An overview of the safety and efficacy of LX-9211 in treating neuropathic pain conditions.

INTRODUCTION: LX-9211 is a drug designed to treat neuropathic pain conditions. It functions by inhibiting the adaptor-associated kinase 1 (AAK1) enzyme which promotes clathrin-dependent endocytosis. Preclinical studies have shown that LX-9211 does produce a reduction in nociceptive related behaviors and produces no major adverse effects in rats. Thus, LX-9211 has advanced to clinical trials to assess its safety and efficacy in humans. So far, phase 1 and phase 2 clinical trials involving patients with postherpetic neuralgia and diabetic peripheral neuropathic pain have been conducted with phase 3 trials planned in the future. AREAS COVERED: This paper highlights preclinical studies involving LX-9211 in rodents. Additionally, phase 1 clinical trials examining the safety of LX-9211 in healthy subjects as well as phase 2 studies looking at the safety and efficacy of LX-9211 compared to placebo in patients with diabetic peripheral neuropathic pain and postherpetic neuralgia are also discussed. EXPERT OPINION: In phase 1 and phase 2 clinical trials conducted so far, LX-9211 has been shown to produce few adverse effects as well as cause a significantly greater reduction in pain compared to placebo. However, more clinical studies are needed to further assess its effects in humans to ensure its safety.

A Randomized Trial Utilizing EEG Brain Computer Interface to Improve Facial Emotion Recognition in Autistic Adults.

PURPOSE: Many individuals with autism spectrum disorder (ASD) experience challenges with facial emotion recognition (FER), which may exacerbate social difficulties in ASD. Few studies have examined whether FER can be experimentally manipulated and improved for autistic people. This study utilized a randomized controlled trial design to examine acceptability and preliminary clinical impact of a novel mixed reality-based neurofeedback program, FER Assistant, using EEG brain computer interface (BCI)-assisted technology to improve FER for autistic adolescents and adults. METHODS: Twenty-seven autistic male participants (M age: 21.12 years; M IQ: 105.78; 85% white) were randomized to the active condition to receive FER Assistant (n = 17) or waitlist control (n = 10). FER Assistant participants received ten sessions utilizing BCI-assisted neurofeedback training in FER. All participants, regardless of randomization, completed a computerized FER task at baseline and endpoint. RESULTS: Results partially indicated that FER Assistant was acceptable to participants. Regression analyses demonstrated that participation in FER Assistant led to group differences in FER at endpoint, compared to a waitlist control. However, analyses examining reliable change in FER indicated no reliable improvement or decline for FER Assistant participants, whereas two waitlist participants demonstrated reliable decline. CONCLUSION: Given the preliminary nature of this work, results collectively suggest that FER Assistant may be an acceptable intervention. Results also suggest that FER may be a potential mechanism that is amenable to intervention for autistic individuals, although additional trials using larger sample sizes are warranted.

IPACK Block Efficacy for Acute Pain Management after Total Knee Replacement: A Review.

PURPOSE OF REVIEW: Patients often experience a significant degree of knee pain following total knee replacement (TKR). To alleviate this pain, nerve blocks may be performed such as the adductor canal block (ACB). However, ACBs are unable to relieve pain originating from the posterior region of the knee. A new type of nerve block known as the IPACK block may be used in conjunction with ACBs as it is designed to inhibit nerve branches innervating this area. In this article, we examine the rationale behind the IPACK procedure, how it is performed, and clinical trials examining its efficacy. RECENT FINDINGS: 5 of the 7 clinical trials examined in this article showed the IPACK + ACB block to show superior efficacy in treating pain following TKR compared to other blocks. These blocks included PMDI+ACB, SPANK+ACB, PAI+ACB, ACB alone, and SCAB. 2 of the 7 clinical trials showed the IPACK + ACB to be less effective in managing patients pain following TKR compared to other blocks which included the CACB and 4 in 1 block. In most instances, the IPACK + ACB showed superior efficacy in managing patients' pain following TKR when compared to other types of nerve blocks. This was determined by measuring usage of opioids, reported postoperative pain, and length of hospital stays following TKR. Thus, we suppose the IPACK block may be used in conjunction with the ACB to effectively reduce patient's pain following TKR.

Trying to name what doesn't change: Neural nonresponse to Cognitive Therapy for depression.

BACKGROUND: Theoretical models of neural mechanisms underlying Cognitive Behavior Therapy (CBT) for major depressive disorder (MDD) propose that psychotherapy changes neural functioning of prefrontal cortical structures associated with cognitive-control processes (DeRubeis, Siegle, & Hollon, ); however, MDD is persistent and characterized by long-lasting vulnerabilities to recurrence after intervention, suggesting that underlying neural mechanisms of MDD remain despite treatment. It follows that identification of treatment-resistant aberrant neural processes in MDD may inform clinical and research efforts targeting sustained remission. Thus, we sought to identify brain regions showing aberrant neural functioning in MDD that either (1) fail to exhibit substantive change (nonresponse) or (2) exhibit functional changes (response) following CBT. METHODS: To identify treatment-resistant neural processes (as well as neural processes exhibiting change after treatment), we collected functional magnetic resonance imaging (fMRI) data of MDD patients (n = 58) before and after CBT as well as never-depressed controls (n = 35) before and after a similar amount of time. We evaluated fMRI data using conjunction analyses, which utilized several contrast-based criteria to characterize brain regions showing both differences between patients and controls at baseline and nonresponse or response to CBT. RESULTS: Findings revealed nonresponse in a cerebellar region and response in prefrontal and parietal regions. CONCLUSIONS: Results are consistent with prior theoretical models of CBT's direct effect on cortical regulatory processes but expand on them with identification of additional regions (and associated neural systems) of response and nonresponse to CBT.

Overview of Median Arcuate Ligament Syndrome: A Narrative Review.

Median arcuate ligament syndrome (MALS) is a rare disorder caused primarily by compression of the celiac trunk by the median arcuate ligament (MAL). This disorder typically results in patients presenting with bloating, weight loss, nausea, vomiting, and abdominal pain. The MALS diagnosis is one of exclusion, as the disorder has no specific diagnostic criteria. Imaging modalities are often utilized to assist in making the diagnosis, such as ultrasound, computed tomography angiography (CTA), and magnetic resonance angiography (MRA). These imaging modalities typically reveal a stenosed celiac artery with post-stenotic dilation in patients. This disorder is usually treated by dividing the MAL, thus relieving the compression of the celiac artery. The surgery may be done through either an open approach or a minimally invasive approach, which can be either laparoscopic or robot-assisted. Most patients respond well to this treatment, though certain factors that predict a poorer response to treatment include elderly age, a history of alcohol abuse, and psychiatric illness.

Current advances in pain regimens for percutaneous nephrolithotomy A comprehensive review.

INTRODUCTION: Percutaneous nephrolithotomy (PCNL) causes pain and discomfort after surgery. The primary causes of immediate postoperative pain after PCNL are visceral pain from the ureters and kidneys, and body surface discomfort from incisions. Acute, untreated pain has the potential to develop into chronic pain, which remains a considerable burden for the rehabilitation of patients. The goal of this review was to describe the current options for treating pain post-PCNL. METHODS: We conducted a literature review of all published manuscripts on pain protocols for patients undergoing PCNL and related topics; 50 published manuscripts were identified and reviewed. RESULTS: PCNL morbidity must be reduced by an appropriate management of postoperative pain. Opioids, multimodal therapy, tubeless PCNL, reduced size of nephrostomy tube, and regional anesthesia are currently available for reducing postoperative pain. CONCLUSIONS: Implementing successful treatment strategies for postoperative pain after PCNL is key in reducing the morbidity and mortality of PCNL.

Social Anxiety Symptoms Predict Poorer Facial Emotion Recognition in Autistic Male Adolescents and Young Adults Without Intellectual Disability.

Utilizing a novel computerized task, we aimed to examine whether social anxiety symptoms would be related to individual differences in facial emotion recognition (FER) in a sample of autistic male adolescents and young adults without intellectual disability. Results indicated that social anxiety and IQ predicted poorer FER, irrespective of specific emotion type. When probing specific effects within emotion and condition types, social anxiety impacted surprise and disgust FER during a truncated viewing condition and not full viewing condition. Collectively, results suggest that social anxiety in autism may play a larger role in FER than previously thought. Future work should consider the role of social anxiety within autism as a factor that may meaningfully relate to FER assessment and intervention.

Associations between resting-state neural connectivity and positive affect in social anxiety disorder.

INTRODUCTION: Social anxiety disorder (SAD) has been characterized by deficits in social motivation and lack of reactivity to pleasurable stimuli (i.e., positive affect; [PA]). Recent neuroimaging work has shifted toward examining positively valenced motivational systems in SAD focused on reward responses. However, little is known about the associations of reward connectivity and PA in individuals with SAD. As such, the purpose of the current study was to determine whether connectivity among key units of reward neurocircuitry meaningfully relate to PA and whether these key units are more heterogeneous in SAD as compared to controls. METHODS: Thirty-one participants who met diagnostic criteria for SAD and 33 control participants were included (Mage = 24.8, SD = 6.9; 55% cisgender man). Seed-based timeseries correlations were conducted in NiTime to extract region of interest (ROI) coupling correlation strength values. ANOVAs were carried out to assess whether individuals with SAD differed in ROI-to-ROI connectivity strength as compared to controls. Correlations and variance analyses were also conducted to examine the relationship between ROI-to-ROI connectivity strength and PA, as well as heterogeneity in connectivity strength and PA expression. RESULTS: Weaker connectivity between the left and right orbital frontal cortex was observed when comparing the SAD to the control group. Within the SAD group, PA was associated with several reward-related ROI couplings; however, these links were not observed among controls. Results further demonstrated that individuals with SAD had significantly more variability in reward connectivity strength as compared to controls. CONCLUSION: Overall, these results provide emergent evidence for the association between reward regions and PA in individuals with SAD. Additionally, these findings show that individuals with SAD demonstrate greater heterogeneity in reward connectivity.

Arabidopsis TRB proteins function in H3K4me3 demethylation by recruiting JMJ14.

Arabidopsis telomeric repeat binding factors (TRBs) can bind telomeric DNA sequences to protect telomeres from degradation. TRBs can also recruit Polycomb Repressive Complex 2 (PRC2) to deposit tri-methylation of H3 lysine 27 (H3K27me3) over certain target loci. Here, we demonstrate that TRBs also associate and colocalize with JUMONJI14 (JMJ14) and trigger H3K4me3 demethylation at some loci. The trb1/2/3 triple mutant and the jmj14-1 mutant show an increased level of H3K4me3 over TRB and JMJ14 binding sites, resulting in up-regulation of their target genes. Furthermore, tethering TRBs to the promoter region of genes with an artificial zinc finger (TRB-ZF) successfully triggers target gene silencing, as well as H3K27me3 deposition, and H3K4me3 removal. Interestingly, JMJ14 is predominantly recruited to ZF off-target sites with low levels of H3K4me3, which is accompanied with TRB-ZFs triggered H3K4me3 removal at these loci. These results suggest that TRB proteins coordinate PRC2 and JMJ14 activities to repress target genes via H3K27me3 deposition and H3K4me3 removal.

A gene silencing screen uncovers diverse tools for targeted gene repression in Arabidopsis.

DNA methylation has been utilized for target gene silencing in plants. However, it is not well understood whether other silencing pathways can be also used to manipulate gene expression. Here we performed a gain-of-function screen for proteins that could silence a target gene when fused to an artificial zinc finger. We uncovered many proteins that suppressed gene expression through DNA methylation, histone H3K27me3 deposition, H3K4me3 demethylation, histone deacetylation, inhibition of RNA polymerase II transcription elongation or Ser-5 dephosphorylation. These proteins also silenced many other genes with different efficacies, and a machine learning model could accurately predict the efficacy of each silencer on the basis of various chromatin features of the target loci. Furthermore, some proteins were also able to target gene silencing when used in a dCas9-SunTag system. These results provide a more comprehensive understanding of epigenetic regulatory pathways in plants and provide an armament of tools for targeted gene manipulation.

5-year follow-up of adolescents with social anxiety disorder: Current functioning during COVID-19.

The present study followed-up adolescents with social anxiety disorder (SAD) during the COVID-19 pandemic, approximately 5-years following their participation in an Attention Bias Modification Training (ABMT) program (Ollendick et al., 2019). The current study aimed to evaluate current functioning and quality of life (QoL) during the emerging adulthood period. Participants included 27 young adults who completed a randomized controlled trial of ABMT and were available for follow-up. Participants filled out self-report measures of QoL and functioning and underwent a clinical interview to assess current severity of social anxiety. Clinician-rated symptoms of SAD significantly decreased from post-treatment to 5-year follow-up. Additionally, results demonstrated that social anxiety severity was significantly related to poorer self-reported physical and psychological health as well as poorer functioning with regard to social distancing fears during COVID-19. Lastly, when evaluating change in symptoms over time, increases in social anxiety severity over a 5-year period significantly predicted worsened social distancing fears during COVID-19.

Cingulate prediction of response to antidepressant and cognitive behavioral therapies for depression: Meta-analysis and empirical application.

We sought to identify baseline (pre-treatment) neural markers associated with treatment response in major depressive disorder (MDD), specific to treatment type, Cognitive Behavioral Therapy (CBT) or pharmacotherapy (selective serotonin reuptake inhibitors; SSRI). We conducted a meta-analysis of functional magnetic resonance imaging (fMRI) studies to identify neural prognostic indicators of response to CBT or SSRI. To verify the regions derived from literature, the meta-analytic regions were used to predict clinical change in a verification sample of participants with MDD who received either CBT (n = 60) or an SSRI (n = 19) as part of prior clinical trials. The meta-analysis consisted of 21 fMRI studies that used emotion-related tasks. It yielded prognostic regions of the perigenual (meta pgACC) and subgenual anterior cingulate cortex (meta sgACC), associated with SSRI and CBT response, respectively. When applying the meta-analytic regions to predict treatment response in the verification sample, reactivity of the meta pgACC was prognostic for SSRI response, yet the effect direction was opposite of most prior studies. Meta sgACC reactivity failed to be prognostic for CBT response. Results confirm the prognostic potential of neural reactivity of ACC subregions in MDD but further research is necessary for clinical translation.

PEERS® for Preschoolers preliminary outcomes and predictors of treatment response.

PEERS® for Preschoolers (P4P) is a social skills group program for young autistic children and their caregivers, which provides everyday tools for interacting and communicating with others. Twenty-two caregiver-child dyads participated and completed pre-treatment, post-treatment, and follow-up measures (4-16 weeks after). Using single-subject analyses to examine social skills, 60% demonstrated post-treatment improvement, and 53.85% demonstrated follow-up improvement. Regarding a secondary outcome of behavioral difficulties, 33.33% demonstrated post-treatment reduction, and 7.69% demonstrated follow-up reduction. Using regressions, autistic traits predicted outcomes; fewer social communication difficulties predicted both greater social skills and fewer behavioral difficulties at post-treatment, while fewer repetitive behaviors predicted fewer post-treatment and follow-up behavioral difficulties. These results preliminarily demonstrate the benefits of P4P and how autistic traits may impact P4P outcomes.

Can dialectical behavior therapy skills group treat social anxiety disorder? A brief integrative review.

The purposes of this brief integrative review are to identify and critically evaluate recent work in the area of Dialectical Behavior Therapy-Skills Group (DBT-SG) for Social Anxiety Disorder (SAD) with suicidal ideation (SI) and to suggest further how DBT-based skills may be applied to cognitive maintenance factors of SAD. Accordingly, we first evaluate the relevance of DBT in treating SI in other disorders. Second, we evaluate the relationship between SI and SAD, providing considerations for the complexity of comorbid disorders and presentations. Finally, we extend this knowledge to discuss considerations for the use of DBT-SG skills to target specific etiological and maintenance elements of SAD, with a focus on four themes (interpersonal effectiveness, mindfulness, emotion regulation, and distress tolerance). Overall, we conclude that DBT-SG may prove beneficial in reducing SI and symptoms in SAD that impact social and emotional functioning.

Effects of nonsocial and circumscribed interest images on neural mechanisms of emotion regulation in autistic adults.

Introduction: Emotion dysregulation is commonly reported among autistic individuals. Prior work investigating the neurofunctional mechanisms of emotion regulation (ER) in autistic adults has illustrated alterations in dorsolateral prefrontal cortex (dlPFC) activity, as well as concurrent atypical patterns of activation in subcortical regions related to affect during cognitive reappraisal of social images. Whereas most research examining ER in autism has focused on regulation of negative emotions, the effects of regulating positive emotions has been generally understudied. This is surprising given the relevance of positive motivational states to understanding circumscribed interests (CI) in autism. Methods: Accordingly, the purpose of this study was to use fMRI with simultaneous eye-tracking and pupillometry to investigate the neural mechanisms of ER during passive viewing and cognitive reappraisal of a standardized set of nonsocial images and personalized (self-selected) CI images. Results: The autistic group demonstrated comparatively reduced modulation of posterior cingulate cortex (PCC) activation during cognitive reappraisal of CI images compared to viewing of CI, although no eye-tracking/pupillometry differences emerged between-groups. Further, the autistic group demonstrated increased PCC connectivity with left lateral occipital and right supramarginal areas when engaging in cognitive reappraisal vs. viewing CI. Discussion: In autistic adults, CI may be differentially modulated via PCC. Considering the documented role of the PCC as a core hub of the default mode network, we further postulate that ER of CI could potentially be related to self-referential cognition.

Validation of a novel method of ultraviolet-induced cutaneous inflammation and its associations with anhedonia.

Affective immunology of the skin is a growing area; however, established protocols for measuring individual differences in cutaneous inflammation are lacking. To address this, we present a preliminary validation of Precision Implementation of Minimal Erythema Dose (PI-MED) testing as a method for measuring cutaneous inflammation. PI-MED is a recently adapted protocol, optimized for reproducibility and individual differences research, that uses ultraviolet (UV) light to evoke cutaneous erythema, or inflammatory skin reddening. PI-MED's novel UV dosage schedule produces standardized erythema responses across different skin pigmentation types and shows strong internal consistency within person and good test-retest reliability across 8-10 weeks. In line with predictions, increased PI-MED erythema was associated with heightened anhedonia, across several measures, beyond influences of non-affective covariates. While future work should further refine the dosage schedule for the lightest and darkest skin types, overall, evidence supports PI-MED as a protocol for inducing and measuring individual differences in cutaneous inflammation. Further, PI-MED-induced erythema can expand psychoneuroimmunology research by offering a complementary assessment for general inflammatory tone. This work adds to a growing body of evidence demonstrating a distinct relationship between inflammation and anhedonia.

Mindfulness-Based Stress Reduction Specifically Improves Social Anhedonia Among Adults with Chronic Stress.

This randomized controlled trial examined the effects of mindfulness on anhedonic symptoms in a sample of adults reporting high levels of chronic stress. Meditation-naïve adults (N = 68, Mage = 32, 62% female) were randomized to either an 8-week group-based MBSR intervention (N = 35), or a waitlist control group (N = 33). We hypothesized that changes in mindfulness would mediate the relationship between condition and changes in anhedonic symptoms. Additionally, the present study aimed to determine if other theoretically linked mechanisms (i.e., stress, negative affect [NA], depression) were involved in producing changes in anhedonic symptoms. Results provided evidence for full mediation of the effect of MBSR on social anhedonia through its essential mechanism of ΔMindfulness. These results highlight specificity of anhedonic symptoms targeted by MBSR, with social anhedonia symptoms being modified by changes in mindfulness whereas other anhedonic domains were not. The specificity of effects to the social anhedonia domain may be in part due to the group-based nature of MBSR. Additionally, although associative relationships were present for stress, depression, NA, and anhedonic symptoms, no mediational relationships emerged. Results presented here should be evaluated in light of study limitations, such as the reliance on self-report measures as well as a lack of information regarding cultural or geographic diversity.

What does "staying well" after depression mean? Chronic low grade symptomatology after treatment for depression is common.

BACKGROUND: Persistent low grade depression symptoms are common and impairing in major depressive disorder (MDD) yet rarely reported in treatment follow-up studies (Judd et al., 1998a; Kennedy et al., 2004), suggesting that extant sustained remission rates may not reflect this important clinical feature. Furthermore, no long-term MDD treatment follow-up study has reported on quality of life ratings across functioning levels and years throughout the follow-up period, thus the severity, breadth, and persistence of functional impairment remain unclear. Accordingly, the current study evaluated the course of MDD with consideration of low grade depressive symptomatology and holistic features (e.g., quality of life). METHODS: We report long-term (9-14 years) follow-up data from individuals with MDD (N = 37) who underwent either Cognitive Therapy (CBT) or a course of selective serotonin reuptake inhibitor (SSRI) treatment. Patients provided retrospective reports of depression symptoms and quality of life in the years following treatment. RESULTS: Chronic depression symptoms (most often mild in severity) and decreased quality of life in multiple domains are frequent and suggest poorer sustained remission rates than previously observed in the literature. LIMITATIONS: Study limitations include small sample size recruited via convenience sampling methods. CONCLUSIONS: Findings support a conceptualization of depression recovery that entails persistent symptoms and vulnerabilities. Clinical recommendations are provided for discussing these features of depression recovery with patients.

Social anxiety disorder is Associated with Vaccination attitude, stress, and coping responses during COVID-19.

Background: Individuals with Social Anxiety Disorder (SAD) may be at a higher risk for negative outcomes during the COVID-19 pandemic due to isolation that is both characteristic of the disorder and also potentially exacerbated by quarantine and public health restrictions. Accordingly, we evaluated emotional and behavioral responses to stress during COVID-19 and attitudes towards COVID-19 vaccine adoption in socially anxious versus non-socially anxious adults. Methods: Participants (N = 84) were young adults between 18 and 24 years of age who completed a diagnostic interview and self-report measures assessing stress, anxiety and coping responses during COVID-19. Welch's t-tests assessed group differences on mental health outcomes between the SAD versus non-SAD group, and Pearson's χ2 test evaluated COVID-19 vaccination status by group. Lastly, logistic regression examined whether SAD predicted positive COVID-19 vaccination attitude. Results: Results indicated the SAD group demonstrated significantly elevated rates of anxiety and depression as compared to individuals without SAD and had significantly increased rates of engagement in safety behaviors as well as maladaptive coping mechanisms in response to COVID-19 stress. Individuals with SAD were significantly more likely to receive or plan to receive the COVID-19 vaccine. Conclusions: The current study provides evidence that social anxiety may be a significant factor associated with the impact of COVID-19 as well as attitudes with vaccine compliance. Supplementary information: The online version contains supplementary material available at 10.1007/s10608-022-10310-3.

Neural Mechanisms of Facial Emotion Recognition in Autism: Distinct Roles for Anterior Cingulate and dlPFC.

OBJECTIVE: The present study sought to measure and internally validate neural markers of facial emotion recognition (FER) in adolescents and young adults with ASD to inform targeted intervention. METHOD: We utilized fMRI to measure patterns of brain activity among individuals with ASD (N = 21) and matched controls (CON; N = 20) 2 s prior to judgments about the identity of six distinct facial emotions (happy, sad, angry, surprised, fearful, disgust). RESULTS: Predictive modeling of fMRI data (support vector classification; SVC) identified mechanistic roles for brain regions that forecasted correct and incorrect identification of facial emotion as well as sources of errors over these decisions. BOLD signal activation in bilateral insula, anterior cingulate (ACC) and right dorsolateral prefrontal cortex (dlPFC) preceded accurate FER in both controls and ASD. Predictive modeling utilizing SVC confirmed the utility of ACC in forecasting correct decisions in controls but not ASD, and further indicated that a region within the right dlPFC was the source of a type 1 error signal in ASD (i.e. neural marker reflecting an impending correct judgment followed by an incorrect behavioral response) approximately two seconds prior to emotion judgments during fMRI. CONCLUSIONS: ACC forecasted correct decisions only among control participants. Right dlPFC was the source of a false-positive signal immediately prior to an error about the nature of a facial emotion in adolescents and young adults with ASD, potentially consistent with prior work indicating that dlPFC may play a role in attention to and regulation of emotional experience.