Biology subjects

Iacoviello, F.

Publications and source records attributed to Iacoviello, F..

7 recordsLinked to original sources

bioRxiv2024

Anatomical and functional organization of cardiac fibers in the porcine cervical vagus nerve allows spatially selective efferent neuromodulation

Cardiac disease progression reflects the dynamic interaction between adversely remodeled neurohumoral control systems and an abnormal cardiac substrate. Vagal nerve stimulation (VNS) is an attractive neuromodulatory option to dampen this dynamic interaction; however, it is limited by off-target effects. Spatially-selective VNS (sVNS) offers a promising solution to induce cardioprotection while mitigating off-target effects by specifically targeting pre-ganglionic parasympathetic efferent cardiac fibers. This approach also has the potential to enhance therapeutic outcomes by eliminating time-consuming titration required for optimal VNS. Recent studies have demonstrated the independent modulation of breathing rate, heart rate, and laryngeal contraction through sVNS. However, the spatial organization of afferent and efferent cardiac-related fibers within the vagus nerve remains unexplored. By using trial-and-error sVNS in vivo in combination with ex vivo micro-computed tomography fascicle tracing, we show the significant spatial separation of cardiac afferent and efferent fibers (179{+/-}55{degrees} SD microCT, p<0.05 and 200{+/-}137{degrees} SD, p<0.05 sVNS - degrees of separation across a cross-section of nerve) at the mid-cervical level. We also show that cardiac afferent fibers are located in proximity to pulmonary fibers consistent with recent findings of cardiopulmonary convergent neurons and circuits. We demonstrate the ability of sVNS to selectively elicit desired scalable heart rate decrease without stimulating afferent-related reflexes. By elucidating the spatial organization of cardiac-related fibers within the vagus nerve, our findings pave the way for more targeted neuromodulation, thereby reducing off-target effects and eliminating the need for titration. This, in turn, will enhance the precision and efficacy of VNS therapy in treating cardiac pathology, allowing for improved therapeutic efficacy. Condensed AbstractSpatially-selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart disease with enhanced precision. Our study reveals significant spatial separation between cardiac afferent and efferent fibers in the vagus nerve, particularly at the mid-cervical level. Utilizing trial-and-error sVNS in vivo and micro-computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects like scalable heart rate decrease without stimulating afferent-related reflexes. This spatial understanding opens avenues for more effective VNS therapy, minimizing off-target effects and eliminating the need for titration, thereby expediting therapeutic outcomes in myocardial infarction and related conditions. TweetWith functional and structural imaging, we found organization of vagal efferent & afferent cardiac regions. We can selectively activate only cardiac efferents to achieve bradycardia; desired to reduce the effects of sympathetic overactivation associated with heart disease #VNS #Cardiac #VagusNerve Key PointsO_LISpatially-selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart disease with enhanced precision. C_LIO_LIOur study reveals significant spatial separation between cardiac afferent and efferent fibers in the vagus nerve, particularly at the mid-cervical level. C_LIO_LIUtilizing trial-and-error sVNS in vivo and micro-computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects like scalable heart rate decrease without stimulating afferent-related reflexes. C_LIO_LIThis spatial understanding opens avenues for more effective VNS therapy, minimizing off-target effects and eliminating the need for titration, thereby expediting therapeutic outcomes in myocardial infarction and related conditions. C_LI

neuroscience↗

bioRxiv2023

Human vagus nerve fascicular anatomy: a microCT segmentation and histological study

BackgroundPrevious research has revealed the logical mapping of fascicles in both human somatic and pig vagus nerves, but the organization of fascicles within the human vagus nerve remains largely unknown. Understanding its fascicular arrangement would significantly advance our knowledge of the autonomic nervous system and facilitate studies and application of selective vagus nerve stimulation to avoid off-target effects. The purpose of this study was to trace the thoracic branches of human vagus nerves, investigate their fascicular organization, and analyze the nerves histologically and morphologically. MethodsBoth left and right vagus nerves were dissected from human cadavers, preserving the cardiac, recurrent laryngeal, and pulmonary branches. The nerves were prepared, scanned using microCT, and the fascicles segmented and traced from their branching points. Histology and immunohistochemistry were performed for morphological analysis and validation of the microCT segmentation. The data was then analyzed and compared between nerves. ResultsThe organization of the cardiac, pulmonary, and recurrent laryngeal fascicles was observed for a short distance from their entry point into the nerves. Initially, left vagus nerves showed merging of cardiac and pulmonary fascicles, while the recurrent laryngeal fascicles remained separate. In right vagus nerves, the cardiac fascicles merged with both pulmonary and recurrent laryngeal fascicles. MicroCT imaging limitations prevented visualization and tracing of fiber organization within merged fascicles. Immunohistochemistry and morphological analysis revealed that right vagus nerves were larger and had more fascicles than the left and fascicle counts varied along the nerve, indicating anastomoses. The superior cardiac branch was separate from other fascicles near the VNS cuff placement. ConclusionsIt is possible that organ-specific fibers may still retain some spatial organization despite most fascicles being merged at cervical level. However, fiber tracing and in vivo studies could provide valuable information beyond microCT to resolve this further. The separate superior cardiac fascicles offer potential for targeted neuromodulation of the heart, benefiting conditions like myocardial infarction, heart failure, and atrial fibrillation. Overall, the study provides insights into the morphology and anatomy of human vagus nerves. Our findings thereby contribute to the development of selective vagus nerve stimulation strategies for more precise autonomic regulation.

neuroscience↗

bioRxiv2022

Organotopic organisation of the cervical vagus nerve

Despite detailed characterization of fascicular organization of somatic nerves, the functional anatomy of fascicles evident in human and large mammal cervical vagus nerve is unknown. The vagus nerve is a prime target for intervention in the field of electroceuticals due to its extensive distribution to the heart, larynx, lungs, and abdominal viscera. However, current practice of the approved vagus nerve stimulation (VNS) technique is to stimulate the entire nerve. This produces indiscriminate stimulation of non-targeted effectors and undesired side effects. Selective neuromodulation is now a possibility with a spatially-selective vagal nerve cuff. However, this requires the knowledge of the fascicular organization at the level of cuff placement to inform selectivity of only the desired target organ or function. We imaged function over milliseconds with fast neural electrical impedance tomography and selective stimulation, and found consistent spatially separated regions within the nerve correlating with the three fascicular groups of interest, suggesting organotopy. This was independently verified with structural imaging by tracing anatomical connections from the end organ with microCT and the development of an anatomical map of the vagus nerve. This confirmed organotopic organization. Here we show, for the first time, localized fascicles in the porcine cervical vagus nerve which map to cardiac, pulmonary and recurrent laryngeal function (N=4). These findings pave the way for improved outcomes in VNS as unwanted side effects could be reduced by targeted selective stimulation of identified organ-specific fascicles and the extension of this technique clinically beyond the currently approved disorders to treat heart failure, chronic inflammatory disorders and more.

neuroscience↗

bioRxiv2022

Time-dependent Role of Bisphosphonates on Atherosclerotic Plaque Calcification

Atherosclerotic plaque calcification directly contributes to the leading cause of morbidity and mortality by affecting the plaque vulnerability and rupture risk. Small microcalcifications can increase plaque stress and promote rupture, whereas large calcifications can stabilize plaques. Drugs that target bone mineralization may lead to unintended consequences on ectopic plaque calcification and cardiovascular outcomes. Bisphosphonates, common anti-osteoporotic agents, elicited unexpected cardiovascular events in clinical trials. Here, we investigated the role of bisphosphonates treatment and timing on the disruption or promotion of vascular calcification and bone mineral in a mouse model of atherosclerosis. We started the bisphosphonate treatment either before plaque formation, at early plaque formation times associated with the onset of calcification, or at late stages of plaque development. Our data indicate that long term bisphosphonate treatment (beginning prior to plaque development) leads to higher levels of plaque calcification, with a narrower mineral size distribution. When given later in plaque development, we measured a wider distribution of mineral size. These morphological alterations may associate with higher risk of plaque rupture by creating stress foci. Yet, bone mineral density positively correlated with the duration of bisphosphonate treatment.

bioengineering↗

bioRxiv2021

Epidermal Growth Factor Receptor Inhibition Prevents Caveolin-1-dependent Calcifying Extracellular Vesicle Biogenesis

Chronic kidney disease (CKD) increases the risk of cardiovascular disease, including vascular calcification, leading to higher mortality. Release of calcifying extracellular vesicles (EVs) by vascular smooth muscle cells (VSMCs) promotes the ectopic mineralization of vessel walls. Caveolin-1 (CAV1) protein plays a key role in genesis of calcifying EVs in VSMCs. Epidermal growth factor receptor (EGFR) co-localizes with and influences the intracellular trafficking of CAV1. Using a diet-induced mouse model of CKD, we measured serum EGFR and assessed the potential of EGFR inhibition to prevent vascular calcification. Mice with CKD developed widespread vascular calcification, which associated with increased serum levels of EGFR. We computationally analyzed 7651 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) and Framingham cohorts to assess potential correlations between coronary artery calcium and single nucleotide polymorphisms (SNPs) associated with elevated serum levels of EGFR. Individuals in the MESA and Framingham cohorts with SNPs associated with increased serum EGFR exhibit elevated coronary artery calcium. In both the CKD mice and human VSMC culture, EGFR inhibition significantly reduced vascular calcification by mitigating the release of CAV1-positive calcifying EVs. EGFR inhibition also increased bone mineral density in CKD mice. Given that EGFR inhibitors exhibit clinical safety and efficacy in other pathologies, the current data suggest that EGFR may be an ideal target to prevent pathological vascular calcification.

pathology↗

bioRxiv2020

Imaging fascicular organization of peripheral nerves with fast neural Electrical Impedance Tomography (EIT)

Imaging of the compound action potential (CAP) in fascicles in peripheral nerves could help avoid side effects in neuromodulation by selective stimulation of identified fascicles. Existing methods have low resolution, limited imaging depth, or are invasive. We propose fast neural electrical impedance tomography (EIT), which allows fascicular CAP imaging with a high resolution of [~]200 m, <1 ms. This uses a non-penetrating flexible cuff electrode array with 14 circumferential electrodes. This has been validated in rat sciatic nerve by comparison to micro-computed tomography (microCT) and histology with fluorescent dextran tracers (n=5). With EIT, there were reproducible localized changes in tissue impedance in response to stimulation of individual fascicles (tibial, peroneal and sural). The reconstructed EIT images corresponded to microCT scans and neural tracer histology, with significant separation between the fascicles (p<0.01), and no significant difference between techniques. The standard deviation from the mean fascicle position for EIT was 86 m (6% of nerve diameter). This suggests fast neural EIT can reliably image the functional fascicular anatomy of the nerves and so aid selective neuromodulation.

bioengineering↗

bioRxiv2019

MicroCT optimisation for imaging fascicular anatomy in peripheral nerves

Vagus nerve stimulation (VNS) is a promising therapy for treatment of various conditions resistant to standard therapeutics. However, due to the lack of understanding of the fascicular organisation of the vagus nerve, VNS leads to unwanted off-target effects. Micro-computed tomography (microCT) can be used to trace fascicles from periphery and image fascicular anatomy. In this work we optimised the microCT protocol of the rat sciatic and subsequent pig vagus nerves.\n\nAfter differential staining, the optimal staining time was selected and scanning parameters were altered in subsequent scans. Scans were reconstructed, visualised in ImageJ and fascicles segmented with a custom algorithm in Matlab to determine ultimate parameters for tracking of the nerve. Successful segmentation for tracking of individual fascicles was achieved after 24 hours and 120 hours of staining with Lugols solution (1% total iodine) for rat sciatic and pig vagus nerves, respectively, and the following scanning parameters: 4 {micro}m voxel size, 35 kVp energy, 114 {micro}A current, 4 W power, 0.25 fps in 4 s exposure time, 3176 projections and a molybdenum target.\n\nThe optimised microCT protocol allows for segmentation and tracking of the fascicles within the nerve. This will be used to scan the full length of the pig, and possibly, the human vagus nerves. The resulting segmentation map of the functional anatomical organisation of the vagus nerve will enable selective VNS ultimately allowing for the avoidance of the off-target effects and improving its therapeutic efficacy.

neuroscience↗