Biology subjects

Hahn, N.

Publications and source records attributed to Hahn, N..

8 recordsLinked to original sources

bioRxiv2025

Pathophysiological remodeling of the skeletal muscle microenvironment in patients with lung cancer

Background Muscle wasting, systemic inflammation, and functional decline are highly prevalent and detrimental in patients with advanced-stage non small cell lung cancer (NSCLC). Methods: In this cross sectional study, we investigated NSCLC associated muscle remodeling by analyzing skeletal muscle biopsies from patients with NSCLC (n = 18) and matched controls (n = 18) using quantitative proteomics, histology, fluorescence-activated cell sorting, gene expression profiling, and high resolution respirometry. Findings: NSCLC muscle was characterized by type II muscle fiber atrophy, greater collagen deposition, and redistribution of lipids to the extracellular matrix (ECM), together with remodeling of the inflammatory, immune, ECM and mitochondrial proteome. Additionally, mitochondrial respiratory capacity and morphology were altered in patients with NSCLC, which was associated with increased oxidative stress and dysregulated calcium handling. Concomitantly, we detected STAT3 activation and immune cell alterations, which may negatively impact skeletal muscle health in patients with NSCLC. Finally, we identified a shift in fibro-adipogenic progenitors (FAPs), favoring the CD90 subtype. Mechanistically, conditioned media from patient-derived FAPs reduced myotube width in vitro, uncovering a novel mechanism by which altered paracrine signaling from the muscle resident stromal compartment drives atrophy in cancer cachexia. Interpretation: These findings provide human evidence that altered FAP composition, mitochondrial homeostasis, calcium handling, and immune cell landscape accompany muscle wasting in NSCLC, which may inform therapeutic strategies to preserve skeletal muscle health in patients with cancer.

molecular biology↗

bioRxiv2025

Improved interpretability in LFADS models using a learned, context-dependent per-trial bias

The computation-through-dynamics perspective argues that biological neural circuits process information via the continuous evolution of their internal states. Inspired by this perspective, Latent Factor Activity using Dynamical systems (LFADS, [1]) identifies a generative model consistent with the neural activity recordings. LFADS models neural dynamics with a recurrent neural network (RNN) generator, which results in excellent fit to the data. However, it has been difficult to understand the dynamics of the LFADS generator. In this work, we show that this poor interpretability arises in part because the generator implements complex, multi-stable dynamics. We introduce a simple modification to LFADS that ameliorates issues with interpretability by providing an inferred per-trial bias (modeled as a constant input) to the RNN generator, enabling it to contextually adapt a simpler dynamical system to individual trials. In both simulated neural recordings from pendulum oscillations and real recordings during arm movements in nonhuman primates, we observed that the standard LFADS learned complex, multi-stable dynamics, whereas the modified LFADS learned easier-to-understand contextual dynamics. This enabled direct analysis of the generator, which reproduced at a single-trial level previous results shown only through more complex analyses at the trial average. Finally, we applied the per-trial inferred bias LFADS model to human intracortical brain computer interface recordings during attempted finger movements and speech. We show that modifying neural dynamics using linear operations of the per-trial bias addresses non-stationarity and identifies the extent of behavioral variability, problems known to plague BCI. We call our modification to LFADS as "contextual LFADS".

neuroscience↗

bioRxiv2025

Preparatory encoding of diverse features of intended movement in the human motor cortex

Over the course of a voluntary movement, motor cortical activity exhibits a transition from preparation to execution, with markedly different activity across these phases. Preparatory activity in particular might be used to improve brain-computer interfaces (BCIs) that harness brain activity to control external assistive devices, for example by anticipating a users intended movement trajectory for quick and fluid performance. However, to leverage preparatory activity for clinical BCIs, we must first understand which features of upcoming movements are encoded by preparatory activity in humans. In this work, we collected intracortical recordings from 3 research participants in the BrainGate2 clinical trial to investigate whether diverse features of movement, such as direction, curvature, and distance, are encoded by preparatory activity in the human motor cortex. We first show that preparatory activity is tuned to the direction of upcoming movements, and this tuning is largely preserved across movements with different effectors. Further investigation demonstrated this preparatory activity is also informative of initial and endpoint directions of curved movement trajectories, and encodes movement distance and speed independently. Finally, we present an online control paradigm that leverages preparatory activity to predict movements towards intended directions in advance, yielding rapid, self-paced control of a computer cursor by human participants. Altogether, these results demonstrate that preparatory activity in the human motor cortex encodes rich features of upcoming movement, highlighting its potential use for high performance brain-computer interface applications.

neuroscience↗

bioRxiv2025

Error encoding in human speech motor cortex

Humans monitor their actions, including detecting errors during speech production. This self-monitoring capability also enables speech neuroprosthesis users to recognize mistakes in decoded output upon receiving visual or auditory feedback. However, it remains unknown whether neural activity related to error detection is present in the speech motor cortex. In this study, we demonstrate the existence of neural error signals in speech motor cortex firing rates during intracortical brain-to-text speech neuroprosthesis use. This activity could be decoded to enable the neuroprosthesis to identify its own errors with up to 86% accuracy. Additionally, we observed distinct neural patterns associated with specific types of mistakes, such as phonemic or semantic differences between the persons intended and displayed words. These findings reveal how feedback errors are represented within the speech motor cortex, and suggest strategies for leveraging these additional cognitive signals to improve neuroprostheses.

neuroscience↗

bioRxiv2024

Representation of Verbal Thought in Motor Cortex and Implications for Speech Neuroprostheses

Speech brain-computer interfaces show great promise in restoring communication for people who can no longer speak1-3, but have also raised privacy concerns regarding their potential to decode private verbal thought4-6. Using multi-unit recordings in three participants with dysarthria, we studied the representation of inner speech in the motor cortex. We found a robust neural encoding of inner speech, such that individual words and continuously imagined sentences could be decoded in real-time This neural representation was highly correlated with overt and perceived speech. We investigated the possibility of "eavesdropping" on private verbal thought, and demonstrated that verbal memory can be decoded during a non-speech task. Nevertheless, we found a neural "overtness" dimension that can help to avoid any unintentional decoding. Together, these results demonstrate the strong representation of verbal thought in the motor cortex, and highlight important design considerations and risks that must be addressed as speech neuroprostheses become more widespread.

neuroscience↗

bioRxiv2024

A flexible intracortical brain-computer interface for typing using finger movements

Keyboard typing with finger movements is a versatile digital interface for users with diverse skills, needs, and preferences. Currently, such an interface does not exist for people with paralysis. We developed an intracortical brain-computer interface (BCI) for typing with attempted flexion/extension movements of three finger groups on the right hand, or both hands, and demonstrated its flexibility in two dominant typing paradigms. The first paradigm is "point-and-click" typing, where a BCI user selects one key at a time using continuous real-time control, allowing selection of arbitrary sequences of symbols. During cued character selection with this paradigm, a human research participant with paralysis achieved 30-40 selections per minute with nearly 90% accuracy. The second paradigm is "keystroke" typing, where the BCI user selects each character by a discrete movement without real-time feedback, often giving a faster speed for natural language sentences. With 90 cued characters per minute, decoding attempted finger movements and correcting errors using a language model resulted in more than 90% accuracy. Notably, both paradigms matched the state-of-the-art for BCI performance and enabled further flexibility by the simultaneous selection of multiple characters as well as efficient decoder estimation across paradigms. Overall, the high-performance interface is a step towards the wider accessibility of BCI technology by addressing unmet user needs for flexibility.

neuroscience↗

bioRxiv2022

Circulating plasma IL-13 and periostin are dysregulated type 2 inflammatory biomarkers in prurigo nodularis: a cluster analysis

BackgroundPrurigo nodularis (PN) is a chronic inflammatory skin disease characterized by severe pruritus and notable disease heterogeneity. There is evidence of systemic inflammation in PN, including dysregulation observed in type 2 inflammation in subsets of patients. We aimed to elucidate which components of type 2 inflammation are dysregulated in PN patients using plasma immunoassay cytokine profiling. Materials and MethodsWhole blood was obtained from PN patients with uncontrolled disease and control patients without pruritus. Plasma samples were isolated from whole blood and assayed for IL-4, IL-5, IL-13, IgE, and periostin. For statistical analysis, ANOVA was utilized to compare PN and control patients. For multiple hypothesis, adjusted p-value was calculated with a Benjamini-Hochberg procedure with the significance threshold at 0.05. Clustering was performed using K-means clustering in R version 4.0.3. ResultsSingle-plex assays of the Th2 biomarkers demonstrated significantly elevated circulating plasma IL-13 (0.13 vs. 0.006 pg/mL, p=0.0008) and periostin (80.3 vs. 60.2 ng/mL, p=0.012) in PN patients compared to controls. IL-4 (0.11 vs. 0.02 pg/mL, p=0.30) and IL-5 (0.75 vs. 0.40 pg/mL, p=0.10) were not significantly elevated, while IgE approached significance in PN (1202.0 vs. 432.7 ng/mL, p=0.08). Clustering of PN and control patients together revealed mean silhouette maximization at two clusters. Cluster 1 (n=36) consisted of 18 PN patients and 18 controls. Cluster 2 (n=11) consisted entirely of PN patients (p<0.01) (Figure 1b). When comparing the two clusters, cluster 2 had higher levels of IL-13 (0.33 vs. 0.008 pg/mL, p=0.0001) and IL-5 (1.22 vs. 0.43 pg/mL, p=0.03) compared to cluster 1. There were no significant differences in any of the biomarkers between PN patients from cluster 1 and the healthy control patients in this cluster. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/495051v1_fig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@101432dorg.highwire.dtl.DTLVardef@1e16d01org.highwire.dtl.DTLVardef@bb8edborg.highwire.dtl.DTLVardef@19fd785_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Single-plex plasma immunoassays of prurigo nodularis vs. controls (a) Plasma single-plex immunoassays (b) Heatmap of Z-scored biomarker levels for each patient, delineated by cluster. PN, prurigo nodularis; HC, healthy control C_FIG ConclusionsThis study demonstrates elevation of IL-13 and periostin in PN patients with distinct clusters with varying degrees of type 2 inflammation. Given this heterogeneity, further biomarker studies with single-cell resolution will provide better guidance towards future precision medicine approaches in the treatment of PN.

immunology↗

bioRxiv2021

Arc rescues defective synaptic plasticity and cognitive dysfunction in sepsis-associated encephalopathy

Sepsis-associated encephalopathy (SAE) is a frequent complication in patients with severe systemic infection resulting in acute brain dysfunction and incapacitating long-term sequelae. SAE includes delirium, premature death, post-traumatic stress disorder, and major long-term cognitive impairment. The underlying pathophysiology of SAE is largely unresolved and specific treatment options are missing. We induced the peritoneal contamination and infection (PCI) sepsis model in 769 mice and compared these with 259 control mice. We found that experimental sepsis causes synaptic pathology in the brain characterized by severely disordered synaptic plasticity with reduced long-term potentiation, changes in CA1 pyramidal neuron dendritic spines, and behavioral abnormalities indicating cognitive dysfunction. Using electrophysiology, we found reduced frequency of quantal and spontaneous excitatory postsynaptic currents whereas amplitudes of miniature, spontaneous, and evoked excitatory currents were increased, pointing towards a homeostatic synaptic scaling mechanism. Corresponding to dysfunctional excitatory synaptic function we discovered downregulation of genes related to neuronal and synaptic signaling in the brain, including the gene for activity-regulated cytoskeleton-associated protein (Arc/Arg3.1), members of the transcription-regulatory EGR gene family, and the gene for dual-specificity phosphatase 6 (Dusp6). At the protein level, ARC expression and MAP kinase signaling in the brain were affected. For targeted rescue of dysfunctional synaptic signaling and plasticity, we overexpressed ARC in the hippocampus by microinjection of an adeno-associated virus containing a neuron-specific plasmid of the ARC transgene. Hereby we achieved recovery of defective synaptic plasticity in the hippocampal Schaffer collateral-CA1 pathway and improvement of memory dysfunction. Using a different rescue paradigm, PCI mice were subjected to enriched environment providing multiple activating stimuli. Enriched environment led to restoration of disordered long-term potentiation and memory, thus demonstrating the potential for activity-induced improvement. Together, we identified synaptic pathomechanisms of SAE after severe systemic infection and provide a conceptual approach to treat SAE-related disease mechanisms which may be applicable to patients afflicted with SAE.

neuroscience↗