Faculty Bibliography

BACKGROUND:Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, including the fully humanized monoclonal antibody (IgG2Δa) fremanezumab, have demonstrated safety and efficacy for migraine prevention. Clinical trials include responders and nonresponders; efficacy outcomes describe mean values across both groups and thus provide little insight into the clinical benefit in responders. Clinicians and their patients want to understand the extent of clinical improvement in patients who respond. This post hoc analysis of fremanezumab treatment attempts to answer this question: what is the benefit in subjects who responded to treatment during the two, phase 3 HALO clinical trials? METHODS:We included subjects with episodic migraine (EM) or chronic migraine (CM) who received fremanezumab quarterly (675 mg/placebo/placebo) or monthly (EM: 225 mg/225 mg/225 mg; CM: 675 mg/225 mg/225 mg) during the 12-week randomized, double-blind, placebo-controlled HALO EM and HALO CM clinical trials. EM and CM responders were defined as participants with a reduction of ≥ 2 or ≥ 4 monthly migraine days, respectively. Treatment benefits evaluated included reductions in monthly migraine days, acute headache medication use, and headache-related disability, and changes in health-related quality of life (HRQoL). RESULTS:Overall, 857 participants from the HALO trials were identified as responders (EM: 429 [73.8%]; CM: 428 [56.7%]). Reductions in the monthly average number of migraine days were greater among EM (quarterly: 5.4 days; monthly: 5.5 days) and CM (quarterly: 8.7 days; monthly: 9.1 days) responders compared with the overall population. The proportion of participants achieving ≥ 50% reduction in the average monthly number of migraine days was also greater in responders (EM: quarterly, 59.8%; monthly, 63.7%; CM: quarterly, 52.8%; monthly, 59.0%) than in the overall population. Greater reductions in the average number of days of acute headache medication use, greater reductions in headache-related disability scores, and larger improvements in HRQoL were observed among EM and CM responders compared with the overall populations. CONCLUSIONS:Fremanezumab responders achieved clinically meaningful improvements in all outcomes. The magnitude of improvements with fremanezumab across efficacy outcomes was far greater in responders than in the overall trial population, providing insight into expected treatment benefits in participants who respond to fremanezumab in clinical practice. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov identifiers: NCT02629861 (HALO EM) and NCT02621931 (HALO CM).

Prior knowledge profoundly influences perceptual processing. Previous studies have revealed consistent suppression of predicted stimulus information in sensory areas, but how prior knowledge modulates processing higher up in the cortical hierarchy remains poorly understood. In addition, the mechanism leading to suppression of predicted sensory information remains unclear, and studies thus far have revealed a mixed pattern of results in support of either the 'sharpening' or 'dampening' model. Here, using 7T fMRI in humans (both sexes), we observed that prior knowledge acquired from fast, one-shot perceptual learning sharpens neural representation throughout the ventral visual stream, generating suppressed sensory responses. In contrast, the frontoparietal (FPN) and default-mode (DMN) networks exhibit similar sharpening of content-specific neural representation but in the context of unchanged and enhanced activity magnitudes, respectively-a pattern we refer to as 'selective enhancement'. Together, these results reveal a heretofore unknown macroscopic gradient of prior knowledge's sharpening effect on neural representations across the cortical hierarchy.SIGNIFICANCE STATEMENT:A fundamental question in neuroscience is how prior knowledge shapes perceptual processing. Perception is constantly informed by internal priors in the brain acquired from past experiences, but the neural mechanisms underlying this process are poorly understood. To date, research on this question has focused on early visual regions, reporting a consistent downregulation when predicted stimuli are encountered. Here, using a dramatic one-shot perceptual learning paradigm, we observed that prior knowledge results in sharper neural representations across the cortical hierarchy of the human brain through a gradient of mechanisms. In visual regions, neural responses tuned away from internal predictions are suppressed. In frontoparietal regions, neural activity consistent with priors is selectively enhanced. These results deepen our understanding of how prior knowledge informs perception.

BACKGROUND:Capsaicin, the main pungent ingredient in hot chili peppers, causes excitation of small sensory neurons. It also provides the basic pungent flavor in Capsicum fruits. SUMMARY/CONCLUSIONS:Capsaicin plays a vital role as an agonist for the TRPV1 (transient receptor potential cation channel, subfamily V, member 1) receptor. TRPV1 is essential for the reduction of oxidative stress, pain sensations, and inflammation. Therefore, it has many pros related to health issue. Activation and positive impact of TRPV1 via capsaicin has been studied in various dermatological conditions and in other skin-related issues. Past studies documented that capsaicin plays a vital role in the prevention of atopic dermatitis as well as psoriasis. Moreover, TRPV1 is also very important for skin health because it acts as a capsaicin receptor. It is found in nociceptive nerve fibers and nonneural structures. It prompts the release of a compound that is involved in communicating pain between the spinal cord nerves and other parts of the body. Key Messages: Here, we summarize the growing evidence for the beneficial role of capsaicin and TRPV1 and how they help in the relief of skin diseases such as inflammation, permeation, dysfunction, atopic dermatitis, and psoriasis and in pain amplification syndrome.

PIM1 is a serine/threonine kinase that promotes and maintains prostate tumorigenesis. While PIM1 protein levels are elevated in prostate cancer relative to local disease, the mechanisms by which PIM1 contributes to oncogenesis have not been fully elucidated. Here, we performed a direct, unbiased chemical genetic screen to identify PIM1 substrates in prostate cancer cells. The PIM1 substrates we identified were involved in a variety of oncogenic processes, and included N-Myc Downstream-Regulated Gene 1 (NDRG1), which has reported roles in suppressing cancer cell invasion and metastasis. NDRG1 is phosphorylated by PIM1 at serine 330 (pS330), and the level of NDRG1 pS330 is associated higher grade prostate tumors. We have shown that PIM1 phosphorylation of NDRG1 at S330 reduced its stability, nuclear localization, and interaction with AR, resulting in enhanced cell migration and invasion.

Recently, the mechanistic framework of active inference has been put forward as a principled foundation to develop an overarching theory of consciousness which would help address conceptual disparities in the field (Wiese 2018; Hohwy and Seth 2020). For that promise to bear out, we argue that current proposals resting on the active inference scheme need refinement to become a process theory of consciousness. One way of improving a theory in mechanistic terms is to use formalisms such as computational models that implement, attune and validate the conceptual notions put forward. Here, we examine how computational modelling approaches have been used to refine the theoretical proposals linking active inference and consciousness, with a focus on the extent and success to which they have been developed to accommodate different facets of consciousness and experimental paradigms, as well as how simulations and empirical data have been used to test and improve these computational models. While current attempts using this approach have shown promising results, we argue they remain preliminary in nature. To refine their predictive and structural validity, testing those models against empirical data is needed i.e., new and unobserved neural data. A remaining challenge for active inference to become a theory of consciousness is to generalize the model to accommodate the broad range of consciousness explananda; and in particular to account for the phenomenological aspects of experience. Notwithstanding these gaps, this approach has proven to be a valuable avenue for theory advancement and holds great potential for future research.

Importance:Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. Objective:To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. Design, Setting, and Participants:This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. Main Outcomes and Measures:Diagnosis of Alzheimer disease. Results:A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and Relevance:While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

Persistent post-traumatic headache (PPTH) is often the most common injury post mild traumatic brain injury (mTBI), reported by 47%-95% of patients. Progressive muscle relaxation (PMR) has level A evidence in preventing migraine and tension headaches. However, research on this behavioral therapy for PPTH, let alone smartphone-delivered, is limited. We performed a single-arm study of prospective patients calling our Concussion Center between June 2017-July 2018. Inclusion criteria were that subjects had to meet ICHD-3 criteria for PPTH secondary to mTBI, have four or more headache days a month, be age 18-85 and 3-12 months post injury, own a smartphone and not tried headache behavioral therapy within the year. We recorded baseline headache and neuropsychiatric data. Using the RELAXaHEAD smartphone application, which has a headache diary and PMR audio files, participants were instructed to record headache symptoms and practice 20 minutes of PMR daily. There were three monthly follow-up assessments. There were 49 subjects enrolled. Basic demographics were: 33 (67%) female with mean age 40.1±14.6 [20,75]. Of the 49 subjects, 15 (31%) had pre-existing headaches. In 11 (22%) subjects, mTBI was sports-related. Subjects reported 17.7±9.3 [4,31] headache days in the month before enrollment, and 49 (100%) experienced over three concussion symptoms. Participants inputted data in the RELAXaHEAD app on average 18.3±12.0 days [0,31] the first month. Number of participants who did PMR over 4 times/week was 12 (24.5%) the first month, 9 (22.5 %) the second month, and 6 (15%) the third month. After three months, 17 (42.5 %) participants continued doing PMR. Participants cited time constraints, forgetfulness, application glitches and repetitiveness as obstacles to practicing PMR. It is feasible to get PPTH subjects to practice behavioral therapy through low-cost smartphone-based PMR two times weekly. Future work will assess efficacy and examine how to optimize barriers to PMR.