Faculty Bibliography

Efficacy of monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (calcitonin receptor-like receptor/receptor activity modifying protein-1, CLR/RAMP1) implicates peripherally-released CGRP in migraine pain. However, the site and mechanism of CGRP-evoked peripheral pain remain unclear. By cell-selective RAMP1 gene deletion, we reveal that CGRP released from mouse cutaneous trigeminal fibers targets CLR/RAMP1 on surrounding Schwann cells to evoke periorbital mechanical allodynia. CLR/RAMP1 activation in human and mouse Schwann cells generates long-lasting signals from endosomes that evoke cAMP-dependent formation of NO. NO, by gating Schwann cell transient receptor potential ankyrin 1 (TRPA1), releases ROS, which in a feed-forward manner sustain allodynia via nociceptor TRPA1. When encapsulated into nanoparticles that release cargo in acidified endosomes, a CLR/RAMP1 antagonist provides superior inhibition of CGRP signaling and allodynia in mice. Our data suggest that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice.

Attention-deficit/hyperactivity disorder (ADHD) has been the focus of magnetic resonance imaging studies for more than 30 years, with more than 2200 articles listed in PubMed. Nevertheless, the brain substrates of ADHD remain poorly understood. This reflects the crisis of replicability across nearly all scientific endeavors, deriving from factors such as small sample sizes combined with a proliferation in analytical approaches, yielding high rates of false positive results. The field of molecular genetics confronted this by adopting open and immediate sharing of raw data and insistence on rigorous corrections for multiple comparisons. These strategies are yielding more robust genetic findings, albeit with much smaller effect sizes than before. This brief review focuses on two recent consortium efforts, i.e., the international Enhancing Neuro-Imaging Genetics through Meta-Analysis (ENIGMA), and the U.S. Adolescent Behavior & Cognitive Developm ent Study (ABCD). Both embrace the culture of open science, and are beginning to yield credible findings, despite being limited initially to cross-sectional analyses. As the field continues to mature, these and other ongoing longitudinal large-scale studies are poised to transform our understanding of the pathophysiology of ADHD to bring closer the day when neuroimaging can contribute to clinical utility.

BACKGROUND:Patients with head and neck cancer (HNC) treated with radiation therapy (RT) are at risk for jaw osteoradionecrosis (ORN), which is largely characterized by the presence of exposed necrotic bone. This report describes the incidence and clinical course of and risk factors for exposed intraoral bone in the multicenter Observational Study of Dental Outcomes in Head and Neck Cancer Patients (OraRad) cohort. METHODS:Participants were evaluated before RT and at 6, 12, 18, and 24 months after RT. Exposed bone was characterized by location, sequestrum formation, and other associated features. The radiation dose to the affected area was determined, and the history of treatment for exposed bone was recorded. RESULTS:The study enrolled 572 participants; 35 (6.1%) were diagnosed with incident exposed bone at 6 (47% of reports), 12 (24%), 18 (20%), and 24 months (8%), with 60% being sequestrum and with 7 cases (20%) persisting for >6 months. The average maximum RT dose to the affected area of exposed bone was 5456 cGy (SD, 1768 cGy); the most frequent associated primary RT sites were the oropharynx (42.9%) and oral cavity (31.4%), and 76% of episodes occurred in the mandible. The diagnosis of ORN was confirmed in 18 participants for an incidence rate of 3.1% (18 of 572). Risk factors included pre-RT extractions (P = .008), a higher RT dose (P = .039), and tobacco use (P = .048). CONCLUSIONS:The 2-year incidence of exposed bone in the OraRad cohort was 6.1%; the incidence of confirmed ORN was 3.1%. Exposed bone after RT for HNC is relatively uncommon and, in most cases, is a short-term complication, not a recurring or persistent one.

Social interactions powerfully impact the brain and the body, but high-resolution descriptions of these important physical interactions and their neural correlates are lacking. Currently, most studies rely on labor-intensive methods such as manual annotation. Scalable and objective tracking methods are required to understand the neural circuits underlying social behavior. Here we describe a hardware/software system and analysis pipeline that combines 3D videography, deep learning, physical modeling, and GPU-accelerated robust optimization, with automatic analysis of neuronal receptive fields recorded in interacting mice. Our system ("3DDD Social Mouse Tracker") is capable of fully automatic multi-animal tracking with minimal errors (including in complete darkness) during complex, spontaneous social encounters, together with simultaneous electrophysiological recordings. We capture posture dynamics of multiple unmarked mice with high spatiotemporal precision (~2 mm, 60 frames/s). A statistical model that relates 3D behavior and neural activity reveals multiplexed 'social receptive fields' of neurons in barrel cortex. Our approach could be broadly useful for neurobehavioral studies of multiple animals interacting in complex low-light environments.

Avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy with increased mannose-6-phosphate content for increased cellular uptake, is approved in the United States for late-onset Pompe disease (LOPD) patients >=1 year of age and in Japan for all Pompe disease patients (NexviazymeTM, Sanofi Genzyme, Cambridge, MA). During the 49-week, double-blinded primary-analysis period (PAP) of the Phase 3 COMET trial (NCT02782741) comparing avalglucosidase alfa with alglucosidase alfa, avalglucosidase alfa resulted in greater improvements in forced vital capacity (FVC), 6-Minute Walk Test (6MWT), and other outcomes and a more favorable safety profile than alglucosidase alfa in treatment-naive LOPD participants. During the open-label extension-treatment period (ETP), 51/51 participants receiving avalglucosidase alfa during the PAP continued this treatment and 44/49 receiving alglucosidase alfa during the PAP switched to avalglucosidase alfa. Changes (LS mean [SE]) from Baseline at Week 97 are reported. Changes in FVC %predicted were + 2.65 (1.05) for avalglucosidase alfa PAP participants and + 0.36 (1.12) for alglucosidase alfa PAP participants. Changes in 6MWT distance (meters) were + 18.60 (12.01) for avalglucosidase alfa PAP participants versus +4.56 (12.44) for alglucosidase alfa PAP participants. Similar trends occurred in other Week-97 outcomes. Treatment-emergent adverse events (AEs) during the ETP occurred in 49 (96.1%) and 42 (95.5%) participants from the avalglucosidase alfa and alglucosidase alfa PAP groups, respectively. Five participants discontinued during the ETP by Week 97 due to AEs (ocular hyperemia, erythema, urticaria, respiratory distress, acute myocardial infarction, pancreatic adenocarcinoma). Twenty-two participants had treatment-emergent serious AEs during the ETP. Patients switched from alglucosidase alfa to avalglucosidase alfa presented no safety- or immunogenicity-related concerns. Overall results demonstrate sustained treatment effect for improvements observed with avalglucosidase alfa during the PAP and stabilization of treatment effect after switching from alglucosidase alfa to avalglucosidase alfa over 97 weeks, supporting long-term maintenance of outcomes and persistence of avalglucosidase alfa's effect.
Funding(s): Sanofi-Genzyme.
Copyright

During conversation, people take turns speaking by rapidly responding to their partners while simultaneously avoiding interruption^1,2. Such interactions display a remarkable degree of coordination, as gaps between turns are typically about 200 milliseconds³-approximately the duration of an eyeblink⁴. These latencies are considerably shorter than those observed in simple word-production tasks, which indicates that speakers often plan their responses while listening to their partners². Although a distributed network of brain regions has been implicated in speech planning^5-9, the neural dynamics underlying the specific preparatory processes that enable rapid turn-taking are poorly understood. Here we use intracranial electrocorticography to precisely measure neural activity as participants perform interactive tasks, and we observe a functionally and anatomically distinct class of planning-related cortical dynamics. We localize these responses to a frontotemporal circuit centred on the language-critical caudal inferior frontal cortex¹⁰ (Broca's region) and the caudal middle frontal gyrus-a region not normally implicated in speech planning^11-13. Using a series of motor tasks, we then show that this planning network is more active when preparing speech as opposed to non-linguistic actions. Finally, we delineate planning-related circuitry during natural conversation that is nearly identical to the network mapped with our interactive tasks, and we find this circuit to be most active before participant speech during unconstrained turn-taking. Therefore, we have identified a speech planning network that is central to natural language generation during social interaction.

We report an energy-efficient, cancellation-free, bit-wise time-division duplex (B-TDD) transceiver (TRX) for real-time closed-loop control of high channel count neural interfaces. The proposed B-TDD architecture consists of a duty-cycled ultra-wide band (UWB) transmitter (3.15 GHz) and a switching U-NII band (5.2 GHz) receiver. An energy-efficient duplex is realized in a single antenna without power-hungry self-interference cancellation circuits which are prevalently used in the conventional full-duplex, single antenna transceivers. To suppress the interference between up- and down-links and enhance the isolation between the two, we devised a fast-switching scheme in a low noise amplifier and used 5 oversampling with a built-in winner-take-all voting in the receiver. The B-TDD transceiver was fabricated in 65 nm CMOS RF process, achieving low energy consumption of 0.32 nJ/b at 10 Mbps in the receiver and 9.7 pJ/b at 200 Mbps in the transmitter, respectively. For validation, the B-TDD TRX has been integrated with a LED optoelectrode and a custom analog frontend integrated circuit in a prototype wireless bidirectional neural interface system. Successful in-vivo operation for simultaneously recording broadband neural signals and optical stimulation was demonstrated in a transgenic rodent.

Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited disorder that may result in multisystem involvement of varying phenotypes including inclusion body myopathy, Paget's disease of bone (PDB), frontotemporal dementia (FTD), parkinsonism, and amyotrophic lateral sclerosis (ALS), among others. An international multidisciplinary consortium of 40+ experts in neuromuscular disease, dementia, movement disorders, psychology, cardiology, pulmonology, physical therapy, occupational therapy, speech and language pathology, nutrition, genetics, integrative medicine, and endocrinology were convened by the patient advocacy organization, Cure VCP Disease, in December 2020 to develop a standard of care for this heterogeneous and under-diagnosed disease. To achieve this goal, working groups collaborated to generate expert consensus recommendations in 10 key areas: genetic diagnosis, myopathy, FTD, PDB, ALS, Charcot Marie Tooth disease (CMT), parkinsonism, cardiomyopathy, pulmonology, supportive therapies, nutrition and supplements, and mental health. In April 2021, facilitated discussion of each working group's conclusions with consensus building techniques enabled final agreement on the proposed standard of care for VCP patients. Timely referral to a specialty neuromuscular center is recommended to aid in efficient diagnosis of VCP MSP via single-gene testing in the case of a known familial VCP variant, or multi-gene panel sequencing in undifferentiated cases. Additionally, regular and ongoing multidisciplinary team follow up is essential for proactive screening and management of secondary complications. The goal of our consortium is to raise awareness of VCP MSP, expedite the time to accurate diagnosis, define gaps and inequities in patient care, initiate appropriate pharmacotherapies and supportive therapies for optimal management, and elevate the recommended best practices guidelines for multidisciplinary care internationally.