The role of the amygdala in enhanced remembrance of negative episodes and acquired negativity of related neutral cues.

Prior research on the interaction between emotion and episodic memory established that negatively charged events are better remembered compared to neutral events (i.e. enhanced remembrance), as well as that a priori neutral cues that were present in the environment during a negative event can attain aversive meaning by themselves (i.e. acquired negativity). Improved understanding the neural mechanisms that mediate enhanced remembrance of negative episodes and acquired negativity of related neutral cues may carry substantial clinical relevance, particularly in the context of posttraumatic pathophysiology. In order to address this point forty-nine healthy participants completed a novel fMRI task that involve the presentation of neutral pictures before and after a series of short neutral and aversive video-clips from which the neutral pictures were originally extracted, and a subsequent presentation of these pictures as cues for clip recall [termed, Picture-Clip-Picture-Recall (PCPR) task]. Behavioral results indicate that aversive clips were indeed better remembered compared to neutral clips (i.e. enhanced remembrance of negative episode) and that a priori neutral pictures that appeared in aversive clips were rated more negatively after relative to before the exposure to the aversive clips (i.e. acquired negativity of related neutral cues). Whole-brain fMRI analysis revealed that increased amygdala activation in response to pictures when presented as cues for clip recall predicted successful clip remembrance, particularly remembrance of aversive clips. This amygdala activation was also correlated with the magnitude of acquired negativity of the cues following their appearance in aversive clips. Taken together our findings implicate the PCPR as a novel, naturalistic, framework for investigating the neural interface of emotional episodic memory, while highlighting the role of the amygdala in enhanced remembrance of negative episodes and acquired negativity of related neutral cues. Clinical implications are discussed.

Neural - hormonal responses to negative affective stimuli: Impact of dysphoric mood and sex.

BACKGROUND: Maladaptive responses to negative affective stimuli are pervasive, including clinically ill and healthy people, and men and women respond differently at neural and hormonal levels. Inspired by the Research Domain Criteria initiative, we used a transdiagnostic approach to investigate the impact of sex and dysphoric mood on neural-hormonal responses to negative affective stimuli. METHODS: Participants included 99 individuals with major depressive disorder, psychosis and healthy controls. Functional magnetic resonance imaging (fMRI) was complemented with real-time acquisition of hypothalamo-pituitary-adrenal (HPA) and -gonadal (HPG) hormones. fMRI data were analyzed in SPM8 and task-related connectivity was assessed using generalized psychophysiological interaction. RESULTS: Across all participants, elevated cortisol response predicted lower brain activity in orbitofrontal cortex and hypothalamus-amygdala connectivity. In those with worse dysphoric mood, elevated cortisol response predicted lower activity in hypothalamus and hippocampus. In women, elevated cortisol response was associated with lower activity in medial prefrontal cortex and low hypothalamo-hippocampal connectivity. In women with high dysphoric mood, elevated cortisol response was associated with low hypothalamo-hippocampal connectivity. There were no interactions with diagnosis or medication. LIMITATIONS: There was limited power to correct for multiple comparisons across total number of ROIs and connectivity targets; cortisol responses were relatively low. CONCLUSIONS: We conclude that the pathophysiology in neural-hormonal responses to negative affective stimuli is shared across healthy and clinical populations and varies as a function of sex and dysphoric mood. Our findings may contribute to the development of hormonal adjunctive therapeutics that are sex-dependent, underscoring the importance of one's sex to precision medicine.

Intensified vmPFC surveillance over PTSS under perturbed microRNA-608/AChE interaction.

Trauma causes variable risk of posttraumatic stress symptoms (PTSS) owing to yet-unknown genome-neuronal interactions. Here, we report co-intensified amygdala and ventromedial prefrontal cortex (vmPFC) emotional responses that may overcome PTSS in individuals with the single-nucleotide polymorphism (SNP) rs17228616 in the acetylcholinesterase (AChE) gene. We have recently shown that in individuals with the minor rs17228616 allele, this SNP interrupts AChE suppression by microRNA (miRNA)-608, leading to cortical elevation of brain AChE and reduced cortisol and the miRNA-608 target GABAergic modulator CDC42, all stress-associated. To examine whether this SNP has effects on PTSS and threat-related brain circuits, we exposed 76 healthy Israel Defense Forces soldiers who experienced chronic military stress to a functional magnetic resonance imaging task of emotional and neutral visual stimuli. Minor allele individuals predictably reacted to emotional stimuli by hyperactivated amygdala, a hallmark of PTSS and a predisposing factor of posttraumatic stress disorder (PTSD). Despite this, minor allele individuals showed no difference in PTSS levels. Mediation analyses indicated that the potentiated amygdala reactivity in minor allele soldiers promoted enhanced vmPFC recruitment that was associated with their limited PTSS. Furthermore, we found interrelated expression levels of several miRNA-608 targets including CD44, CDC42 and interleukin 6 in human amygdala samples (N=7). Our findings suggest that miRNA-608/AChE interaction is involved in the threat circuitry and PTSS and support a model where greater vmPFC regulatory activity compensates for amygdala hyperactivation in minor allele individuals to neutralize their PTSS susceptibility.

Dissociable cortico-striatal connectivity abnormalities in major depression in response to monetary gains and penalties.

BACKGROUND: Individuals with major depressive disorder (MDD) are characterized by maladaptive responses to both positive and negative outcomes, which have been linked to localized abnormal activations in cortical and striatal brain regions. However, the exact neural circuitry implicated in such abnormalities remains largely unexplored. METHOD: In this study 26 unmedicated adults with MDD and 29 matched healthy controls (HCs) completed a monetary incentive delay task during functional magnetic resonance imaging (fMRI). Psychophysiological interaction (PPI) analyses probed group differences in connectivity separately in response to positive and negative outcomes (i.e. monetary gains and penalties). RESULTS: Relative to HCs, MDD subjects displayed decreased connectivity between the caudate and dorsal anterior cingulate cortex (dACC) in response to monetary gains, yet increased connectivity between the caudate and a different, more rostral, dACC subregion in response to monetary penalties. Moreover, exploratory analyses of 14 MDD patients who completed a 12-week, double-blind, placebo-controlled clinical trial after the baseline fMRI scans indicated that a more normative pattern of cortico-striatal connectivity pre-treatment was associated with greater improvement in symptoms 12 weeks later. CONCLUSIONS: These results identify the caudate as a region with dissociable incentive-dependent dACC connectivity abnormalities in MDD, and provide initial evidence that cortico-striatal circuitry may play a role in MDD treatment response. Given the role of cortico-striatal circuitry in encoding action-outcome contingencies, such dysregulated connectivity may relate to the prominent disruptions in goal-directed behavior that characterize MDD.

A neurobehavioral account for individual differences in resilience to chronic military stress.

BACKGROUND: Military training is a chronic stressful period that often induces stress-related psychopathology. Stress vulnerability and resilience depend on personality trait anxiety, attentional threat bias and prefrontal-limbic dysfunction. However, how these neurobehavioral elements interact with regard to the development of symptoms following stress remains unclear. METHOD: Fifty-five healthy combat soldiers undergoing intensive military training completed functional magnetic resonance imaging (fMRI) testing while performing the dot-probe task (DPT) composed of angry (threat) and neutral faces. Participants were then stratified according to their bias tendency to avoidance (n = 25) or vigilance (n = 30) groups, categorized as high or low trait anxiety and assessed for post-stress symptom severity. RESULTS: Avoidance compared to vigilance tendency was associated with fewer post-trauma symptoms and increased hippocampal response to threat among high anxious but not low anxious individuals. Importantly, mediation analysis revealed that only among high anxious individuals did hippocampal activity lead to lower levels of symptoms through avoidance bias tendency. However, in the whole group, avoidance bias was modulated by the interplay between the hippocampus and the dorsal anterior cingulate cortex (dACC). CONCLUSIONS: Our results provide a neurobehavioral model to explain the resilience to post-trauma symptoms following chronic exposure. The model points to the importance of considering threat bias tendency in addition to personality traits when investigating the brain response and symptoms of trauma. Such a multi-parametric approach that accounts for individual behavioral sensitivities may also improve brain-driven treatments of anxiety, possibly by targeting the interplay between the hippocampus and the dACC.