Amygdala Activation Research Articles

The Cdk5 inhibitor β-butyrolactone impairs reconsolidation of heroin-associated memory in the rat basolateral amygdala.

The persistence of maladaptive heroin-associated memory, which is triggered by drug-related stimuli that remind the individual of the drug's pleasurable and rewarding effects, can impede abstinence efforts. Cyclin-dependent kinase 5 (Cdk5), a neuronal serine/threonine protein kinase that plays a role in multiple neuronal functions, has been demonstrated to be involved in drug addiction and learning and memory. Here, we aimed to investigate the role of cdk5 activity in the basolateral amygdala (BLA) in relapse to heroin seeking, using a self-administration rat model. Male rats underwent 10days of heroin self-administration training, during which an active nose poke resulted in an intravenous infusion of heroin that was accompanied by a cue. The rats then underwent nose poke extinction for 10days, followed by subsequent tests of heroin-seeking behaviour. We found that intra-BLA infusion of β-butyrolactone (100 ng/side), a Cdk5 inhibitor, administered 5 min after reactivation, led to a subsequent decrease in heroin-seeking behaviour. Further experiments demonstrated that the effects of β-butyrolactone are dependent on reactivated memories, temporal-specific and long-lasting on relapse of heroin-associated memory. Results provide suggestive evidence that the activity of Cdk5 in BLA is critical for heroin-associated memory and that the specific inhibitor, β-butyrolactone, may hold potential as a substance for the treatment of heroin abuse.

Neural correlates of context-dependent extinction recall in social anxiety disorder: relevance of intrusions in response to aversive social experiences.

There are phenomenological similarities between social anxiety disorder (SAD) and posttraumatic stress disorder, such as a provoking aversive event, posttraumatic stress symptoms (e.g. intrusions) in response to these events and deficient (context-dependent) fear conditioning processes. This study investigated the neural correlates of context-dependent extinction recall and fear renewal in SAD, specifically in patients with intrusions in response to an etiologically relevant aversive social event. During functional magnetic resonance imaging a two-day context-dependent fear conditioning paradigm was conducted in 54 patients with SAD and 54 healthy controls (HC). This included fear acquisition (context A) and extinction learning (context B) on one day, and extinction recall (context B) as well as fear renewal (contexts C and A) one day later. The main outcome measures were blood oxygen level-dependent responses in regions of interest and skin conductance responses. Patients with SAD showed reduced differential conditioned amygdala activation during extinction recall in the safe extinction context and during fear renewal in the acquisition context compared to HC. Patients with clinically relevant intrusions moreover exhibited hypoactivation of the ventromedial prefrontal cortex (vmPFC) during extinction learning, extinction recall, and fear renewal in a novel context, while amygdala activation more strongly decreased during extinction learning and increased during fear renewal in the acquisition context compared with patients without intrusions. Our study provides first evidence that intrusions in SAD are associated with similar deficits in context-dependent regulation of conditioned fear via the vmPFC as previously demonstrated in posttraumatic stress disorder.

The Neural Correlates of the Social Perception Dysfunction in Schizophrenia: An fMRI Study.

Patients with schizophrenia show deficits in facial emotion recognition and emotional intensity assessment, and also exhibit structural and functional irregularities in specific brain regions. In this study, we aimed to examine differences in active brain regions involved in processing the Emotion Intensity Recognition Task (EIRT), which can serve as an indicator of emotion recognition and ability to perceive intensity, between patients with schizophrenia and healthy controls (HCs). The purpose of this study was to investigate dysfunctional brain regions and investigate the role of the amygdala in social cognition deficits in patients with schizophrenia by focusing on alterations in amygdala activity linked to facial emotion recognition. Twenty-two patients who met a diagnostic criteria for schizophrenia according to DSM-IV and 27 HCs participated in an MRI scan while completing the EIRT. Behavioral and MRI data were collected and analyzed. Behavioral results showed that patients with schizophrenia made significantly more errors in recognizing surprise, happiness, sadness, fear, and neutral expressions, and patients with schizophrenia exhibited significantly slower response times in recognizing happy facial expressions. Imaging results showed that schizophrenia patients found hypoactivation in several inferior parietal and temporal regions, in the cerebrum and anterior cingulate; and decreased amygdala activation in individuals with schizophrenia was associated with impaired recognition of fear in facial expressions. Facial emotion processing deficits are emotion-specific (surprise, happiness, sadness, fear, and neutral expressions) in schizophrenia. Hypoactivation in several inferior parietal and temporal regions, in the cerebrum and anterior cingulate, was thought to contribute to symptom formation in schizophrenia. Reduction in amygdala activation in schizophrenia patients was associated with impairment of the fear-emotional process.

Pre-treatment amygdala activation and habituation predict symptom change in post-traumatic stress disorder.

Trauma-focused psychotherapy approaches are the first-line treatment option for post-traumatic stress disorder (PTSD); however, up to a third of patients remain symptomatic even after completion of the treatment. Predicting which patients will respond to a given treatment option would support personalized treatments and improve the efficiency of healthcare systems. Although previous neuroimaging studies have examined possible pre-treatment predictors of response to treatment, the findings have been somewhat inconsistent, and no other study has examined habituation to stimuli as a predictor. In this study, 16 treatment-seeking adults (MAge = 43.63, n = 10 women) with a primary diagnosis of PTSD passively viewed pictures of emotional facial expressions during functional magnetic resonance imaging (fMRI). After scanning, participants rated facial expressions on both valence and arousal. Participants then completed eight weekly sessions of prolonged exposure (PE) therapy. PTSD symptom severity was measured before and after treatment. Overall, participants showed symptomatic improvement with PE. Consistent with hypotheses, lesser activation in the amygdala and greater activation in the ventromedial prefrontal cortex during the presentation of fearful vs. happy facial expressions, as well as a greater decline in amygdala activation across blocks of fearful facial expressions at baseline, were associated with greater reduction of PTSD symptoms. Given that the repeated presentation of emotional material underlies PE, changes in brain responses with repeated stimulus presentations warrant further studies as potential predictors of response to exposure therapies.

Diazepam promotes active avoidance extinction associating with increased dorsal CA3 and amygdala activity

Active avoidance (AA) is an adaptive response to potentially harmful situations while maladapted avoidance that does not extinguish is one of the core symptoms of anxiety and post-traumatic stress disorder. However, the neural mechanisms of AA extinction and its relationship to anxiety remain unclear. We examined AA extinction during three extinction training sessions in two-way active avoidance paradigm and tested the effect of anxiolytic on AA extinction. Then we performed a meta-analysis of rodent studies, identified anxiolytic diazepam facilitates AA acquisition, and tested the same treatment in AA extinction. Diazepam-treated rats significantly reduced avoidance in the first two extinction training, compared with the saline-treated rats, and the reduction in avoidance remained in the third drug-free session. Then we explored extinction associated hippocampal and amygdala activity in saline-and diazepam-treated rats using c-Fos immunostaining following the last extinction session. The density of c-Fos positive cells was higher in dorsal CA3 of the diazepam group than in that of saline-treated animals, and was also higher in the central and basolateral amygdala regions of diazepam-treated rats than in that of saline-treated animals. Combined, these results suggest anxiolytics promotes AA extinction associated with dorsal CA3 and amygdala activity changes.

Neural underpinnings of preferential pain learning and the modulatory role of fear.

Due to its unique biological relevance, pain-related learning might differ from learning from other aversive experiences. This functional magnetic resonance imaging study compared neural mechanisms underlying the acquisition and extinction of different threats in healthy humans. We investigated whether cue-pain associations are acquired faster and extinguished slower than cue associations with an equally unpleasant tone. Additionally, we studied the modulatory role of stimulus-related fear. Therefore, we used a differential conditioning paradigm, in which somatic heat pain stimuli and unpleasantness-matched auditory stimuli served as US. Our results show stronger acquisition learning for pain- than tone-predicting cues, which was augmented in participants with relatively higher levels of fear of pain. These behavioral findings were paralleled by activation of brain regions implicated in threat processing (insula, amygdala) and personal significance (ventromedial prefrontal cortex). By contrast, extinction learning seemed to be less dependent on the threat value of the US, both on the behavioral and neural levels. Amygdala activity, however, scaled with pain-related fear during extinction learning. Our findings on faster and stronger (i.e. "preferential") pain learning and the role of fear of pain are consistent with the biological relevance of pain and may be relevant to the development or maintenance of chronic pain.

Conflict and control in cortical responses to inconsistent emotional signals in a face-word Stroop.

Social communication is fraught with ambiguity. Negotiating the social world requires interpreting the affective signals we receive and often selecting between channels of conflicting affective information. The affective face-word Stroop (AFWS) provides an experimental paradigm which may identify cognitive-affective control mechanisms underpinning essential social-affective skills. Initial functional magnetic resonance imaging (fMRI) study of the AFWS identified right amygdala as driving this affective conflict and left rostral anterior cingulate cortex (rACC) as the locus of conflict control. We employed electroencephalogram (EEG) and eLORETA source localization to investigate the timing, location, and sequence of control processes when responding to affective conflict generated during the AFWS. However we designated affective word as the response target and affective face as the distractor to maximize conflict and control effects. Reaction times showed slowed responses in high vs. low control conditions, corresponding to a Rabbitt type control effect rather than the previously observed Grattan effect. Control related activation occurred in right rACC 96-118 ms post-stimulus, corresponding to the resolution of the P1 peak in the Visual Evoked Potential (VEP). Face distractors elicit right hemisphere control, while word distractors elicit left hemisphere control. Low control trials require rapid "booting up" control resources observable through VEPs. Incongruent trial activity in right fusiform face area is suppressed 118-156 ms post stimulus corresponding to onset and development of the N170 VEP component. Results are consistent with a predicted sequence of rapid early amygdala activation by affective conflict, then rACC inhibition of amygdala decreasing facilitation of affective face processing (however, amygdala activity is not observable with EEG).

One Year of Outpatient Dialectical Behavioral Therapy and Its Impact on Neuronal Correlates of Attachment Representation in Patients with Borderline Personality Disorder Using a Personalized fMRI Task.

(1) Background: BPD is characterized by affect dysregulation, interpersonal problems, and disturbances in attachment, but neuroimaging studies investigating attachment representations in BPD are rare. No study has examined longitudinal neural changes associated with interventions targeting these impairments. (2) Methods: We aimed to address this gap by performing a longitudinal neuroimaging study on n = 26 patients with BPD treated with Dialectic Behavioral Therapy (DBT) and n = 26 matched healthy controls (HCs; post intervention point: n = 18 BPD and n = 23 HCs). For functional imaging, we applied an attachment paradigm presenting attachment related scenes represented in drawings paired with related neutral or personalized sentences from one's own attachment narratives. In a prior cross-sectional investigation, we identified increased fMRI-activation in the human attachment network, in areas related to fear response and the conflict monitoring network in BPD patients. These were especially evident for scenes from the context of loneliness (monadic pictures paired with individual narrative sentences). Here, we tested whether these correlates of attachment representation show a near-to-normal development over one year of DBT intervention. In addition, we were interested in possible associations between fMRI-activation in these regions-of-interest (ROI) and clinical scores. (3) Results: Patients improved clinically, showing decreased symptoms of borderline personality organization (BPI) and increased self-directedness (Temperament and Character Inventory, TCI) over treatment. fMRI-activation was increased in the anterior medial cingulate cortex (aMCC) and left amygdala in BPD patients at baseline which was absent after intervention. When investigating associations between scores (BPI, TCI) and functional activation, we found significant effects in the bilateral amygdala. In contrast, aMCC activation at baseline was negatively associated with treatment outcome, indicating less effective treatment effects for those with higher aMCC activation at baseline. (4) Conclusions: Monadic attachment scenes with personalized sentences presented in an fMRI setup are capable of identifying increased activation magnitude in BPD. After successful DBT treatment, these increased activations tend to normalize which could be interpreted as signs of a better capability to regulate intensive emotions in the context of "social pain" towards a more organized/secure attachment representation. Amygdala activation, however, indicates high correlations with pre-treatment scores; activation in the aMCC is predictive for treatment gain. Functional activation of the amygdala and the aMCC as a response to attachment scenes representing loneness at baseline might be relevant influencing factors for DBT-intervention outcomes.

Sex Differences in Neural Correlates of Emotion Regulation in Relation to Resting Heart Rate Variability

Prior studies suggest that sex differences in emotion regulation (ER) ability contribute to sex disparities in affective disorders. In behavioral studies, females rely more on maladaptive strategies to cope with emotional distress than males. Neuroimaging studies suggest that males more efficiently regulate emotion than females by showing less prefrontal cortex activity (suggesting less effort) for similar amygdala activity (similar regulation outcome). However, physiological studies involving heart rate variability (HRV) indicated that, compared with males, females have higher resting HRV, indicative of parasympathetic dominance and better control of emotion. To help resolve these apparently inconsistent findings, we examined sex differences in how resting HRV relates to brain activity while using cognitive reappraisal, one of the adaptive strategies. Based on 51 males and 49 females, we found that females showed different levels of self-rated emotional intensity and amygdala activity for negative versus positive emotions, while males did not. Females also showed greater overall prefrontal cortex activity but similar levels of amygdala activity compared to males. Sex differences in how resting HRV related to brain activity during ER were evident only during viewing or regulating positive emotion. The results suggest that sex differences in the neural correlates of ER and resting HRV might lie in valence more than arousal modulation.

Functional Magnetic Resonance Imaging of the Amygdala and Subregions at 3 Tesla: A Scoping Review.

The amygdalae are a pair of small brain structures, each of which is composed of three main subregions and whose function is implicated in neuropsychiatric conditions. Functional Magnetic Resonance Imaging (fMRI) has been utilized extensively in investigation of amygdala activation and functional connectivity (FC) with most clinical research sites now utilizing 3 Tesla (3T) MR systems. However, accurate imaging and analysis remains challenging not just due to the small size of the amygdala, but also its location deep in the temporal lobe. Selection of imaging parameters can significantly impact data quality with implications for the accuracy of study results and validity of conclusions. Wide variation exists in acquisition protocols with spatial resolution of some protocols suboptimal for accurate assessment of the amygdala as a whole, and for measuring activation and FC of the three main subregions, each of which contains multiple nuclei with specialized roles. The primary objective of this scoping review is to provide a broad overview of 3T fMRI protocols in use to image the activation and FC of the amygdala with particular reference to spatial resolution. The secondary objective is to provide context for a discussion culminating in recommendations for a standardized protocol for imaging activation of the amygdala and its subregions. As the advantages of big data and protocol harmonization in imaging become more apparent so, too, do the disadvantages of data heterogeneity. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Expanding upon the relationship between gender-affirming hormone therapy, neural connectivity, mental health, and body image dissatisfaction

ObjectiveTransgender/non-binary (TNB) youth are at increased risk for anxiety, depression, and suicidality compared to cisgender youth. Gender affirming hormone therapy (GAHT, i.e., testosterone or estrogen) is a standard of care option for TNB youth, and we have recently shown that GAHT (testosterone) in transgender youth assigned a female sex at birth is associated with reductions in internalizing symptomatology. The current analysis explores: 1) whether these benefits are observed in both TNB youth assigned female at birth (TNBAFAB) and TNB youth assigned male at birth (TNBAMAB) and 2) the extent to which body image dissatisfaction and alteration in neural circuitry relate to internalizing symptoms. MethodThe current study is an expansion of a previous publication from our lab that explored the association between gender-affirming testosterone and internalizing symptomatology. While participants in our previous study consisted of 42 TNBAFAB youth, participants in the current study included adolescent TNBAFAB receiving GAHT (n = 21; GAHT+) and not receiving GAHT (n = 29; GAHT-) as well as adolescent GAHT+ TNBAMAB (n = 15) and GAHT- TNBAMAB (n = 17). Participants reported symptoms of trait and social anxiety, depression, suicidality in the past year, and body image dissatisfaction. Brain activation was measured during a face processing task designed to elicit amygdala activation during functional MRI. ResultsGAHT+ TNBAFAB had significantly lower rates of social anxiety, depression, and suicidality compared to GAHT- TNBAFAB. While there were no significant relationships between estrogen and depression and anxiety symptoms, longer duration of estrogen was related to less suicidality. Both testosterone and estrogen administration were related to significantly lower rates of body image dissatisfaction compared to GAHT- youth. No significant differences emerged for BOLD response in the left or right amygdala during the face processing task, however, there was a significant main effect of GAHT on functional connectivity between the right amygdala and the ventromedial prefrontal cortex, such that GAHT+ youth had stronger co-activation between the two regions during the task. Body image dissatisfaction, greater functional connectivity, their interaction effect, and age predicted depression symptomatology and body image dissatisfaction additionally predicted suicidality in the past year. ConclusionThe current study suggests that GAHT is associated with fewer short-term internalizing symptoms in TNBAFAB than in TNBAMAB, although internalizing symptoms among TNBAMAB may diminish with longer durations of estrogen treatment. Controlling for age and sex assigned at birth, our findings indicate that less body image dissatisfaction and greater functional connectivity between the amygdala and ventromedial prefrontal cortex were both predictors of fewer levels of internalizing symptoms following GAHT.

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.

Sodium aescinate improve behavioral performance by inhibiting dorsal raphe nucleus NLRP3 inflammasome in Post-traumatic stress disorder Rat Model

Growing evidence suggest that NLRP3 inflammasome activation in hippocampus and amygdala is involved in the pathophysiology of PTSD. Our previous studies have demonstrated that apoptosis of dorsal raphe nucleus (DRN) contributes to the pathological progression of PTSD. Recent studies by others have shown that in brain injury sodium aescinate (SA) has a protective effect on neurons by inhibiting inflammatory response pathways, thereby relieving symptoms. Here, we extend the therapeutic effects of SA to PTSD rats. We found that PTSD was associated with significant activation of the NLRP3 inflammasome in DRN, whereas administration of SA significantly inhibited DRN NLRP3 inflammasome activation and reduced DRN apoptosis level. SA also improved learning and memory ability and reduced anxiety and depression level in PTSD rats. In addition, NLRP3 inflammasome activation in DRN of PTSD rats impaired mitochondria function by inhibiting ATP synthesis and increasing ROS production, whereas SA can effectively reverse the pathological progression of mitochondria. We recommend SA as a new candidate for the pharmacological treatment of PTSD.

Glucocorticoid receptors regulate central amygdala GABAergic synapses in Marchigian-Sardinian alcohol-preferring rats

Impairments in the function of the hypothalamic-pituitary-adrenal (HPA) axis and enhanced glucocorticoid receptor (GR) activity in the central amygdala (CeA) are critical mechanisms in the pathogenesis of alcohol use disorder (AUD). The GR antagonist mifepristone attenuates craving in AUD patients, alcohol consumption in AUD models, and decreases CeA γ-aminobutyric acid (GABA) transmission in alcohol-dependent rats. Previous studies suggest elevated GR activity in the CeA of male alcohol-preferring Marchigian-Sardinian (msP) rats, but its contribution to heightened CeA GABA transmission driving their characteristic post-dependent phenotype is largely unknown.We determined Nr3c1 (the gene encoding GR) gene transcription in the CeA in male and female msP and Wistar rats using in situ hybridization and studied acute effects of mifepristone (10 μM) and its interaction with ethanol (44 mM) on pharmacologically isolated spontaneous inhibitory postsynaptic currents (sIPSCs) and electrically evoked inhibitory postsynaptic potentials (eIPSPs) in the CeA using ex vivo slice electrophysiology.Female rats of both genotypes expressed more CeA GRs than males, suggesting a sexually dimorphic GR regulation of CeA activity. Mifepristone reduced sIPSC frequencies (GABA release) and eIPSP amplitudes in msP rats of both sexes, but not in their Wistar counterparts; however, it did not prevent acute ethanol-induced increase in CeA GABA transmission in male rats.In msP rats, GR regulates CeA GABAergic signaling under basal conditions, indicative of intrinsically active GR. Thus, enhanced GR function in the CeA represents a key mechanism contributing to maladaptive behaviors associated with AUD.

Long term structural and functional neural changes following a single infusion of Ketamine in PTSD

NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a labile state and can be reconsolidated in an altered form. This concept might have significant clinical implications in treating PTSD. In this pilot study we tested the potential of a single infusion of ketamine, followed by brief exposure therapy, to enhance post-retrieval extinction of PTSD trauma memories. 27 individuals diagnosed with PTSD were randomly assigned to receive either ketamine (0.5 mg/kg 40 min; N = 14) or midazolam (0.045 mg/kg; N = 13) after retrieval of the traumatic memory. 24 h following infusion, participants received a four-day trauma-focused psychotherapy. Symptoms and brain activity were assessed before treatment, at the end of treatment, and at 30-day follow-up. Amygdala activation to trauma scripts (a major biomarker of fear response) served as the main study outcome. Although PTSD symptoms improved equally in both groups, post-treatment, ketamine recipients showed a lower amygdala (−0.33, sd = 0.13, 95%HDI [−0.56,−0.04]) and hippocampus (−0.3 (sd = 0.19), 95%HDI [−0.65, 0.04]; marginal effect) reactivation to trauma memories, compared to midazolam recipients. Post-retrieval ketamine administration was also associated with decreased connectivity between the amygdala and hippocampus (−0.28, sd = 0.11, 95%HDI [−0.46, −0.11]), with no change in amygdala-vmPFC connectivity. Moreover, reduction in fractional anisotropy in bi-lateral uncinate fasciculus was seen in the Ketamine recipients compared with the midazolam recipients (right: post-treatment: −0.01108, 95% HDI [−0.0184,−0.003]; follow-up: −0.0183, 95% HDI [−0.02719,−0.0107]; left: post-treatment: −0.019, 95% HDI [−0.028,−0.011]; follow-up: −0.017, 95% HDI [−0.026,−0.007]). Taken together it is possible that ketamine may enhance post-retrieval extinction of the original trauma memories in humans. These preliminary findings show promising direction toward the capacity to rewrite human traumatic memories and modulate the fear response for at least 30 days post-extinction. When combined with psychotherapy for PTSD, further investigation of ketamine dose, timing of administration, and frequency of administration, is warranted.

Emotional characteristics associate with fronto‐amygdala connectivity in older‐old adults: Results from I‐CONECT

AbstractBackgroundResearch into the emotional health of older adults, as it relates to brain network function, lags research into cognitive health, despite the importance of emotional health to quality of life. Here, we examine associations between three summary scores of emotional health from the NIH Toolbox Emotion Battery (NIHTB‐EB) – negative affect, social satisfaction, and psychological well‐being – and their associations with intrinsic brain network functional connectivity within three systems implicated in emotional function – the default mode network (DMN), salience network (SAL), and amygdala‐based connectivity.MethodFifty participants completed resting‐state functional magnetic resonance imaging (rs‐fMRI; 33 women, 80.7±4.4 years). We used two analytic approaches:Seed‐to‐voxel (amygdala): We extracted timeseries from bilateral amygdalae for a voxelwise, whole‐brain analysis. Separate analyses were conducted for each NIHTB‐EB summary score.ROI‐to‐ROI (DMN/SAL): Pairwise correlations were averaged to provide a single measure of within‐network connectivity for each network. ROI‐to‐ROI analyses were calculated in separate regression models using each NIHTB‐EB summary score to predict connectivity within each brain network.NIHTB‐EB outcomes were generated with subscale scores weighted by factor loading. Both sets of analyses included age, sex, site, in‐scanner motion, and cognitive status (unimpaired cognition or mild cognitive impairment).ResultPsychological well‐being associated negatively with amygdala connectivity with ventromedial prefrontal cortex (vmPFC; Fig1; peak T = ‐4.28; MNI xyz: [‐6,24,‐24]; k = 63 voxels). Conversely, negative affect associated positively with amygdala connectivity with vmPFC (Fig2; T = 4.24; [8,22,‐22]; k = 27).NIHTB‐EB summary scores did not associate with DMN or SAL connectivity.ConclusionThese results highlight the relevance of fronto‐amygdala connectivity in understanding emotional aging in older‐old adults. Previous research suggests that the inhibition of amygdala activity by frontal regions plays a key role in emotion regulation. In this light, diminished amygdala‐vmPFC connectivity may reflect better emotion regulation, which here associates with higher levels of psychological well‐being and lower levels of negative affect.While research on younger adults has established the relevance of DMN and SAL connectivity to emotional health, this work suggests that these networks may not be as relevant to emotional health in the older‐old population. These results should be interpreted with caution, as they use an uncorrected voxelwise threshold (p<0.001).

Blunted diurnal interleukin-6 rhythm is associated with amygdala emotional hyporeactivity and depression: a modulating role of gene-stressor interactions.

The immune system has major roles in the brain and related psychopathology. Disrupted interleukin-6 secretion and aberrant amygdala emotional reactivity are well-documented in stress-related mental disorders. The amygdala regulates psychosocial stress-related interleukin-6 affected by related genes. These led us to comprehensively examine the relationship between interleukin-6, amygdala activity, and stress-related mental symptoms under gene-stressor interactions. One hundred eight nonclinical participants with various levels of anxiety/depression underwent magnetic resonance imaging scans during an emotional face task for amygdala activity and saliva collection (at 10-time points across 2 days) for the total output and diurnal patterns of interleukin-6. Gene-stressor interactions between rs1800796 (C/G) and rs2228145 (C/A) and stressful life events for the biobehavioral measures were explored. The blunting of interleukin-6 diurnal pattern was associated with hypoactivation of the basolateral amygdala in response to fearful (vs. neutral) faces (t = 3.67, FWE-corrected p = 0.003), and was predominantly observed in individuals with rs1800796 C-allele homozygotes and negative life changes in the past year (F = 19.71, p < 0.001). When considered in a comprehensive model, the diminished diurnal pattern predicted greater depressive symptoms (β = -0.40), modulated by the amygdala hypoactivity (β = 0.36) and rs1800796-stressor interactions (β = -0.41; all p < 0.001). Here we show that the blunted interleukin-6 diurnal rhythm predicts depressive symptoms, modulated by amygdala emotional hyporeactivity and gene-stressor interactions. These findings indicate a potential mechanism underlying vulnerability to depressive disorders, suggesting their early detection, prevention, and treatment through the understanding of immune system dysregulation.

Amygdala downregulation training using fMRI neurofeedback in post-traumatic stress disorder: a randomized, double-blind trial

Hyperactivation of amygdala is a neural marker for post-traumatic stress disorder (PTSD) and improvement in control over amygdala activity has been associated with treatment success in PTSD. In this randomized, double-blind clinical trial we evaluated the efficacy of a real-time fMRI neurofeedback intervention designed to train control over amygdala activity following trauma recall. Twenty-five patients with PTSD completed three sessions of neurofeedback training in which they attempted to downregulate the feedback signal after exposure to personalized trauma scripts. For subjects in the active experimental group (N = 14), the feedback signal was from a functionally localized region of their amygdala associated with trauma recall. For subjects in the control group (N = 11), yoked-sham feedback was provided. Changes in control over the amygdala and PTSD symptoms served as the primary and secondary outcome measurements, respectively. We found significantly greater improvements in control over amygdala activity in the active group than in the control group 30-days following the intervention. Both groups showed improvements in symptom scores, however the symptom reduction in the active group was not significantly greater than in the control group. Our finding of greater improvement in amygdala control suggests potential clinical application of neurofeedback in PTSD treatment. Thus, further development of amygdala neurofeedback training in PTSD treatment, including evaluation in larger samples, is warranted.

What a difference timing makes: Cortisol effects on neural underpinnings of emotion regulation

The ability of emotion regulation under stress is of crucial importance to psychosocial health. Yet, the dynamic function of stress hormones for the cognitive control of emotions over time via non-genomic and genomic cortisol effects remains to be elucidated. In this randomized, double-blind, placebo-controlled neuroimaging experiment, 105 participants (54 men, 51 women) received 20 mg hydrocortisone (cortisol) or a placebo either 30min (rapid, non-genomic cortisol effects) or 90min (slow, genomic cortisol effects) prior to a cognitive reappraisal task including different regulatory goals (i.e., downregulate vs. upregulate negative emotions). On the behavioral level, cortisol rapidly reduced and slowly enhanced emotional responsivity to negative pictures. However, only slow cortisol effects improved downregulation of negative emotions. On the neural level, cortisol rapidly enhanced, but slowly reduced amygdala and dorsolateral prefrontal activation as well as functional connectivity between both structures in the down- minus upregulate contrast. This interaction speaks for an effortful but ineffective regulation of negative emotions during rapid cortisol effects and improved emotion regulation capacities during slow cortisol effects. Taken together, these results indicate a functional shift of cortisol effects on emotion regulation processes over time which may foster successful adaptation to and recovery from stressful life events.

Proteasome-independent K63 polyubiquitination selectively regulates ATP levels and proteasome activity during fear memory formation in the female amygdala.

Females are more likely than males to develop post-traumatic stress disorder (PTSD). However, the neurobiological mechanisms responsible for these sex differences remain elusive. The ubiquitin proteasome system (UPS) is involved in fear memory formation and implicated in PTSD development. Despite this, proteasome-independent functions of the UPS have rarely been studied in the brain. Here, using a combination of molecular, biochemical, proteomic, behavioral, and novel genetic approaches, we investigated the role of proteasome-independent lysine-63 (K63)-polyubiquitination, the second most abundant ubiquitin modification in cells, in the amygdala during fear memory formation in male and female rats. Only females had increased levels of K63-polyubiquitination targeting in the amygdala following fear conditioning, which targeted proteins involved in ATP synthesis and proteasome function. CRISPR-dCas13b-mediated knockdown of K63-polyubiquitination in the amygdala via editing of the K63 codon in the major ubiquitin gene, Ubc, impaired fear memory in females, but not males, and caused a reduction in learning-related increases in ATP levels and proteasome activity in the female amygdala. These results suggest that proteasome-independent K63-polyubiquitination is selectively involved in fear memory formation in the female amygdala, where it is involved in the regulation of ATP synthesis and proteasome activity following learning. This indicates the first link between proteasome-independent and proteasome-dependent UPS functions in the brain during fear memory formation. Importantly, these data are congruent with reported sex differences in PTSD development and may contribute to our understanding of why females are more likely to develop PTSD than males.