bioRxiv Science⌕ Search

Biology subjects

Heimel, P.

Publications and source records attributed to Heimel, P..

4 recordsLinked to original sources

golgi: an open-source graphical platform for image-to-recruitment modeling of peripheral nerve stimulation

Computational models of peripheral nerve stimulation--coupling finite-element bioelectric fields to biophysical axon models--have become essential for designing electrodes and waveforms for neuromodulation therapies. Yet the established open tools are code-first and assume substantial modeling expertise, and several depend on commercial finite-element solvers, placing realistic nerve modeling out of reach for many experimentalists and clinicians. We present golgi, an open-source platform that takes a peripheral nerve from image to stimulated fiber population through a single graphical interface, with an equivalent scriptable Python API and command-line interface for batch studies. golgi integrates the full pipeline: image segmentation (or import of surfaces or masks), automated multi-region tetrahedral meshing, anisotropic finite-element solution of the extracellular field with explicit perineurium contact impedance, generation of realistic fiber populations and their three-dimensional trajectories (straight, or curved via a quasi-static streamline solver), and biophysical activation thresholds through interchangeable NEURON and a GPU-accelerated surrogate backend. We demonstrate golgi on extruded multifascicular swine and human cervical vagus nerves and on real three-dimensional, branching human and rabbit vagus nerves reconstructed from micro-computed tomography. It reproduces the physiological fiber-diameter recruitment order, quantifies fascicular selectivity and current steering with a multi-contact cuff electrode, and resolves anatomically defined nerve branches. Using this branch resolution, we find that selectively engaging a vagal cardiac branch from a proximal cuff depends on anatomy. In the rabbit, whose cardiac fibers are predominantly small and whose superior cardiac branch forms a discrete, spatially segregated tract, current steering isolates even its small cardiac (B-type) fibers; in the human cervical vagus only the large myelinated fibers are separable, because the high thresholds of the small cardiac fibers force stimulus currents that also recruit off-target fibers. Every study can be exported as an integrity-hashed, self-contained bundle whose finite-element-to-recruitment provenance is verifiable byte-for-byte with a single command--a reproducibility guarantee absent from existing tools. By combining non-specialist usability, anatomical realism, and verifiable reproducibility in one open package, golgi lowers the barrier to in-silico peripheral nerve stimulation modeling. golgi is freely available as open-source software. Author summaryElectrical stimulation of peripheral nerves treats a growing range of conditions, from epilepsy to inflammatory and cardiovascular disease. Deciding where to place an electrode and how to shape the stimulus increasingly relies on computer models that combine the electric field around the electrode with detailed models of how individual nerve fibers respond. We found that existing software for this is powerful but primarily designed for expert modelers: it generally requires programming, substantial modeling expertise, and sometimes expensive commercial software, which can limit its adoption by experimentalists and clinicians. We built golgi to remove that barrier. With golgi, a user can go from a nerve image all the way to predicted fiber recruitment through a single point-and-click interface, while advanced users keep full scripting control. golgi builds anatomically realistic nerve models, simulates how different fiber types and fascicles are recruited, and lets users compare electrode designs. Using golgi, we also found that whether a small but clinically important nerve branch--such as the cardiac branch of the vagus nerve--can be selectively stimulated depends on its anatomy. In a rabbit nerve, where this branch forms a discrete, spatially separated bundle and its fibers are mostly small, even its small fibers can be targeted from a cuff on the main trunk; in the human, only the large fibers can be reached selectively, because the small cardiac fibers are harder to excite and the stronger currents needed to reach them also activate off-target fibers. Critically, every result can be packaged so that anyone else can verify it reproduces exactly--making peripheral nerve stimulation models easier to build, share, and trust.

bioengineering↗

The p-rpS6-zone delineates wounding response and the healing process

It is unknown what the spatial boundaries of tissue response to wounding are. Here we show that in mammals the ribosomal protein S6 (rpS6) is phosphorylated in response to skin injury forming a zone of activation surrounding the region of the initial insult. This p-rpS6-zone forms within minutes after wounding and is present until healing is complete. The zone encapsulates markers of the healing process, including proliferation, senescence, and angiogenesis in wounded skin. A mouse model unable to phosphorylate rpS6 shows an initial acceleration of wound closure, but results in disrupted healing. Finally, the p-rpS6-zone accurately reports on the status of dermal vasculature and the effectiveness of healing. In summary, the zone divides an otherwise homogenous tissue into regions with distinct properties.

physiology↗

MicroRNA levels in bone and blood change during bisphosphonate and teriparatide therapy in an animal model of postmenopausal osteoporosis

MicroRNAs control the activity of a variety of genes that are pivotal to bone metabolism. Therefore, the clinical utility of miRNAs as biomarkers and drug targets for bone diseases certainly merits further investigation. This study describes the use of an animal model of postmenopausal osteoporosis to generate a comprehensive dataset on miRNA regulation in bone tissue and peripheral blood during bone loss and specifically anti-resorptive and osteo-anabolic treatment.\n\nForty-two Sprague-Dawley rats were randomized to SHAM surgery (n=10) or ovariectomy (OVX, n=32). Eight weeks after surgery, OVX animals were further randomized to anti-resorptive treatment with zoledronate (n=11), osteo-anabolic treatment with teriparatide (n=11), or vehicle treatment (n=10). After 12 weeks of treatment, bone and serum samples were used for microRNA analysis using next-generation sequencing (NGS), mRNA levels using RT-qPCR, and bone microarchitecture analysis using nanoCT.\n\nOvariectomy resulted in loss of trabecular bone, which was fully rescued using osteo-anabolic treatment, and partially rescued using anti-resorptive treatment. NGS revealed that both, anti-resorptive and anabolic treatment had a significant impact on miRNA levels in bone tissue and serum: out of 426 detected miRNAs, 46 miRNAs were regulated by teriparatide treatment an d 10 by zoledronate treatment (p-adj. < 0.1). Interestingly, teriparatide and zoledronate treatment were able to revert miRNA changes in tissue and serum of untreated OVX animals, such as the up-regulation of miR-203a-3p, a known osteo-inhibitory miRNA. We confirmed previously established mechanisms of miR-203a by analyzing its direct target Dlx5 in femoral head.\n\nOur data reveal a significant effect of ovariectomy-induced bone loss, as well as the two major types of anti-osteoporotic treatment on miRNA transcription in femoral head tissue. These changes are associated with altered activity of target genes relevant to bone formation, such as Dlx5. The observed effects of bone loss and treatment response on miRNA levels in bone are also reflected in the peripheral blood, suggesting the possibility of minimally-invasive monitoring of bone-derived miRNAs using liquid biopsies.\n\nHighlightsO_LImicroRNA expression in bone tissue is altered by osteo-anabolic and anti-resorptive therapy in OVX rats.\nC_LIO_LImicroRNA changes in untreated OVX rats are reverted by anti-osteoporotic therapy.\nC_LIO_LImiR-203a is up-regulated during bone loss and down-regulated following therapy.\nC_LIO_LIBone tissue and serum levels of miR-203a are highly correlated.\nC_LI

molecular biology↗

Iodine-enhanced micro-CT imaging of soft tissue on the example of peripheral nerve regeneration

Microcomputed tomography (CT) is widely used for the study of mineralized tissues but a similar use for soft tissues is hindered by their low X-ray attenuation. This limitation can be overcome by the recent development of different staining techniques. Staining with Lugols solution, a mixture of one part iodine and two parts potassium iodide in water, stands out among these techniques for its low complexity and cost. Currently, Lugol staining is mostly used for anatomical examination of tissues. In the present study we seek to optimize the quality and reproducibility of the staining for ex vivo visualization of soft tissues in the context of a peripheral nerve regeneration model in the rat. We show that the staining result not only depends on the concentration of the staining solution, but also on the amount of stain in relation to the tissue volume and composition, necessitating careful adaptation of the staining protocol to the respective specimen tissue. This optimization can be simplified by a stepwise staining which we show to yield a similar result compared to staining in a single step. Lugol staining solution results in concentration dependent tissue shrinkage which can be minimized but not eliminated. We compared the shrinkage of tendon, nerve, skeletal muscle, heart, brain and kidney with six iterations of Lugol staining. 60 ml of 0.3% Lugols solution per cm3 of tissue for 24h yielded good results on the example of a peripheral nerve regeneration model and we were able to show that the regenerating nerve inside a silk fibroin tube can be visualized in 3D using this staining technique. This information helps in deciding the region of interest for histological imaging and provides a 3D context to histological findings. Correlating both imaging modalities has the potential to improve the understanding of the regenerative process.

neuroscience↗