The role of BDNF methylation and Val66 Met in amygdala reactivity during emotion processing.

Epigenetic alterations of the brain-derived neurotrophic factor (BDNF) gene have been associated with psychiatric disorders in humans and with differences in amygdala BDNF mRNA levels in rodents. This human study aimed to investigate the relationship between the functional BDNF-Val66 Met polymorphism, its surrounding DNA methylation in BDNF exon IX, amygdala reactivity to emotional faces, and personality traits. Healthy controls (HC, n = 189) underwent functional MRI during an emotional face-matching task. Harm avoidance, novelty seeking and reward dependence were measured using the Tridimensional Personality Questionnaire (TPQ). Individual BDNF methylation profiles were ascertained and associated with several BDNF single nucleotide polymorphisms surrounding the BDNF-Val66 Met, amygdala reactivity, novelty seeking and harm avoidance. Higher BDNF methylation was associated with higher amygdala reactivity (x = 34, y = 0, z = -26, t(166) = 3.00, TFCE = 42.39, p(FWE) = .045), whereby the BDNF-Val66 Met genotype per se did not show any significant association with brain function. Furthermore, novelty seeking was negatively associated with BDNF methylation (r = -.19, p = .015) and amygdala reactivity (r = -.17, p = .028), while harm avoidance showed a trend for a positive association with BDNF methylation (r = .14, p = .066). The study provides first insights into the relationship among BDNF methylation, BDNF genotype, amygdala reactivity and personality traits in humans, highlighting the multidimensional relations among genetics, epigenetics, and neuronal functions. The present study suggests a possible involvement of epigenetic BDNF modifications in psychiatric disorders and related brain functions, whereby high BDNF methylation might reduce BDNF mRNA expression and upregulate amygdala reactivity.

Probing the association between serotonin-1A autoreceptor binding and amygdala reactivity in healthy volunteers.

INTRODUCTION: The serotonergic system modulates affect and is a target in the treatment of mood disorders. 5-HT1A autoreceptors in the raphe control serotonin release by means of negative feedback inhibition. Hence, 5-HT1A autoreceptor function should influence the serotonergic regulation of emotional reactivity in limbic regions. Previous findings suggest an inverse relationship between 5-HT1A autoreceptor binding and amygdala reactivity to facial emotional expressions. The aim of the current multimodal neuroimaging study was to replicate the previous finding in a larger cohort. METHODS: 31 healthy participants underwent fMRI as well as PET using the radioligand [carbonyl-11C]WAY-100635 to quantify 5-HT1A autoreceptor binding in the dorsal raphe. The binding potential (BPND) was quantified using the multilinear reference tissue model (MRTM2) and cerebellar white matter as reference tissue. Functional MRI was done at 3T using a well-established facial emotion discrimination task (EDT). Here, participants had to match the emotional valence of facial expressions, while in a control condition they had to match geometric shapes. Effects of 5-HT1A autoreceptor binding on amygdala reactivity were investigated using linear regression analysis with SPM8. RESULTS: Regression analysis between 5-HT1A autoreceptor binding and mean amygdala reactivity revealed no statistically significant associations. Investigating amygdala reactivity in a voxel-wise approach revealed a positive association in the right amygdala (peak-T = 3.64, p < .05 FWE corrected for the amygdala volume) which was however conditional on the omission of age and sex as covariates in the model. CONCLUSION: Despite highly significant amygdala reactivity to facial emotional expressions, we were unable to replicate the inverse relationship between 5-HT1A autoreceptor binding in the DRN and amygdala reactivity. Our results oppose previous multimodal imaging studies but seem to be in line with recent animal research. Deviation in results may be explained by methodological differences between our and previous multimodal studies.

Mismatch negativity (MMN) stands at the crossroads between explicit and implicit emotional processing.

The amygdala is known as a key brain region involved in the explicit and implicit processing of emotional faces, and plays a crucial role in salience detection. Not until recently was the mismatch negativity (MMN), a component of the event-related potentials to an odd stimulus in a sequence of stimuli, utilized as an index of preattentive salience detection of emotional voice processing. However, their relationship remains to be delineated. This study combined the fMRI scanning and event-related potential recording by examining amygdala reactivity in response to explicit and implicit (backward masked) perception of fearful and angry faces, along with recording MMN in response to the fearfully and angrily spoken syllables dada in healthy subjects who varied in trait anxiety (STAI-T). Results indicated that the amplitudes of fearful MMN were positively correlated with left amygdala reactivity to explicit perception of fear, but negatively correlated with right amygdala reactivity to implicit perception of fear. The fearful MMN predicted STAI-T along with left amygdala reactivity to explicit fear, whereas the association between fearful MMN and STAI-T was mediated by right amygdala reactivity to implicit fear. These findings suggest that amygdala reactivity in response to explicit and implicit threatening faces exhibits opposite associations with emotional MMN. In terms of emotional processing, MMN not only reflects preattentive saliency detection but also stands at the crossroads of explicit and implicit perception. Hum Brain Mapp 38:140-150, 2017. © 2016 Wiley Periodicals, Inc.

Increased amygdala reactivity following early life stress: a potential resilience enhancer role.

BACKGROUND: Amygdala hyper-reactivity is sometimes assumed to be a vulnerability factor that predates depression; however, in healthy people, who experience early life stress but do not become depressed, it may represent a resilience mechanism. We aimed to test these hypothesis examining whether increased amygdala activity in association with a history of early life stress (ELS) was negatively or positively associated with depressive symptoms and impact of negative life event stress in never-depressed adults. METHODS: Twenty-four healthy participants completed an individually tailored negative mood induction task during functional magnetic resonance imaging (fMRI) assessment along with evaluation of ELS. RESULTS: Mood change and amygdala reactivity were increased in never-depressed participants who reported ELS compared to participants who reported no ELS. Yet, increased amygdala reactivity lowered effects of ELS on depressive symptoms and negative life events stress. Amygdala reactivity also had positive functional connectivity with the bilateral DLPFC, motor cortex and striatum in people with ELS during sad memory recall. CONCLUSIONS: Increased amygdala activity in those with ELS was associated with decreased symptoms and increased neural features, consistent with emotion regulation, suggesting that preservation of robust amygdala reactions may reflect a stress buffering or resilience enhancing factor against depression and negative stressful events.

Associations Between Sleep Health and Amygdala Reactivity to Negative Facial Expressions in the UK Biobank Cohort.

BACKGROUND: Sleep health (SH) is considered a key determinant of human physiological and psychological well-being. In line with this, previous studies have found that poor sleep is associated with various psychiatric disorders, in particular, with anxiety and depression. Although little is known about the neural mechanisms underlying these associations, recent findings suggest that essential dimensions of SH are associated with altered amygdala reactivity (AR); however, evidence to date is inconsistent and reliant on small sample sizes. METHODS: To address this problem, the current preregistered study investigated associations between SH and AR to negative facial expressions in the UK Biobank cohort (25,758 participants). Drawing on a large sample size and consistent data acquisition, 5 dimensions of SH (insomnia symptoms, sleep duration, daytime sleepiness, chronotype, and sleep medication) were examined. RESULTS: Exploratory analyses revealed that short sleep duration was associated with decreased AR. The remaining SH dimensions and a composite measure of all SH dimensions were not associated with AR. CONCLUSIONS: To our knowledge, this is the largest study to test associations between SH and AR. Habitual short sleep duration may be associated with decreased AR, possibly indicating compensation for impaired prefrontal processes and hampered emotion regulation.

Impact of Oxytocin on the neural correlates of fearful face processing in PTSD related to childhood Trauma.

Background: Posttraumatic stress disorder (PTSD) related to exposure to abuse and neglect during childhood is associated with particularly severe and persistent deleterious outcomes. Amygdala hyperreactivity has been observed in childhood trauma survivors and implicated in symptoms of PTSD. Objective: The neuropeptide oxytocin holds promise as a potential treatment for PTSD due to its ability to attenuate amygdala response to threat cues. However, the effect of oxytocin on amygdala reactivity in individuals with childhood trauma-related PTSD has not been investigated. Method: We employed a double-blind, randomized, placebo-controlled crossover design to examine the effects of intranasal oxytocin (24 IU) versus placebo on amygdala reactivity to fearful faces among childhood-trauma exposed individuals with PTSD (n = 17) and without PTSD (control group; n = 16). Results: Region-of-interest based amygdala fMRI signal magnitude did not differ by group, drug, or group x drug interaction. Self-report of childhood trauma exposure severity was negatively associated with the oxytocin-related change in left amygdala response in the PTSD group, but not in the control group. Supplementary and exploratory whole-brain analyses conducted separately in each group revealed that left amygdala reactivity to fearful faces was absent on placebo but increased on oxytocin in the control group. The PTSD group showed right amygdala activation to fearful faces in both the oxytocin and placebo conditions, but the left amygdala response observed in the placebo condition was diminished on oxytocin. Conclusions: Findings extend the literature pertaining to the potential for oxytocin to attenuate neural correlates of PTSD to a childhood trauma-related PTSD sample.

Antecedentes: El trastorno de Estrés Postraumático (TEPT) relacionado con exposición a abuso y negligencia durante la infancia se asocia con consecuencias deletéreas particularmente persistentes y severas. Se ha observado una hiperreactividad de la amígdala en sobrevivientes de trauma infantil y también se ha implicado en los síntomas de TEPT. Objetivo: El neuropéptido oxitocina es prometedor como un potencial tratamiento para el TEPT debido a su habilidad de atenuar la respuesta de la amígdala frente a señales de amenaza. Sin embargo, el efecto de la oxitocina en la reactividad de la amígdala en individuos con TEPT relacionado a trauma infantil no ha sido investigado. Método: Empleamos un diseño doble ciego, aleatorizado, cruzado placebo-control para examinar los efectos de la oxitocina intranasal (24 IU) versus placebo en la reactividad de la amígdala a las caras de miedo entre individuos expuestos a trauma infantil con TEPT (n=17) y sin TEPT (grupo control; n=16). Resultados: La magnitud de la señal por IRMf de la amígdala basada en la región de interés no difirió por grupo, droga, o interacción droga x grupo. El auto-reporte de la severidad de la exposición a trauma infantil se asoció negativamente con el cambio asociado a oxitocina en la respuesta de la amígdala izquierda en el grupo con TEPT, pero no en el grupo control. Los análisis suplementarios de todo el cerebro revelaron que la reactividad de la amígdala izquierda a caras de miedo estuvo ausente con placebo, pero aumentó con la oxitocina en el grupo control. El grupo con TEPT mostró una activación de la amígdala derecha a caras de miedo en ambas condiciones, con oxitocina y con placebo, pero la respuesta de la amígdala izquierda observada en la condición de placebo estuvo disminuida con la oxitocina. Conclusiones: Los hallazgos amplían la literatura sobre el potencial de la oxitocina para atenuar los correlatos neurales del TEPT a una muestra de TEPT relacionado con trauma infantil.

Atypical Anxiety-Related Amygdala Reactivity and Functional Connectivity in Sant Mat Meditation.

While meditation has drawn much attention in cognitive neuroscience, the neural mechanisms underlying its emotional processing remains elusive. Sant Mat meditators were recruited, who adopt a loving-kindness mode of meditation along with a vegetarian diet and an alcohol-restricted lifestyle and novices. We assessed their State-Trait Anxiety Inventory (STAI) and scanned their amygdala reactivity in response to an explicit and implicit (backward masked) perception of fearful and happy faces. In contrast with novices, meditators reported lower STAI scores. Meditators showed stronger amygdala reactivity to explicit happiness than to fear, whereas novices exhibited the opposite pattern. The amygdala reactivity was reduced in meditators regardless of implicit fear or happiness. Those who had more lifetime practice in meditation reported lower STAI and showed a weaker amygdala response to fear. Furthermore, the amygdala in meditators, relative to novices, had a stronger positive functional connectivity with the ventrolateral prefrontal cortex (PFC) to explicit happiness, but a more negative connectivity with the insula and medial orbitofrontal cortex (OFC) to explicit fear. Mediation analysis indicated the amygdala reactivity as the mediator for the linkage between meditation experience and trait anxiety. The findings demonstrate the neural correlates that underpin the beneficial effects of meditation in Sant Mat. Long-term meditation could be functionally coupled with the amygdala reactivity to explicit and implicit emotional processing, which would help reduce anxiety and potentially enhance well-being.