Amygdala Activation In Response Research Articles

Sex differences in neural response to an acute stressor in individuals with an alcohol use disorder.

Alcohol use disorder (AUD) and stress influence overlapping neural circuits in the brain. The literature is mixed regarding the presence of sex differences in the neural response to acute stressors, and this issue has not been examined in individuals with AUD. We validated a stress functional magnetic resonance imaging (fMRI) paradigm in individuals with AUD and tested for sex differences. Twenty-five treatment-seeking individuals with AUD (15M/10F) were recruited to participate in the neuroimaging study linked to a clinical trial of ibudilast (NCT03594435). To assess social-evaluative stress, participants completed the Montreal Imaging Stress Task (MIST). Whole brain and amygdala region-of-interest analyses were conducted. Subjective ratings of anxiety and distress were collected. Repeated measures ANCOVAs were performed to evaluate the effect of stress on anxiety and distress and to evaluate sex differences. There were trend-level effects of stress on anxiety ratings and amygdala activation (p's = 0.06). There was a significant effect of stress in the bilateral thalamus, ventral tegmental area, and paracingulate (Z's > 4.09, p's < 0.03). There was a trend-level effect of sex on subjective ratings of stress (p's = 0.07). Females had higher amygdala activation in response to stress (p = 0.02). Females also had greater activation than males in the precuneus, posterior cingulate cortex, and right inferior frontal gyrus during acute stress (Z's > 3.56, p's < 0.03). This study provides an initial validation of the MIST in a sample of individuals with AUD. It also provides preliminary evidence of sex differences in the response to social-evaluative stress, which is important, given the relevance of stress and negative emotionality as motivators for alcohol use in females.

The neural representations of valence transformation in indole processing.

Indole is often associated with a sweet and floral odor typical of jasmine flowers at low concentrations and an unpleasant, animal-like odor at high concentrations. However, the mechanism whereby the brain processes this opposite valence of indole is not fully understood yet. In this study, we aimed to investigate the neural mechanisms underlying indole valence encoding in conversion and nonconversion groups using the smelling task to arouse pleasantness. For this purpose, 12 conversion individuals and 15 nonconversion individuals participated in an event-related functional magnetic resonance imaging paradigm with low (low-indole) and high (high-indole) indole concentrations in which valence was manipulated independent of intensity. The results of this experiment showed that neural activity in the right amygdala, orbitofrontal cortex and insula was associated with valence independent of intensity. Furthermore, activation in the right orbitofrontal cortex in response to low-indole was positively associated with subjective pleasantness ratings. Conversely, activation in the right insula and amygdala in response to low-indole was positively correlated with anticipatory hedonic traits. Interestingly, while amygdala activation in response to high-indole also showed a positive correlation with these hedonic traits, such correlation was observed solely with right insula activation in response to high-indole. Additionally, activation in the right amygdala in response to low-indole was positively correlated with consummatory pleasure and hedonic traits. Regarding olfactory function, only activation in the right orbitofrontal cortex in response to high-indole was positively correlated with olfactory identification, whereas activation in the insula in response to low-indole was negatively correlated with the level of self-reported olfactory dysfunction. Based on these findings, valence transformation of indole processing in the right orbitofrontal cortex, insula, and amygdala may be associated with individual hedonic traits and perceptual differences.

Altered amygdala functional connectivity after real-time functional MRI emotion self-regulation training.

Real-time functional MRI neurofeedback (rtfMRI-NF) is a noninvasive technique that extracts concurrent brain states and provides feedback to subjects in an online method. Our study aims to investigate the effect of rtfMRI-NF on amygdala-based emotion self-regulation by analyzing resting-state functional connectivity. We conducted a task experiment to train subjects in self-regulating amygdala activity in response to emotional stimuli. Twenty subjects were divided into two groups. The up-regulate group (URG) viewed positive stimulus, while the down-regulate group (DRG) viewed negative stimulus. The rtfMRI-NF experiment paradigm consisted of three conditions. The URG's percent amplitude fluctuation (PerAF) scores are significant, indicating that positive emotions may be a partial side effect, with increased activity in the left hemisphere. Resting-state functional connectivity was analyzed via a paired-sample t-test before and after neurofeedback training. Brain network properties and functional connectivity analysis showed a significant difference between the default mode network (DMN) and the brain region associated with the limbic system. These results reveal to some extent the mechanism of neurofeedback training to improve individuals' emotional regulate regulation ability. Our study has shown that rtfMRI-neurofeedback training can effectively enhance the ability to voluntarily control brain responses. Furthermore, the results of the functional analysis have revealed distinct changes in the amygdala functional connectivity circuits following rtfMRI-neurofeedback training. These findings may suggest the potential clinical applications of rtfMRI-neurofeedback as a new therapy for emotionally related mental disorders.

ODP370 Disconnect Between Hypothalamic-Pituitary-Adrenal Activity and Amygdala Activation Using Novel Neuroimaging Fear Paradigm in Youth With Avoidant/Restrictive Food Intake Disorder

Abstract Background Avoidant/restrictive food intake disorder (ARFID) is characterized by restrictive eating patterns without shape or weight concerns, leading to nutritional deficits and psychosocial impairment. Three distinct phenotypes have been described that can co-occur: 1) sensory sensitivity, 2) lack of interest in eating or food, and 3) food avoidance due to fear of aversive consequences. Hyperactivation of a "defensive motive system", characterized by a neurocircuit activation of the amygdala and the hypothalamic-pituitary-adrenal (HPA) axis, could mediate fear/threat pathways in ARFID. We hypothesized that youth with ARFID would show amygdala hyperactivation in response to an ARFID-specific fear paradigm, and greater amygdala activation would be associated with higher levels of cortisol. Method76 youth with ARFID assessed using the Pica, ARFID and Rumination Disorder Interview and 27 healthy controls (HC) underwent functional MRI scanning (3T Siemens) during a novel visual fear task. Subjects viewed a series of developmentally appropriate images: ARFID-specific fear (e. g., a person vomiting or choking) and neutral (e. g., household items, geometric shapes). Serum cortisol was measured prior to the MRI in the late morning after a 2-hour fast. Amygdala activation was compared between ARFID and HC for the contrast ARFID-specific fear vs. neutral images using SPM12. For this contrast, beta values were extracted and correlated with fasting cortisol levels using Pearson's correlation coefficient. Results Groups did not differ for age, sex, or BMI z-score (ARFID mean (SD) age 16.5 (3.9) years, HC 17.8 (4. 0) years (p=0.14); ARFID 50% male, HC 42% male (p=0.66); ARFID BMI z-score -0.5 (1.7), HC 0. 0 (0.8) (p=0.15). In response to ARFID-specific fear vs. neutral images, both HC and ARFID exhibited increased activation in the bilateral amygdala (p&amp;lt;0. 05), however there were no significant differences in amygdala activation between ARFID vs. HC. Cortisol levels did not differ between groups (p=0.83). In the HC group, there was a positive correlation between amygdala activation in response to the contrast ARFID-specific fear vs. neutral images and cortisol levels (r=0.54, p=0. 02), which was absent in ARFID (r=-0. 02, p=0.88) (between-group difference p=0. 01). Conclusion Using a novel fMRI paradigm, our results show that images related to ARFID-specific fears elicit robust increases in amygdala activation across ARFID and HC subjects, but no between-group differences. While higher amygdala activation was associated with higher cortisol levels in HC, this relationship was absent in ARFID, suggesting a disconnect of amygdala response and basal HPA activation to fear inducing stimuli. Future research will be important to improve our understanding of endocrine modulation of the fear response and relationship to restrictive eating in ARFID. Presentation: No date and time listed

Neuronal effects of glabellar botulinum toxin injections using a valenced inhibition task in borderline personality disorder

Previous studies have indicated that glabellar botulinum toxin (BTX) injections may lead to a sustained alleviation of depression. This may be accomplished by the disruption of a facial feedback loop, which potentially mitigates the experience of negative emotions. Accordingly, glabellar BTX injection can attenuate amygdala activity in response to emotional stimuli. A prototypic condition with an excess of negative emotionality and impulsivity accompanied by elevated amygdala reactivity to emotional stimuli is borderline personality disorder (BPD). In order to improve the understanding of how glabellar BTX may affect the processing of emotional stimuli and impulsivity, we conducted a functional magnetic resonance imaging (fMRI) study. Our hypotheses were (1) glabellar BTX leads to increased activation in prefrontal areas during inhibition performance and (2) BTX decreases amygdala activity during the processing of emotional stimuli in general. Using an emotional go-/no-go paradigm during fMRI, the interference of emotion processing and impulsivity in a sample of n = 45 women with BPD was assessed. Subjects were randomly assigned to BTX treatment or serial acupuncture (ACU) of the head. After 4 weeks, both treatments led to a reduction in the symptoms of BPD. However, BTX treatment was specifically associated with improved inhibition performance and increased activity in the motor cortex. In addition, the processing of negative emotional faces was accompanied by a reduction in right amygdala activity. This study provides the first evidence that glabellar BTX injections may modify central neurobiological and behavioural aspects of BPD. Since the control treatment produced similar clinical effects, these neurobiological findings may be specific to BTX and not a general correlate of symptomatic improvement.

The genetics of ME: A commentary on Hajdarevic et al.

Depression is characterized by altered neurobiological responses to threat and inflammation may be involved in the development and maintenance of symptoms. However, the mechanistic pathways underlying the relationship between the neural underpinnings of threat, inflammation and depressive symptoms remain unknown.Twenty participants with major depressive disorder (MDD) and 17 healthy controls (HCs) completed this study. Peripheral blood mononuclear cells (PBMCs) were collected and stimulated ex vivo with lipopolysaccharide (LPS). We then measured a broad array of secreted proteins and performed principal component analysis to compute an aggregated immune reactivity score. Subjects completed a well-validated emotional face processing task during functional magnetic resonance imaging (fMRI). Amygdala activation was measured during perception of threat for the main contrast of interest: fear > happy face. Participants completed the Mood and Anxiety Symptom Questionnaire (MASQ) and the Perceived Stress Scale (PSS). Correlation analyses between amygdala activation, the aggregate immune score, and symptom were computed across groups. A mediation analysis was also performed across groups to further explore the relationship between these three variables.In line with our hypotheses and with prior work, the MDD group showed greater amygdala activation in response to threat compared to the HC group [t35 = -2.038, p = 0.049]. Internal consistency of amygdala activation to threat was found to be moderate. Response to an ex vivo immune challenge was greater in MDD than HC based on the computed immune reactivity score (PC1; t35 = 2.674, p = 0.011). Amygdala activation was positively correlated with the immune score (r = 0.331, p = 0.045). Moreover, higher amygdala activation was associated with greater anxious arousal measured by the MASQ (r = 0.390, p = 0.017). Exploring the role of stress, we found that higher perceived stress was positively associated with both inflammatory response (r = 0.367, p = 0.026) and amygdala response to threat (r = 0.325, p = 0.050). Mediation analyses showed that perceived stress predicted anxious arousal, but neither inflammation nor amygdala activation fully accounted for the effect of perceived stress on anxious arousal.These data highlight the potential importance of threat circuitry hyperactivation in MDD, consistent with prior reports. We found that higher levels of inflammatory biomarkers were associated with higher amygdala activation, which in turn was associated with anxious arousal. Future research utilizing larger sample sizes are needed to replicate these preliminary results.

Exaggerated amygdala response to threat and association with immune hyperactivity in depression

BackgroundDepression is characterized by altered neurobiological responses to threat and inflammation may be involved in the development and maintenance of symptoms. However, the mechanistic pathways underlying the relationship between the neural underpinnings of threat, inflammation and depressive symptoms remain unknown. MethodsTwenty participants with major depressive disorder (MDD) and 17 healthy controls (HCs) completed this study. Peripheral blood mononuclear cells (PBMCs) were collected and stimulated ex vivo with lipopolysaccharide (LPS). We then measured a broad array of secreted proteins and performed principal component analysis to compute an aggregated immune reactivity score. Subjects completed a well-validated emotional face processing task during functional magnetic resonance imaging (fMRI). Amygdala activation was measured during perception of threat for the main contrast of interest: fear > happy face. Participants completed the Mood and Anxiety Symptom Questionnaire (MASQ) and the Perceived Stress Scale (PSS). Correlation analyses between amygdala activation, the aggregate immune score, and symptom were computed across groups. A mediation analysis was also performed across groups to further explore the relationship between these three variables. ResultsIn line with our hypotheses and with prior work, the MDD group showed greater amygdala activation in response to threat compared to the HC group [t35 = -2.038, p = 0.049]. Internal consistency of amygdala activation to threat was found to be moderate. Response to an ex vivo immune challenge was greater in MDD than HC based on the computed immune reactivity score (PC1; t35 = 2.674, p = 0.011). Amygdala activation was positively correlated with the immune score (r = 0.331, p = 0.045). Moreover, higher amygdala activation was associated with greater anxious arousal measured by the MASQ (r = 0.390, p = 0.017). Exploring the role of stress, we found that higher perceived stress was positively associated with both inflammatory response (r = 0.367, p = 0.026) and amygdala response to threat (r = 0.325, p = 0.050). Mediation analyses showed that perceived stress predicted anxious arousal, but neither inflammation nor amygdala activation fully accounted for the effect of perceived stress on anxious arousal. ConclusionThese data highlight the potential importance of threat circuitry hyperactivation in MDD, consistent with prior reports. We found that higher levels of inflammatory biomarkers were associated with higher amygdala activation, which in turn was associated with anxious arousal. Future research utilizing larger sample sizes are needed to replicate these preliminary results.

P345. Amygdala Stability and Depression Related Activation Patterns in Adolescents

Depression and non-suicidal self-injury (NSSI) are related yet distinct phenomena, commonly emerge during adolescence, and represent risk factors for suicide ideation (SI). The amygdala has been implicated in altered threat processing and regulation in individuals with depression and NSSI. Amygdala activation in response to threatening stimuli could represent a potential biomarker to track the course of depression and NSSI in adolescents.

Adult attachment style moderates the effect of oxytocin on neural responses to infant emotional faces

Oxytocin (OT) is known for its positive influence on maternal motivation and behavior, however, the effects of intranasal oxytocin (IN-OT) on neural activity during the perception of infant stimuli are often inconsistent. These discrepancies further reveal the need to take into account individual differences in IN-OT research. The present study aims to examine whether the effects of IN-OT on maternal-related neural responses to infant faces were moderated by participants' attachment style. Using a between-groups, double-blind, placebo-controlled design, 65 nulliparous females were randomly assigned to groups receiving a single dose of 24 IU oxytocin or a placebo via intranasal administration. The neural responses of participants were assessed during a facial recognition task with joy, neutral, and crying infant faces. The results indicated that females with high levels of attachment anxiety exhibited decreased right amygdala activity in response to infant joy faces and decreased bilateral insula activity in response to infant crying faces following IN-OT. Meanwhile, IN-OT enhanced bilateral amygdala and left inferior orbital frontal cortex (OFC) activity in response to infant crying faces in females with high levels of attachment avoidance. In addition, some beneficial effects of IN-OT were also observed in females with low levels of attachment avoidance or anxiety. Our findings demonstrated that the beneficial effects of IN-OT on neural responses to infant faces may depend on individual differences in adult attachment style, thereby contributing to our understanding of the role of OT in maternal caregiving.

A Mechanism-Based Approach to Anti-Aggression Psychotherapy in Borderline Personality Disorder: Group Treatment Affects Amygdala Activation and Connectivity.

Aggression is highly prevalent in borderline personality disorder (BPD). Previous studies have identified specific biobehavioral mechanisms underlying aggression in BPD, threat sensitivity being among them. We composited the mechanism-based anti-aggression psychotherapy (MAAP) in order to target these specific mechanisms, and MAAP was found to be superior to non-specific supportive psychotherapy (NSSP) in reducing aggressive behavior. In the present study, we investigated whether underlying brain mechanisms expected to be involved were affected by MAAP. To this end, n = 33 patients with BPD and overt aggressive behavior (n = 20 in MAAP, n = 13 in NSSP) and n = 25 healthy participants took part in a functional magnetic resonance imaging emotional face-matching task before and after treatment, or at a similar time interval for controls. Overt aggressive behavior was assessed using the overt aggression scale, modified. Results showed a decrease in amygdala activation in response to facial stimuli after MAAP, whereas an increase in amygdala activation was found after NSSP. Furthermore, in the MAAP group, connectivity between amygdala and dorsomedial prefrontal cortex increased from pre- to post-treatment compared to the NSSP group. Hence, the results suggest an impact of MAAP on brain mechanisms underlying the salience circuit in response to threat cues.

Recent Perceived Stress, Amygdala Reactivity to Acute Psychosocial Stress, and Alcohol and Cannabis Use in Adolescents and Young Adults With Bipolar Disorder.

Background: Psychosocial stress negatively affects the clinical course of bipolar disorder. Studies primarily focused on adults with bipolar disorder suggest the impact of stress is progressive, i.e., stress response sensitizes with age. Neural mechanisms underlying stress sensitization are unknown. As stress-related mechanisms contribute to alcohol/substance use disorders, variation in stress response in youth with bipolar disorder may contribute to development of co-occurring alcohol/substance use disorders. This study investigated relations between psychosocial stress, amygdala reactivity, and alcohol and cannabis use in youth with bipolar disorder, compared to typically developing youth.Methods: Forty-two adolescents/young adults [19 with bipolar disorder, 23 typically developing, 71% female, agemean ± SD = 21 ± 2 years] completed the Perceived Stress Scale (PSS), Daily Drinking Questionnaire modified for heaviest drinking week, and a modified Montreal Imaging Stress functional MRI Task. Amygdala activation was measured for both the control and stress conditions. Main effects of group, condition, total PSS, and their interactions on amygdala activation were modeled. Relationships between amygdala response to acute stress with recent alcohol/cannabis use were investigated.Results: Greater perceived stress related to increased right amygdala activation in response to the stress, compared to control, condition in bipolar disorder, but not in typically developing youth (group × condition × PSS interaction, p = 0.02). Greater amygdala reactivity to acute stress correlated with greater quantity and frequency of alcohol use and frequency of cannabis use in bipolar disorder.Conclusion: Recent perceived stress is associated with changes in amygdala activation during acute stress with amygdala reactivity related to alcohol/cannabis use in youth with bipolar disorder.

Robust BOLD Responses to Faces But Not to Conditioned Threat: Challenging the Amygdala's Reputation in Human Fear and Extinction Learning.

Most of our knowledge about human emotional memory comes from animal research. Based on this work, the amygdala is often labeled the brain's “fear center”, but it is unclear to what degree neural circuitries underlying fear and extinction learning are conserved across species. Neuroimaging studies in humans yield conflicting findings, with many studies failing to show amygdala activation in response to learned threat. Such null findings are often treated as resulting from MRI-specific problems related to measuring deep brain structures. Here we test this assumption in a mega-analysis of three studies on fear acquisition (n = 98; 68 female) and extinction learning (n = 79; 53 female). The conditioning procedure involved the presentation of two pictures of faces and two pictures of houses: one of each pair was followed by an electric shock [a conditioned stimulus (CS+)], the other one was never followed by a shock (CS–), and participants were instructed to learn these contingencies. Results revealed widespread responses to the CS+ compared with the CS– in the fear network, including anterior insula, midcingulate cortex, thalamus, and bed nucleus of the stria terminalis, but not the amygdala, which actually responded stronger to the CS–. Results were independent of spatial smoothing, and of individual differences in trait anxiety and conditioned pupil responses. In contrast, robust amygdala activation distinguished faces from houses, refuting the idea that a poor signal could account for the absence of effects. Moving forward, we suggest that, apart from imaging larger samples at higher resolution, alternative statistical approaches may be used to identify cross-species similarities in fear and extinction learning.SIGNIFICANCE STATEMENT The science of emotional memory provides the foundation of numerous theories on psychopathology, including stress and anxiety disorders. This field relies heavily on animal research, which suggests a central role of the amygdala in fear learning and memory. However, this finding is not strongly corroborated by neuroimaging evidence in humans, and null findings are too easily explained away by methodological limitations inherent to imaging deep brain structures. In a large nonclinical sample, we find widespread BOLD activation in response to learned fear, but not in the amygdala. A poor signal could not account for the absence of effects. While these findings do not disprove the involvement of the amygdala in human fear learning, they challenge its typical portrayals and illustrate the complexities of translational science.

Relations between lab indices of emotion dysregulation and negative affect reactivity in daily life in two independent studies

BackgroundWe investigated the extent to which physiological/biological measures of emotion dysregulation collected in the lab, resting respiratory sinus arrhythmia (RSA) in Study 1 and amygdala activation in response to negative stimuli in Study 2, combined with daily measures of interpersonal stressors predicted negative emotional states in outpatients better than the stressors alone. MethodsParticipants were adult outpatients with emotional distress disorders (N=30 individuals in Study 1, and N=26 women in Study 2). After completing a laboratory session that collected physiological/biological measures of emotion dysregulation, participants then completed 1–3 weeks of ambulatory assessment during which they reported on interpersonal stressors and negative affective states several times per day. ResultsLaboratory measures of emotion dysregulation were largely unrelated to either momentary or mean levels of daily-life hostility, sadness, and fear in both studies. However, resting RSA significantly moderated the association between day-level interpersonal stressors and momentary fear such that low resting RSA strengthened this association. Similarly, amygdala activation tended to moderate this relationship in the predicted direction. LimitationsBoth samples were relatively small and focused on only a limited set of diagnoses associated with emotion dysregulation. Only two possible physiological/biological markers of emotion dysregulation were examined. ConclusionsThe current studies support the collection of physiological/biological data on emotion dysregulation when indexing daily-life emotion dysregulation as the degree of emotional reactivity to stressors in daily life among outpatients with emotional distress disorders.

An Experimental Medicine Investigation of the Effects of Subacute Pramipexole Treatment on Emotional Information Processing in Healthy Volunteers.

Treatment with the dopamine D2/D3 receptor agonist pramipexole has demonstrated promising clinical effects in patients with depression. However, the mechanisms through which pramipexole might alleviate depressive symptoms are currently not well understood. Conventional antidepressant drugs are thought to work by biasing the processing of emotional information in favour of positive relative to negative appraisal. In this study, we used an established experimental medicine assay to explore whether pramipexole treatment might have a similar effect. Employing a double-blind, parallel-group design, 40 healthy volunteers (aged 18 to 43 years, 50% female) were randomly allocated to 12 to 15 days of treatment with either pramipexole (at a peak daily dose of 1.0 mg pramipexole salt) or placebo. After treatment was established, emotional information processing was assessed on the neural level by measuring amygdala activity in response to positive and negative facial emotional expressions, using functional magnetic resonance imaging (MRI). In addition, behavioural measures of emotional information processing were collected at baseline and on drug, using an established computerized task battery, tapping into different cognitive domains. As predicted, pramipexole-treated participants, compared to those receiving placebo, showed decreased neural activity in response to negative (fearful) vs. positive (happy) facial expressions in bilateral amygdala. Contrary to our predictions, however, pramipexole treatment had no significant antidepressant-like effect on behavioural measures of emotional processing. This study provides the first experimental evidence that subacute pramipexole treatment in healthy volunteers modifies neural responses to emotional information in a manner that resembles the effects of conventional antidepressant drugs.

Neuroimaging of emotional dysregulation in multiple sclerosis: relationship with alexithymia

Patients with multiple sclerosis (MS) often show alexithymia, but the brain mechanisms underlying this emotional disorder remains unknown. We used functional magnetic resonance imaging (fMRI) to investigate alterations of emotion processing and emotion regulation in patients with MS, and their relationships with alexithymia. Nineteen MS patients with minimal disability and twenty healthy control (HC) participants took part in this cross-sectional study. During fMRI, participants viewed scenes conveying negative or positive emotions, and were asked to rate the intensity of their emotional state (1) after spontaneous viewing and (2) after emotion regulation (cognitive reappraisal). Self-reported questionnaires targeting alexithymia and other affective disorders were collected, in addition to functional and anatomical MRI. We compared brain activity and functional connectivity between each group during emotion processing and reappraisal. Moreover, we performed correlation analyses between affective questionnaire scores, subjective emotion ratings, brain activity, and structural integrity. Results showed a higher rate of alexithymia in MS patients. Globally, subjective ratings of emotional state were similar between MS and HC during both spontaneous perception and reappraisal. However, in both task conditions, the MS group showed increased responses to emotional scenes in the orbital inferior frontal gyrus, compared with controls. Moreover, during the reappraisal of negative scenes, these regions displayed increased functional connectivity with the amygdala, whose activity was positively correlated with alexithymia severity in MS. Our findings suggest a direct relationship between alexithymia and a lack of down-regulation of amygdala activity in response to negative emotions during reappraisal in MS. Moreover, they highlight compensatory mechanisms in minimally disabled MS patients, recruiting fronto-striatal circuits, which may serve to preserve homeostasis of amygdala activity and affective state.

Relationships Between Early Maternal Warmth and Social Connection: A Randomized Clinical Trial With Naltrexone.

Early experiences of having received maternal warmth predict responses to opportunities to connect with others later in life. However, the understanding of neurochemical mechanisms by which such relationships emerge remains incomplete. Endogenous opioids, involved in social connection in both animals and humans, may contribute to this link. Therefore, the current study examined a) relationships between early maternal warmth and brain and self-report responses to novel social targets (i.e., outcomes that may promote social connection) and b) the effect of the opioid antagonist, naltrexone, on such relationships. Eighty-two adult participants completed a retrospective report of early maternal warmth. On a second visit, participants were randomized to 50 mg of oral naltrexone (n = 42) or placebo (n = 40), followed by a magnetic resonance imaging scan where functional brain activity in response to images of novel social targets (strangers) was assessed. Approximately 24 hours later, participants reported on their feelings of social connection since leaving the scanner. In the placebo condition, greater early maternal warmth was associated with less dorsal anterior cingulate cortex, anterior insula, ventral striatum, and amygdala activity in response to images of novel social targets (r values ≥ -0.360, p values ≤ .031), and greater feelings of social connection (r = 0.524, p < .001) outside of the laboratory. The same relationships, however, were not present in the naltrexone condition. Results highlight relationships between early maternal warmth and responses to the social world at large and suggest that opioids might contribute to social connection by supporting the buffering effects of warm early life experiences on social connection later in life.Trial Registration: Clinical Trials NCT02818036.

Case of Asperger's Syndrome and Lesion of the Right Amygdala: Deficits in Implicit and Explicit Fearful Face Recognition.

Introduction: Studies of brain-damaged patients revealed that amygdala lesions cause deficits in the processing and recognition of emotional faces. Patients with autism spectrum disorders (ASD) have similar deficits also related to dysfunctions of the limbic system including the amygdala.Methods: We investigated a male patient who had been diagnosed with Asperger's syndrome. He also presented with a lesion of the right mesial temporal cortex, including the amygdala. We used functional magnetic resonance imaging (fMRI) to investigate neuronal processing during a passive viewing task of implicit and explicit emotional faces. Clinical assessment included a facial emotion recognition task.Results: There was no amygdala activation on both sides during the presentation of masked emotional faces compared to the no-face control condition. Presentation of unmasked happy and angry faces activated the left amygdala compared to the no-face control condition. There was no amygdala activation in response to unmasked fearful faces on both sides. In the facial emotion recognition task, the patient biased positive and neutral expressions as negative.Conclusions: This case report describes a male patient with right amygdala damage and an ASD. He displayed a non-response of the amygdala to fearful faces and tended to misinterpret fearful expressions. Moreover, a non-reactivity of both amygdalae to emotional facial expressions at an implicit processing level was revealed. It is discussed whether the deficient implicit processing of facial emotional information and abnormalities in fear processing could contribute and aggravate the patient's impairments in social behavior and interaction.

Effects of Mindfulness Training on Emotion Regulation in Patients With Depression: Reduced Dorsolateral Prefrontal Cortex Activation Indexes Early Beneficial Changes.

Mindfulness-based interventions (MBIs) have been found to be a promising approach for the treatment of recurrent courses of depression. However, little is known about their neural mechanisms. This functional magnetic resonance imaging study set out to investigate activation changes in corticolimbic regions during implicit emotion regulation. Depressed patients with a recurrent lifetime history were randomized to receive a 2-week MBI (n = 16 completers) or psychoeducation and resting (PER; n = 22 completers). Before and after, patients underwent functional magnetic resonance imaging while labeling the affect of angry, happy, and neutral facial expressions and completed questionnaires assessing ruminative brooding, the ability to decenter from such thinking, and depressive symptoms. Activation decreased in the right dorsolateral prefrontal cortex (dlPFC) in response to angry faces after MBI (p < .01, voxel-wise family-wise error rate correction, T > 3.282; 56 mm3; Montreal Neurological Institute peak coordinate: 32, 24, 40), but not after PER. This change was highly correlated with increased decentring (r = -0.52, p = .033), decreased brooding (r = 0.60, p = .010), and decreased symptoms (r = 0.82, p = .005). Amygdala activation in response to happy faces decreased after PER (p < .01, family-wise error rate corrected; 392 mm3; Montreal Neurological Institute peak coordinate: 28, -4, -16), whereas the MBI group showed no significant change. The dlPFC is involved in emotion regulation, namely, reappraisal or suppression of negative emotions. Decreased right dlPFC activation might indicate that, after the MBI, patients abstained from engaging in elaboration or suppression of negative affective stimuli; a putatively important mechanism for preventing the escalation of negative mood.Trial Registration: The study is registered at ClinicalTrials.gov (NCT02801513; 16/06/2016).

Association between poor tolerability of antidepressant treatment and brain functional activation in youth at risk for bipolar disorder

Objective:To investigate whether poor antidepressant tolerability is associated with functional brain changes in children and adolescents of parents with bipolar I disorder (at-risk youth).Methods:Seventy-three at-risk youth (ages 9-20 years old) who participated in a prospective study and had an available baseline functional magnetic resonance imaging (fMRI) scan were included. Research records were reviewed for the incidence of adverse reactions related to antidepressant exposure during follow-up. The sample was divided among at-risk youth without antidepressant exposure (n=21), at-risk youth with antidepressant exposure and no adverse reaction (n=12), at-risk youth with antidepressant-related adverse reaction (n=21), and healthy controls (n=20). The fMRI task was a continuous performance test with emotional distracters. Region-of-interest mean activation in brain areas of the fronto-limbic emotional circuit was compared among groups.Results:Right amygdala activation in response to emotional distracters significantly differed among groups (F3,66 = 3.1, p = 0.03). At-risk youth with an antidepressant-related adverse reaction had the lowest amygdala activation, while at-risk youth without antidepressant exposure had the highest activation (p = 0.004).Conclusions:Decreased right amygdala activation in response to emotional distracters is associated with experiencing an antidepressant-related adverse reaction in at-risk youth. Further studies to determine whether amygdala activation is a useful biomarker for antidepressant-related adverse events are needed.

What's in a Face? Amygdalar Sensitivity to an Emotional Threatening Faces Task and Transdiagnostic Internalizing Disorder Symptoms in Participants Receiving Attention Bias Modification Training.

Altered amygdala activation in response to the emotional matching faces (EMF) task, a task thought to reflect implicit emotion detection and reactivity, has been found in some patients with internalizing disorders; mixed findings from the EMF suggest individual differences (within and/or across diagnoses) that may be important to consider. Attention Bias Modification (ABM), a mechanistic attention-targeting intervention, has demonstrated efficacy in treatment of internalizing disorders. Individual differences in neural activation to a relatively attention-independent task, such as the EMF, could reveal novel neural substrates relevant in ABM's transdiagnostic effects, such as the brain's generalized threat reactivity capacity. In a sample of clinically anxious patients randomized to ABM (n = 43) or sham training (n = 18), we measured fMRI activation patterns during the EMF and related them to measures of transdiagnostic internalizing symptoms (i.e., anxious arousal, general distress, anhedonic depression, and general depressive symptoms). Lower baseline right amygdala activation to negative (fearful/angry) faces, relative to shapes, predicted greater pre-to-post reduction in general depression symptoms in ABM-randomized patients. Greater increases in bilateral amygdalae activation from pre-to-post ABM were associated with greater reductions in general distress, anhedonic depression, and general depression symptoms. ABM may lead to greater improvement in depressive symptoms in individuals exhibiting blunted baseline amygdalar responses to the EMF task, potentially by enhancing neural-level discrimination between negative and unambiguously neutral stimuli. Convergently, longitudinal increases in amygdala reactivity from pre-to-post-ABM may be associated with greater improvement in depression, possibly secondary to improved neural discrimination of threat and/or decreased neurophysiological threat avoidance in these specific patients.