Related neural networks underlie suppression of emotion, memory, motor processes as identified by data-driven analysis.

BACKGROUND: Goal-directed behavior benefits from self-regulation of cognitive and affective processes, such as emotional reactivity, memory retrieval, and prepotent motor response. Dysfunction in self-regulation is a common characteristic of many psychiatric disorders, such as PTSD and ADHD. This study sought to determine whether common intrinsic connectivity networks (ICNs; e.g. default mode network) are involved in the regulation of emotion, motor, and memory processes, and if a data-driven approach using independent component analysis (ICA) would successfully identify such ICNs that contribute to inhibitory regulation. METHODS: Eighteen participants underwent neuroimaging while completing an emotion regulation (ER) task, a memory suppression (Think/No-Think; TNT) task, and a motor inhibition (Stop Signal; SS) task. ICA (CONN; MATLAB) was conducted on the neuroimaging data from each task and corresponding components were selected across tasks based on interrelated patterns of activation. Subsequently, ICNs were correlated with behavioral performance variables from each task. RESULTS: ICA indicated a common medial prefrontal network, striatal network, and frontoparietal executive control network, as well as downregulation in task-specific ROIs. CONCLUSIONS: These results illustrate that common ICNs were exhibited across three distinct inhibitory regulation tasks, as successfully identified through a data-driven approach (ICA).

Explicit and Ambiguous Threat Processing: Functionally Dissociable Roles of the Amygdala and Bed Nucleus of the Stria Terminalis.

Highly influential models have proposed that responses to different types of threat are mediated by partially segregated neural systems, with the amygdala underlying phasic responses to explicit threat (fear) and the bed nucleus of the stria terminalis (BNST) mediating sustained responses to ambiguous threat (anxiety). However, newer models have suggested similar recruitment of both regions across a wide spectrum of threat. Therefore, to empirically test these models and further elucidate the activation profiles and connectivity patterns of the amygdala and the BNST during threat processing, 20 participants were scanned using high-resolution fMRI (1.5 mm3). Using fearful faces and human screams as aversive stimuli, two threat conditions were created: Explicit Threat in which threats were certain and predictable (fear) and Ambiguous Threat in which threats were uncertain and unpredictable (anxiety). Results indicated that, although the amygdala and the BNST both showed heightened engagement across both threat conditions, the amygdala showed preferential engagement during Explicit Threat and displayed functional connectivity with regions involved in stimulus processing and motor response. By contrast, the BNST preferentially responded during Ambiguous Threat and exhibited functional connectivity with prefrontal regions underlying interoception and rumination. Furthermore, correlations with questionnaires measuring trait anxiety, worry, and rumination suggested that individual differences in affective style play a modulatory role in regional recruitment and network connectivity during threat processing.

New Frontiers in Anxiety Research: The Translational Potential of the Bed Nucleus of the Stria Terminalis.

After decades of being overshadowed by the amygdala, new perspectives suggest that a tiny basal forebrain region known as the bed nucleus of the stria terminalis (BNST) may hold key insights into understanding and treating anxiety disorders. Converging research indicates that the amygdala and BNST play complementary but distinct functional roles during threat processing, with the BNST specializing in the detection of a potential threat to maintain hypervigilance and anxiety, while the amygdala responds to the perceived presence of an aversive stimulus (i.e., fear). Therefore, given that human anxiety is largely driven by future-oriented hypothetical threats that may never occur, studies involving the BNST stand at the forefront of essential future research with the potential to bring about profound insights for understanding and treating anxiety disorders. In this article, we present a narrative review on the BNST, summarizing its roles in anxiety and the stress response and highlighting the most recent advances in the clinical realm. Furthermore, we discuss oversights in the current state of anxiety research and identify avenues for future exploration.

Convergent Neural Correlates of Empathy and Anxiety During Socioemotional Processing.

Empathy is characterized by the ability to understand and share an emotional experience with another person and is closely tied to compassion and concern for others. Consequently, this increased emotional awareness and sensitivity may also be related to increased anxiety. Taken from another perspective, higher general anxiety may translate into increased concern for others, or concern for how one's actions might affect others, and therefore may be linked to increased empathy. Furthermore, self-reflection is positively related to perspective-taking and empathic concern, while rumination is closely tied to anxiety, thus providing an additional connecting point between empathy and anxiety through enhanced internally generated thought. While previous literature suggests a relationship between empathy and anxiety, this has yet to be empirically studied using neuroimaging tools aimed at investigating the underlying neural correlates that may support these convergent responses. We therefore conducted an functional magnetic resonance imaging (fMRI) study (N = 49) in which participants viewed fearful and neutral human faces and rated how the faces made them feel, to promote introspection. Participants also completed questionnaires assessing empathy Toronto Empathy Questionnaire (TEQ), trait anxiety State Trait Anxiety Inventory (STAI), worry Penn State Worry Questionnaire (PSWQ) and rumination Ruminative Responses Scale (RRS). Behaviorally, empathy positively correlated with worry, worry and rumination positively correlated with anxiety, and significant indirect relationships were found between empathy and anxiety through worry and rumination. Using the neuroimaging face processing task as a backdrop on which the neurobiological mechanisms of empathy and anxiety may interact, regressions of questionnaires with brain activations revealed that empathy related to activation in the temporoparietal junction (TPJ), anxiety related to bilateral insula activation, and worry related to medial prefrontal cortex (mPFC) activation, while rumination showed increased engagement of all three aforementioned regions. Functional connectivity (FC) analyses showed increased communication between the left amygdala and insula related to higher empathy, worry and rumination. Finally, whole-brain analysis using median split groups from questionnaires revealed that the lower halves of anxiety, worry and rumination exhibited increased activation in top-down attentional networks. In sum, empathy, worry and rumination related to enhanced bottom-up processing, while worry, rumination and anxiety exhibited decreased top-down attentional control, suggesting an indirect relationship between empathy and anxiety through the ruminative tendencies of worry.

Cortical morphometry and structural connectivity relate to executive function and estradiol level in healthy adolescents.

INTRODUCTION: Emotional and behavioral control is necessary self-regulatory processes to maintain stable goal-driven behavior. Studies indicate that variance in these executive function (EF) processes is related to morphological features of the brain and white matter (WM) differences. Furthermore, sex hormone level may modulate circuits in the brain important for cognitive function. METHODS: We aimed to investigate the structural neural correlates of EF behavior in gray matter (GM) and WM while taking into account estradiol level, in an adolescent population. The present study obtained neuroimaging behavioral and physiological data from the National Institute of Health's Pediatric Database (NIHPD). We analyzed the relationship between cortical morphometry and structural connectivity (N = 55), using a parent-administered behavioral monitoring instrument (Behavior Rating Inventory of Executive Function-BRIEF), estradiol level, as well as their interaction. RESULTS: Executive function behavior and estradiol level related to bidirectional associations with cortical morphometry in the right posterior dorsolateral prefrontal cortex (pDLPFC) and primary motor cortex (PMC), as well as fractional anisotropy (FA) in the forceps major and minor. Lastly, the interaction of EF behavior and estradiol level related to decreased volume in the right PMC and was linked to altered FA in the right inferior fronto-occipital fasciculus (iFOF). CONCLUSIONS: The study provides evidence that the relationship between EF behavior and estradiol level related to bidirectional GM and WM differences, implying estradiol level has an influence on the putative structural regions underlying EF behavior. The findings represent a crucial link between EF behavior and hormonal influence on brain structure in adolescence.

Lifetime PTSD and geriatric depression symptomatology relate to altered dorsomedial frontal and amygdala morphometry.

Posttraumatic stress disorder (PTSD) affects a large portion of combat deployed Veterans. Moreover, many individuals also suffer from comorbid late life depression (geriatric depression; GD). While a great deal of research has begun to characterize the morphometric features of PTSD and depression individually, few studies have investigated the interacting effect of these two disorders, specifically in a Veteran population. The current study used cortical and subcortical surface-based morphometry (SBM) in combination with psychological assessments of PTSD and GD symptom severity to examine morphometric alterations in Vietnam War Veterans. Our results indicated that increased GD severity, PTSD symptomatology, and their interaction, was related to decreased grey matter volume (GMV) in the left dorsomedial prefrontal cortex (dmPFC). Furthermore, increased symptomatology in the PTSD subscales of reexperiencing and hyperarousal were additionally found to be related to decreased GMV in this same dmPFC region. Subcortically, the interacting effect between PTSD and GD was also significantly related to regional shape variation in the left amygdala. These results suggest that morphometry of cortical (dmPFC) and non-neocortical regions (amygdala) putatively underlying emotional reactivity and the emotional components of memory is altered in PTSD and GD.

Maximizing the success of bile duct cannulation studies in rats: recommendations for best practice.

Bile duct cannulation (BDC) studies are usually carried out in the rat to support the absorption, distribution, metabolism and excretion profiling of novel agrochemicals and pharmaceuticals. The different aspects of these studies (e.g. surgical preparation, dosing and collection of bile) can be intricate and/or technically complex. The animals are often kept singly housed for the duration of the studies following surgical implantation of the cannulas. The generation of insufficient data to meet the study objectives, for example due to failure in cannula patency, can result in the need to repeat these studies. A working group of contract research organizations that routinely carry out BDC studies was brought together by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) to share their experiences, and to establish the key factors necessary to ensure routinely high success rates. Through these discussions the group has identified opportunities for best practice across various aspects of the studies. The aim of these recommendations is to support all staff involved in conducting BDC studies to maximize the amount of useful data generated using the fewest animals possible, while ensuring the highest possible standards of animal welfare.

Reduced lateral prefrontal cortical volume is associated with performance on the modified Iowa Gambling Task: A surface based morphometric analysis of previously deployed veterans.

Post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are two of the most common consequences of combat deployment. Estimates of comorbidity of PTSD and mTBI are as high as 42% in combat exposed Operation Enduring Freedom, Operation Iraqi Freedom and Operation New Dawn (OEF/OIF/OND) Veterans. Combat deployed Veterans with PTSD and/or mTBI exhibit deficits in classic executive function (EF) tasks. Similarly, the extant neuroimaging literature consistently indicates abnormalities of the ventromedial prefrontal cortex (vmPFC) and amygdala/hippocampal complex in these individuals. While studies examining deficits in classical EF constructs and aberrant neural circuitry have been widely replicated, it is surprising that little research examining reward processing and decision-making has been conducted in these individuals, specifically, because the vmPFC has long been implicated in underlying such processes. Therefore, the current study employed the modified Iowa Gambling Task (mIGT) and structural neuroimaging to assess whether behavioral measures related to reward processing and decision-making were compromised and related to cortical morphometric features of OEF/OIF/OND Veterans with PTSD, mTBI, or co-occurring PTSD/mTBI. Results indicated that gray matter morphometry in the lateral prefrontal cortex (lPFC) predicted performance on the mIGT among all three groups and was significantly reduced, as compared to the control group.

Mastering tricyclic ring systems for desirable functional cannabinoid activity.

There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain and other indications. In continuation of our ongoing program aiming for the development of new small molecule cannabinoid ligands, we have synthesized a novel series of carbazole and γ-carboline derivatives. The affinities of the newly synthesized compounds were determined by a competitive radioligand displacement assay for human CB2 cannabinoid receptor and rat CB1 cannabinoid receptor. Functional activity and selectivity at human CB1 and CB2 receptors were characterized using receptor internalization and [(35)S]GTP-γ-S assays. The structure-activity relationship and optimization studies of the carbazole series have led to the discovery of a non-selective CB1 and CB2 agonist, compound 4. Our subsequent research efforts to increase CB2 selectivity of this lead compound have led to the discovery of CB2 selective compound 64, which robustly internalized CB2 receptors. Compound 64 had potent inhibitory effects on pain hypersensitivity in a rat model of neuropathic pain. Other potent and CB2 receptor-selective compounds, including compounds 63 and 68, and a selective CB1 agonist, compound 74 were also discovered. In addition, we identified the CB2 ligand 35 which failed to promote CB2 receptor internalization and inhibited compound CP55,940-induced CB2 internalization despite a high CB2 receptor affinity. The present study provides novel tricyclic series as a starting point for further investigations of CB2 pharmacology and pain treatment.

Pediatric myringoplasty: does previous adenoidectomy improve the likelihood of perforation closure?

OBJECTIVE: To determine whether perforation closure after pediatric myringoplasty is more likely to be achieved in patients who have undergone a previous adenoidectomy and to evaluate the impact of other demographic and clinical parameters on operative success. STUDY DESIGN: Retrospective case review. SETTING: : Teaching hospital. PATIENTS: Children younger than 16 years. INTERVENTION: Primary or revision myringoplasty undertaken between 1999 and 2007. MAIN OUTCOME MEASURE: The integrity of the tympanic membrane was assessed by otoscopy or tympanometry during postoperative follow-up. Success was defined as an intact tympanic membrane with no evidence of middle ear disease. RESULTS: Two hundred thirteen consecutive myringoplasties were performed. Patients' mean age was 12.1 years (range, 4-15 yr) and mean length of follow-up was 16 months (range, 2-99 mo). The overall perforation closure rate was 71.8%. The adenoidectomy group comprised 79 patients (37.1%). Perforation closure was achieved in 79.1% of these patients compared with 67.4% in the nonadenoidectomy group (p = 0.157). Older age (p = 0.032), smaller perforations (p = 0.042), nonanterior perforations (p = 0.022), and operations performed by a consultant (p = 0.047) all resulted in significantly higher rates of perforation closure. CONCLUSION: This study suggests that adenoidectomy before pediatric myringoplasty may not improve the likelihood of a successful outcome.