Biology subjects

Fisher, L.

Publications and source records attributed to Fisher, L..

13 recordsLinked to original sources

bioRxiv2026

The crossmodal congruency task as a measure of intuitiveness of sensory feedback in the lower limb

People with lower limb amputation lack somatosensory feedback from their prosthesis, and this loss contributes to functional deficits, including balance and gait impairments. Recent advances in neuroprostheses have demonstrated that electrical stimulation of sensory nerves in the residual limb and spinal cord can restore lost sensations in the lower limb. To maximize the efficacy of these somatosensory neuroprostheses, the restored sensations should be intuitive, seamlessly integrating into the sensorimotor network. However, it is challenging to quantify the intuitiveness of these evoked sensations. Recent studies have proposed using crossmodal congruency effect (CCE) tasks for this purpose in people with upper-limb amputation. The current study tests the feasibility of the CCE task for assessing the intuitiveness of sensory feedback in the lower limb. We hypothesized that CCE score would reliably differentiate between a more natural (pneumatic) sensation and a less natural (electric) sensation at two locations: the knee and the foot. Across fifteen able-bodied individuals, we observed that the CCE task differentiates sensory modalities at the knee, but not at the foot. Identification of external factors affecting the CCE is needed before it can be implemented to measure intuitiveness of sensory feedback in lower-limb amputees.

bioengineering↗

bioRxiv2026

Intramuscular Delivery of BMP-2 and Increasing Doses of LECT-1 Using Keratin-PEG Gels for Ectopic Tissue Differentiation

Producing bone and cartilage in a controlled and localized manner remains a significant challenge in regenerative medicine. This study investigated the ability of keratin- and polyethylene glycol (PEG)-based degradable hydrogels to deliver bone morphogenetic protein 2 (BMP-2) and leukocyte cell-derived chemotaxin 1 (LECT-1; also known as chondromodulin-1) intramuscularly to induce ectopic tissue formation. Adult male CD-1 mice received intramuscular implants of keratin-PEG gels containing a fixed dose of BMP-2 and increasing amounts of LECT-1. After two weeks, implants and surrounding muscle were analyzed using computed tomography (CT) and histology. The results showed that BMP-2 is necessary for forming new bone and cartilage, whereas LECT-1 alone appeared to trigger muscle dedifferentiation without ossification or chondrogenesis. Co-delivery of BMP-2 and LECT-1 enhanced bone and cartilage formation in a dose-dependent manner: higher LECT-1 doses led to proportionally more ectopic cartilage (linear correlation, r2 {approx} 90%), while bone formation peaked at the third LECT-1 dose at approximately twice the volume of the BMP-2-only group. These findings indicate that muscle-resident cells may be capable of reverting and switching to mesenchymal lineages, recapitulating endochondral ossification. The platform offers a promising strategy for growing bone and cartilage autografts within skeletal muscle bundles. Impact StatementThis study presents a novel strategy for inducing ectopic bone and cartilage formation by delivering BMP-2 and LECT-1 from keratin-PEG hydrogels into skeletal muscle. The findings suggest that muscle-resident cells can dedifferentiate and transdifferentiate into mesenchymal lineages, enabling controlled ectopic tissue regeneration. This approach may inform future tissue engineering therapies in which autografts are harvested from within the body, using skeletal muscle as an in vivo tissue incubator.

bioengineering↗

bioRxiv2026

Functional Somatotopy of Lumbar Dorsal Rootlets and its Role in Selective Recruitment via Lateral Spinal Cord Stimulation

ObjectiveLateral spinal cord stimulation (LSCS) is a promising approach for restoring somatosensory feedback in lower-limb amputees, but its spatial selectivity remains limited. Percepts often spread to unintended regions of the residual limb, and reducing electrode contact size may not improve focality. This study investigated whether the anatomical organization of lumbar dorsal rootlets (DR) imposes fundamental constraints on LSCS selectivity. ApproachAcute neurophysiology experiments were performed in six adult cats. Both LSCS and individual DR stimulation were conducted in the same animals. For DR stimulation, bipolar hook electrodes were used to stimulate individual DR, while antidromic compound action potentials (CAPs) were recorded from femoral and sciatic nerve branches instrumented with nerve cuffs. For LSCS, custom 32-contact epidural paddle electrodes were placed over the lateral surface of the spinal cord at corresponding vertebral levels. Recruitment thresholds, dynamic ranges, and response patterns were analyzed across spinal levels, and DR recruitment patterns were directly compared to those evoked by LSCS within the same animals. Main resultsA clear rostrocaudal organization was observed across spinal levels during stimulation of individual DR, with femoral branches predominantly recruited at L4-L5 and sciatic branches at L6-L7. However, no somatotopic organization was found across DR within each spinal level; individual DR frequently co-activated multiple branches within the same group, and selective recruitment could only be maintained over a narrow dynamic range (median [~]10 {micro}A). LSCS exhibited even a narrower dynamic range ([~]5 {micro}A) but closely mirrored DR recruitment patterns, indicating that LSCS activates sensory afferents in a manner determined by the organizational structure of the DR. SignificanceThese findings demonstrate that the limited spatial selectivity of LSCS can largely be attributed to the coarse organization of DR within each root level rather than due to limitations of epidural electrode design. Moving electrodes intradurally or reducing contact size further is unlikely to substantially improve focality. Instead, improving paddle stability to ensure consistent placement over the appropriate spinal levels may be a more effective strategy for enhancing percept localization.

neuroscience↗

bioRxiv2026

Cervical spinal cord stimulation disrupts proprioception yet improves voluntary arm reaching

Whether proprioception is necessary for upper-limb motor control has been debated for decades. Classic studies in deafferented animals and humans suggested that proprioception may be dispensable for rapid, goal-directed movements. However, chronic sensory loss conflates the absence of proprioceptive input with years of compensatory adaptation. As a result, the field has lacked a strong causal test of proprioceptions contribution to motor control. Here, we leveraged a clinical trial of cervical spinal cord stimulation (SCS) in individuals with chronic post-stroke hemiparesis to study if electrical stimulation of sensory afferents causally perturbs proprioception and affects arm reaching. We found that turning SCS ON causally impaired proprioceptive perception and postural stabilization in response to force perturbations, and enhanced adaptation to visual errors during implicit learning. Yet visually and non-visually rapid, goal-directed reaching improved in smoothness, straightness and spatial accuracy. These findings provide strong causal evidence that proprioception is not required for rapid, goal-directed action, helping resolve a decades-long debate regarding its necessity for effective movement.

bioengineering↗

bioRxiv2026

Selectivity of Lateral Epidural Spinal Cord Stimulation with Varying Electrode Diameters and Stimulation Configurations

Objective. Our prior studies have demonstrated that lateral spinal cord stimulation can evoke somatosensory percepts in the missing foot in individuals with a lower-limb amputation. However, subjects reported concurrent sensations in their residual limb. In this study, we evaluate the hypothesis that using high-density paddle electrodes with smaller contact sizes, and multipolar stimulation configurations could evoke more focal sensations in the foot over a wide range of stimulation amplitudes. Approach. We used a combination of electrophysiology and computational modelling methods to investigate the selective activation of distal nerve branches in response to lateral spinal cord stimulation in cats. In six acute feline experiments, we performed an L3-S1 laminectomy and placed custom 32-electrode paddles laterally over the dura of the spinal cord. We recorded antidromic action potentials in the distal branches of the sciatic and femoral nerve trunks in response to stimulation using three contact diameters (150, 500 and 1000 {micro}m) and two stimulation configurations - monopolar and bipolar stimulation. We replicated the neural recruitment patterns from those experiments in a computational model of the feline lumbar spinal cord. We then used the model to examine neural recruitment with 1.8 mm and 2.5 mm contacts, as well as a tripolar guarded-cathode configuration. Main results. In the electrophysiology experiments, the 500 {micro}m-diameter electrodes achieved the most selective nerve activation (68%) compared to 62% for both 150 and 1000 {micro}m-diameter electrodes. The minimum amplitudes for recruiting nerve branches (i.e., threshold) as well as the dynamic ranges were largely similar for the different contact diameters (median: 35 {micro}A) and stimulation configurations (30 {micro}A for bipolar stimulation; 35 {micro}A for monopolar stimulation). The computational model reproduced the finding that selectivity did not differ significantly among the three contact sizes tested in cat experiments, though it revealed that increasing contact diameter above 1000 {micro}m raised the minimum amplitude required for selective activation and reduced spinal root selectivity. Across both approaches, we consistently recruited large-diameter afferents that are critical for somatosensory applications of spinal cord stimulation. Significance. Our results indicate that, relative to clinical electrodes, reducing the contact diameter of stimulation electrodes can evoke focal sensations, but further reductions below 1000 {micro}m may fail to improve selectivity. This study highlights potential constraints with achieving focal selectivity that are not dependent on the design of the electrodes.

bioengineering↗

bioRxiv2026

Mapping the vRNA Interaction with HIV-1 Integrase

A series of critical interactions within the viral core between the viral RNA (vRNA) and HIV-1 Integrase (IN) has previously been reported. In these studies, contact points between vRNA and IN were identified using RNA-seq and MS-based protein foot-printing approaches. Several IN amino acids located in its C-terminal domain (CTD) were found to be essential for vRNA binding and their alanine substitution severely impacted the correct morphogenesis of the matured viral core. Here, we have extended these studies by performing a comprehensive mapping of the IN-vRNA interaction by deploying RNA crosslinking and NMR methodologies. Together, these approaches were able to identify additional contacts points between the vRNA and IN. Our results reveal several new basic amino acids located in the IN CTD critical for the vRNA-IN interaction, viral replication and correct morphology of the matured viral core.

biochemistry↗

bioRxiv2025

Molecular biointerface characterisation for an implanted medical device using cryogenic orbitrap secondary ion mass spectrometry (Cryo-OrbiSIMS)

Implanted medical devices often fail due to foreign body reaction (FBR), a process still not fully understood. This work presents a new depth profiling approach to provide insight into the spatial metabolomics of the biointerface of implants, revealing biomolecular strata representative of the host response. This study examines silicone rubber poly(dimethyl siloxane) catheters implanted in mice for 1 and 28 days. Cryo-OrbiSIMS was used in combination with ToF-SIMS to identify metabolite profiles from the biological deposit found on the implants after removal from the tissue which were previously unattainable using tissue sectioning. Machine learning and statistical analysis of the profiles were used to help identify early biointerface responses to the implant, including at 1 day of implantation the observation of elevated sugars and itaconate an immunomodulatory metabolite that modulates FBR. At day 28 inflammation associated markers were observed such as urate and palmitic acid (FA 16:0). Depth profiling revealed two distinct molecular layers in the deposits: amino acids, and nucleic acids were preferentially seen towards the host tissue, consistent with the observation of a cell monolayer in the tissue sections, whereas certain lipids and fatty acids where either at the catheter-deposit interface or towards the host tissue after 28 days. The stratification was less well developed at 1-day implantation, but common lipids were seen at the deposit-implant interface across both time points. These insights advance understanding of FBR and support the development of improved implant materials.

bioinformatics↗

bioRxiv2024

Epidural Spinal Cord Recordings (ESRs): Sources of Artifact in Stimulation Evoked Compound Action Potentials

IntroductionEvoked compound action potentials (ECAPs) measured using epidural spinal recordings (ESRs) during epidural spinal cord stimulation (SCS) can help elucidate fundamental mechanisms for the treatment of pain, as well as inform closed-loop control of SCS. Previous studies have used ECAPs to characterize the neural response to various neuromodulation therapies and have demonstrated that ECAPs are highly prone to multiple sources of artifact, including post-stimulus pulse capacitive artifact, electromyography (EMG) bleed-through, and motion artifact resulting from disturbance of the electrode/tissue interface during normal behavior. However, a thorough characterization has yet to be performed for how these sources of artifact may contaminate recordings within the temporal window commonly used to determine activation of A-beta fibers in a large animal model. MethodsWe characterized the sources of artifacts that can contaminate the recording of ECAPs in an epidural SCS swine model using the Abbott Octrode lead. Muscle paralytics were administered to block muscle activation preventing EMG from contaminating the recorded ECAPs. Concurrent EMG recordings of the longissimus, a long muscle of the back, were used to confirm a 2-4 millisecond (ms) latency source of EMG bleed-through that frequently contaminated the A-beta temporal window. Additionally, we obtained recordings approximately 5-10 minutes post-mortem after clear evoked A-beta and associated EMG responses ceased to characterize the representation of stimulation artifact across the array. ResultsSpinal ECAP recordings can be contaminated by capacitive artifact, short latency EMG from nearby long muscles of the back, and motion artifact from multiple sources. In many cases, the capacitive artifact can appear nearly identical in duration and waveshape to evoked A-beta responses. These sources of EMG can have phase shifts across the electrode array, very similar to the phase shift anticipated by propagation of an evoked A-beta fiber response across the array. This short latency EMG is often evident at currents similar to those needed to activate A-beta fibers associated with the treatment of pain. Changes in cerebrospinal fluid between the cord and dura, and motion induced during breathing created a cyclic oscillation in all evoked components of the recorded ECAP signal. ConclusionCareful controls must be implemented to accurately separate neural signal from the sources of artifact in spinal cord ECAPs. To address this, we suggest experimental procedures and associated reporting requirements necessary to disambiguate the underlying neural response from these confounds. These data are important to better understand the conceptual framework for recorded ESRs, with components such as ECAPs, EMG responses and artifacts, and have important implications for closed-loop control algorithms to account for transient motion such as postural changes and cough.

neuroscience↗

bioRxiv2024

Thetis cells induce food-specific Treg cell differentiation and oral tolerance

The intestinal immune system must establish tolerance to food antigens to prevent onset of allergic and inflammatory diseases. Peripherally generated regulatory T (pTreg) cells play an essential role in suppressing inflammatory responses to allergens; however, the antigen-presenting cell (APC) that instructs food-specific pTreg cells is not known. Here, we show that antigen presentation and TGF-{beta} activation by a subset of ROR{gamma}t+ antigen-presenting cells (APC), Thetis cells IV (TC IV), is required for food-induced pTreg cell differentiation and oral tolerance. By contrast, antigen presentation by dendritic cells (DCs) was dispensable for pTreg induction but required for TH1 effector responses, highlighting a division of labor between tolerogenic TCs and pro-inflammatory DCs. While antigen presentation by TCs was required for food-specific pTreg generation both in early life and adulthood, the increased abundance of TCs in the peri-weaning period was associated with a window of opportunity for enhanced pTreg differentiation. These findings establish a critical role for TCs in oral tolerance and suggest that these cells may represent a key therapeutic target for the treatment of food-associated allergic and inflammatory diseases.

immunology↗

bioRxiv2024

Neural and computational mechanisms of effort under the pressure of a deadline

Deadlines fundamentally shape the motivation for effort. Research examining effort-based choices finds high effort is an avoided cost. However, this work overlooks the fact that effort can be valuable when it makes progress on long-term goals before deadlines. We test a new framework where motivation depends on deadline pressure (work remaining / time remaining). Across three studies we use computational modelling on novel tasks examining effort-based decisions when effort makes progress on goals with deadlines. In support of hypotheses, deadline pressure significantly impacts decision-making, shifting people from avoiding effort, to seeking and valuing it. Using ultra-high-field fMRI, we show that functionally connected putamen and midcingulate cortex (MCC) sub-regions process and update estimates of deadline pressure, with distinct anterior cingulate and putamen sub-regions processing the costs or added value of effort. We show the neurocomputational mechanisms for how deadline pressure shapes motivation, and that keep us on track for our goals.

neuroscience↗

bioRxiv2022

Methylene blue, Mycophenolic acid, Posaconazole, and Niclosamide inhibit SARS-CoV-2Omicron variant BA.1 infection of human airway epithelial explant cultures

Sublineages of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Omicron variants continue to amass mutations in the spike (S) glycoprotein, which leads to immune evasion and rapid spread of the virus across the human population. Here we demonstrate the susceptibility of the Omicron variant BA.1 (B.1.1.529.1) to four repurposable drugs, Methylene blue (MB), Mycophenolic acid (MPA), Posaconazole (POS), and Niclosamide (Niclo) in post-exposure treatments of primary human airway cell cultures. MB, MPA, POS, and Niclo are known to block infection of human nasal and bronchial airway epithelial explant cultures (HAEEC) with the Wuhan strain, and four variants of concern (VoC), Alpha (B.1.1.7), Beta (B.1.351), Gamma (B.1.1.28), Delta (B.1.617.2) (1, 2). Our results not only show broad anti-coronavirus effects of MB, MPA, POS and Niclo, but also demonstrate that the Omicron variant BA.1 (B.1.1.529.1) sheds infectious virus from HAEEC over at least 15 days, and maintains both intracellular and extracellular viral genomic RNA without overt toxicity, suggesting viral persistence. The data underscore the broad effects of MB, MPA, POS, and Niclo against SARS-CoV-2 and the currently circulating VoC, and reinforce the concept of repurposing drugs in clinical trials against COVID-19.

microbiology↗

bioRxiv2021

Neural bases of risky decisions involving nicotine vapor versus monetary reward

Substantial effort has gone into neuroimaging studies of neural mechanisms underlying addiction. Human studies of smoking typically either give monetary reward during an fMRI task or else allow subjects to smoke outside the scanner, after the session. This raises a fundamental issue of construct validity, as it is unclear whether the same neural mechanisms process decisions about nicotine that process decisions about money. To address this, we developed a novel MR-compatible nicotine vaping device, such that access to nicotine vapor could be controlled and monitored. We recruited heavy smokers to perform a gambling task with nicotine and monetary reward on separate days. This allowed a direct comparison between the neural mechanisms of choosing and receiving immediate drug vs. monetary reward. We found substantial differences in the neural mechanisms that underlie risky choices about money vs. drug reward, including a reversal of the well-known error effects in the medial prefrontal cortex.

neuroscience↗

bioRxiv2021

Selective stimulation of the ferret abdominal vagus nerve with multi-contact nerve cuff electrodes

Dysfunction and diseases of the gastrointestinal (GI) tract are a major driver of medical care. The vagus nerve innervates and controls multiple organs of the GI tract and vagus nerve stimulation (VNS) could provide a means for affecting GI function and treating disease. However, the vagus nerve also innervates many other organs throughout the body, and off-target effects of VNS could cause major side effects such as changes in blood pressure. In this study, we aimed to achieve selective stimulation of populations of vagal afferents using a multi-contact cuff electrode wrapped around the abdominal trunks of the vagus nerve. Four-contact nerve cuff electrodes were implanted around the dorsal (N=3) or ventral (N=3) abdominal vagus nerve in six ferrets, and the response to stimulation was measured via a 32-channel microelectrode array (MEA) inserted into the nodose ganglion. Selectivity was characterized by the ability to evoke responses in MEA channels through one bipolar pair of cuff contacts but not through the other bipolar pair. We demonstrated that is was possible to selectively activate subpopulations of vagal afferents using abdominal VNS. Additionally, we quantified the conduction velocity of evoked responses to determine what types of nerve fibers (i.e. A{delta} vs. C) responded to stimulation. We also quantified the spatial organization of evoked responses in the nodose MEA to determine if there is somatotopic organization of the neurons in that ganglion. Finally, we demonstrated in a separate set of three ferrets that stimulation of the abdominal vagus via a four-contact cuff could selectively alter gastric myoelectric activity, suggesting that abdominal VNS can potentially be used to control GI function.

bioengineering↗