Faculty Bibliography

BACKGROUND:Elp1, a subunit of the Elongator complex, is essential for tRNA modification and neuronal development. Mutations in ELP1 underlie familial dysautonomia (FD), a disorder marked by sensory and autonomic neuropathy. While loss of Elp1 disrupts trigeminal ganglion formation and survival, the downstream molecular consequences remain poorly defined. RESULTS:We performed quantitative proteomic profiling of trigeminal ganglia from Elp1 conditional knockout (CKO) and control embryos at E13.5. Across 5650 detected proteins, 25 were significantly up-regulated and 26 down-regulated in Elp1 CKO embryos. EnrichR analysis revealed enrichment of up-regulated proteins in amino acid transport and tRNA aminoacylation pathways, with links to neuromuscular and neuropathic diseases. Down-regulated proteins were associated with RNA modification, cholesterol biosynthesis, and synaptic organization. Validation by immunohistochemistry confirmed decreased expression of the neurotrophic receptor Gfra3 and the neuropeptide Galanin, and increased levels of the chromatin regulator Chd1, in Elp1 CKO embryos relative to controls. CONCLUSIONS:These findings demonstrate that Elp1 loss disrupts metabolic, RNA modification, and neurotrophic signaling pathways in the developing trigeminal ganglion. Proteomic analysis thus provides new insight into the molecular consequences of Elp1 deficiency and highlights candidate mechanisms contributing to sensory neuron vulnerability in FD.

Understanding speech in noisy environments is difficult for many people, and current hearing aids often fail because they amplify all sounds rather than the talker of interest. Auditory attention decoding (AAD) offers a potential solution by using the listener's brain signals to identify and enhance the attended speaker, but it has been unclear whether this can provide real-time perceptual benefits. Here we used high-resolution intracranial electroencephalography in patients undergoing neurosurgical procedures to implement a closed-loop system that achieves the decoding fidelity necessary to dynamically amplify the attended talker. Across multiple experiments, the system improved speech intelligibility, reduced listening effort and was consistently preferred by subjects. It also tracked both instructed and self-initiated attention shifts. By providing direct evidence that a real-time, brain-controlled hearing system can enhance perception, this work establishes a key performance benchmark for future auditory brain-computer interfaces and advances AAD from a theoretical concept to a validated solution for personalized assistive hearing.

We present a functional magnetic resonance (fMRI) dataset collected as part of an adversarial collaboration aimed at arbitrating between the Global Neuronal Workspace theory (GNWT) and the Integrated Information Theory (IIT) of consciousness. Participants (N = 118) were presented with suprathreshold visual stimuli belonging to four different categories (faces, objects, letters, false fonts) with three orientations (front, left, right view), and three durations (0.5, 1.0, 1.5 seconds). Participants were asked to identify infrequent targets that changed in each block, thereby rendering two categories task-relevant and two task-irrelevant. The simplicity of the experimental design and of the task given to the participants ensures that these data are broadly reusable. Besides testing predictions from other theories of consciousness, these data can be used to examine various aspects of visual processing. The anonymized data were converted to Brain Imaging Data Structure (BIDS), and can be easily accessed through a web platform or an API. The dataset contains quality reports, demographics, behavioral performance, and eye-tracking data. We also provide code for preprocessing and analyzing the data.

Blood inflammatory marker studies in aging and Alzheimer's disease (AD) research have faced numerous interpretative and methodological challenges that have hindered the field's understanding of the relationship between immune network regulation/dysregulation and aging health factors. We examined how blood inflammation markers directly relate to each other in typical aging, cognitively unimpaired adults using a conditional network analytic modeling approach. We further evaluated how blood inflammation networks relate to key aging risk factors by decomposing the networks into eigenvectors with associated hub proteins and then evaluated the associations of the resulting eigenproteins with demographic information, core biomarkers of AD pathobiology in CSF and blood, and immune health history. Networks of blood inflammation markers showed both divergent and convergent relationships with outcomes, including strong associations between a CXCL5-driven blood inflammation network and age, sex, and CSF Aβ42/Aβ40, and an IL-6- and FGF-21-driven network and sex, CSF Aβ42/Aβ40, and Qalb (CSF-serum albumin ratio). An IFN-gamma- and CXCL9-driven network was associated with both age and CSF Aβ42/Aβ40, whereas blood inflammation networks with hub proteins of CXCL11/CXCL9 and CCL19/CCL4, respectively, were associated solely with sex. Finally, an MCP-3-, MCP-4-, and CXCL6-driven network was associated with cumulative surgical procedure exposures. Despite associations between CSF Aβ42/Aβ40 and multiple networks, plasma Aβ42/Aβ40 was not significantly associated with any blood inflammatory network. Our findings highlight the importance and the challenges of inferring immune pathophysiology from blood-based markers; mirroring the complex pleiotropic biology of inflammation, blood inflammatory markers show associations with multiple demographic and salient health factors in aging adults.

OBJECTIVES/OBJECTIVE:To update evidence-based management recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with sepsis or septic shock. DESIGN/METHODS:A panel of 68 international experts, representing 13 international organizations, as well as six methodologists, was convened. A formal conflict-of-interest policy was developed at the onset of the process and applied throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and subgroup leads as well as within subgroups, served as an integral part of the guideline development process. METHODS:New priority topics and recommendations from the prior guideline iteration were used to identify Population, Intervention, Control, and Outcomes (PICO) questions likely to have new or updated evidence. We conducted a systematic review to identify the best available evidence, summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or conditional, or as a good practice statement. "In our practice," statements were included when evidence was inconclusive to issue a recommendation but the panel felt that some guidance based on practice patterns may be appropriate. RESULTS:The panel provided 61 statements on the management of children with sepsis or septic shock. Overall, five were strong recommendations, 24 were conditional recommendations, and ten were good practice statements. For 22 PICO questions, no recommendations could be made, but, for seven of these, "in our practice" statements were provided. Compared with the 2020 guidelines, 20 recommendations were new, 13 were updated for clarity and/or new evidence, six were reviewed but not changed, and 22 were carried forward based on consensus of the panel that new evidence was not available. Only three recommendations were based on high or moderate certainty of evidence. CONCLUSIONS:Updated management guidelines were issued by a panel of international experts for the best care of children with sepsis or septic shock, acknowledging that most aspects of care continue to have relatively low quality of evidence.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Neuromodulation therapies are approved for the treatment of focal epilepsy based on data from randomized controlled trials (RCTs). After approval of a responsive direct brain stimulation device (The RNS System for focal epilepsy), the Food and Drug Administration required a prospective study to evaluate whether real-world safety and effectiveness differed from outcomes in the RCT. METHODS:This open-labeled study enrolled adult participants who met the RNS System-approved indication for use. The primary effectiveness end point was median percent change in seizure frequency at 3 years of treatment. Interim safety is presented; the primary safety endpoint analysis will be conducted at 5 years. RESULTS:). DISCUSSION/CONCLUSIONS:This prospective real-world study contributes to the body of evidence that adjunctive direct brain-responsive neurostimulation provides significant and sustained reductions in the frequency of focal seizures. Seizure reductions were greater and were achieved faster than in the RCT and long-term treatment trials but were similar to a more recent retrospective multicenter real-world study. As in the preapproval studies, treatment was well-tolerated and safe, and the SUDEP rate was low. The RNS System showed similar safety and improved seizure outcomes in real-world use compared with the RCT. Improvements in efficacy may reflect changes in programming practices. Future research efforts will focus on using the brain data obtained by the device to optimize detection and stimulation paradigms for each patient. TRIAL REGISTRATION INFORMATION/UNASSIGNED:ClinicalTrials.gov, NCT02403843, submitted March 26, 2015. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class IV evidence that in adults with refractory focal-onset seizures, direct brain-responsive neurostimulation reduces seizure frequency without serious adverse events up to 3 years.