (e.g., post-traumatic stress disorder). In recent years, neuroimaging work has yielded a detailed understanding of the neural mechanisms underlying fear conditioning common across participants, however only a minority of studies have investigated the brain basis of inter-individual variation in fear learning. Moreover, the majority of these studies have employed small sample sizes (mean n=17; range n=5-27) and all have failed to meet the minimum recommended sample size for functional magnetic resonance imaging (fMRI) studies of individual differences. Here, using fMRI, we analyzed blood-oxygenation level dependent (BOLD) response recorded simultaneously with skin conductance response (SCR) and ratings of unconditioned stimulus (US) expectancy in 49 participants undergoing Pavlovian fear conditioning. On average, participants became conditioned to the conditioned stimulus (CS+; higher US expectancy ratings and SCR for the CS+ compared to the unpaired conditioned stimulus, CS-); the CS+ also robustly increased activation in the bilateral insula. Amygdala activation was revealed from a regression analysis that incorporated individual differences in fear conditionability (i.e., a between-subjects regressor of mean CS+>CS- SCR). By replicating results observed using much smaller sample sizes, the results confirm that variation in amygdala reactivity covaries with individual differences in fear conditionability. The link between behavior (SCR) and brain (amygdala reactivity) may be a putative endophenotype for the acquisition of fear memories.

Neurostructural abnormalities in pediatric anxiety disorders.

Functional neuroimaging studies have consistently demonstrated abnormalities in fear and threat processing systems in youth with anxiety disorders; however, the structural neuroanatomy of these systems in children and adolescents remains largely unknown. Using voxel-based morphometry (VBM), gray matter volumes were compared between 38 medication-free patients with anxiety disorders (generalized anxiety disorder; social phobia; separation anxiety disorder, mean age: 14.4±3 years) and 27 comparison subjects (mean age: 14.8±4 years). Compared to healthy subjects, youth with anxiety disorders had larger gray matter volumes in the dorsal anterior cingulate and had decreased gray matter volumes in the inferior frontal gyrus (ventrolateral prefrontal cortex), postcentral gyrus, and cuneus/precuneus. These data suggest the presence of structural differences in regions previously implicated in the processing and regulation of fear in pediatric patients with anxiety disorders.

Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder.

The neuropeptide oxytocin (OXT) is thought to attenuate anxiety by dampening amygdala reactivity to threat in individuals with generalized social anxiety disorder (GSAD). Because the brain is organized into networks of interconnected areas, it is likely that OXT impacts functional coupling between the amygdala and other socio-emotional areas of the brain. Therefore, the aim of the current study was to examine the effects of OXT on amygdala functional connectivity during the processing of fearful faces in GSAD subjects and healthy controls (HCs). In a randomized, double-blind, placebo (PBO)-controlled, within-subjects design, 18 HCs and 17 GSAD subjects performed a functional magnetic resonance imaging task designed to probe amygdala response to fearful faces following acute intranasal administration of PBO or OXT. Functional connectivity between the amygdala and the rest of the brain was compared between OXT and PBO sessions using generalized psychophysiological interaction analyses. Results indicated that within individuals with GSAD, but not HCs, OXT enhanced functional connectivity between the amygdala and the bilateral insula and middle cingulate/dorsal anterior cingulate gyrus during the processing of fearful faces. These findings suggest that OXT may have broad pro-social implications such as enhancing the integration and modulation of social responses.

Real-time fMRI of cortico-limbic brain activity during emotional processing.

The ability to detect dynamic changes in brain activity during affective processing within individual subjects in real-time can advance our understanding of the neural mechanisms of emotion, psychiatric illness, and therapeutic intervention. We investigated whether activity in limbic and paralimbic regions elicited by blocks of aversive (AV) and neutral (NEU) pictures can be detected by real-time fMRI. Real-time analysis of signal change during each block revealed that activations in insula and medial frontal cortex were more frequent during AV than NEU epochs. Single subject and group analysis off-line with conventional statistical parametric mapping methods matched the results obtained in real-time. Detecting cortico-limbic brain activation during perception and experience of emotionally salient visual stimuli with real-time fMRI technology is feasible.

Neural correlates of internally-generated disgust via autobiographical recall: a functional magnetic resonance imaging investigation.

Converging lines of evidence suggest the involvement of the insula and basal ganglia in the processing of disgust, an important primary emotion that guides the avoidance of potential physical contamination and disease. Prior human lesion and functional brain imaging studies have employed exteroceptive sensory stimuli such as facial expressions of disgust, and disgust-eliciting pictures. Thus, the neural substrates underlying the internal experience of disgust remain unknown. The present fMRI study examined the neural correlates of self-induced disgust aided by the recall and re-experience of personally salient life events. Subjects were scanned while they recalled and re-experienced either a recent situation that evoked intense disgust or a time-matched, equally vivid neutral/non-emotional event. Relative to the emotionally neutral condition, self-induced disgust was associated with activation of the insula, hippocampus, anterior and posterior cingulate cortex, basal ganglia, thalamus, and primary visual cortex. These findings suggest that areas previously associated with the perception of disgust (e.g., insula, basal ganglia) are also involved interoceptive experience of disgust.