Recent advancements in neuroimaging involve the development of a novel electrocorticography (ECoG) grid. This grid is crafted using a polymer-thick film on an organic substrate (PTFOS), a design that offers several significant improvements over conventional ECoG grids, including Reduced Imaging Artifacts: The PTFOS grid produces negligible artifacts on MR images image quality of brain tissue overlaid with PTFOS grids. Lower Temperature Increase During MRI: In a 30-minute MR imaging session, temperature increases with the PTFOS grid were extremely low (0.4°C). These findings suggest that electrocorticography obtained using PTFOS grids could potentially improve the safety and efficacy of neurosurgical procedures, offering clearer imaging results and reducing risk factors such as excessive heating during MRIs.

We introduce our innovative HF-2 technology that integrates intracranial recordings with magnetic resonance imaging (MRI) for preclinical research. This system enhances our capabilities to simultaneously record signals from electrocortical (ECoG) called Polymer Thick Film Organic Substrate (PTFOS) [1, 2] electrodes, alongside acquiring functional MRI (fMRI) data in animal subjects. Such concurrent ECoG and fMRI recordings offer an unmatched perspective on the comprehensive network activities across cortical areas in animal models, thereby deepening our understanding of neural organization. Simultaneous ECoG/depth/fMRI is particularly transformative, providing insights into functional connectivity and oscillatory properties at both high temporal and spatial resolutions [3]. This multimodal approach is crucial for advancing research in numerous areas of neuroscience and medicine, offering detailed insights into the brain’s functional architecture.

Trans-Spinal Magnetic Stimulation (TSMS) is gaining attention in medical research as a promising, non-invasive alternative to conventional treatments for refractory chronic neuropathic back pain, such as spinal cord stimulation (SCS) [1–2]. Through a time-varying magnetic field, TSMS delivers electrical pulses to the spinal cord through a coil positioned on the patient’s back. The stimulation must be focal and penetrate deeply enough to reach the spinal cord, which may vary in depth depending on the individual [3]. The various commercial TSMS coils are built by winding metal wires with different numbers of turns, which affect the inductance of the coil. The winding wire diameter may be increased to allow for larger currents and increase the magnetic field, $\mathbf{B}$, more profoundly in the tissue. In that case, the coil diameter tends to increase (Fig. 1A), and there may be a loss of focality and, consequently, a lower fiber selectivity.

Neuromodulation with a high spatial and directional specificity is highly desired but very challenging to achieve using electrode-based electrical stimulation. Microscopic magnetic stimulation, eliciting neural elements via induced eddy current, is a promising alternative as it is able to modulate neurons with unprecedented focality and directionality. Moreover, thanks to advanced microfabrication technology, it is possible to fabricate a micrometer-sized coil (i.e., micro-coil) array on a compliant substrate as an implant for long-term neuromodulation. Here we present our design and fabrication of an implantable planar micro-coil chip, consisting of an array of ten spiral-shaped micro-coils in a figure-8 configuration. The fabricated micro-coil array showed high consistency and reproducibility in impedance measurement, with a resistance range of about 10-20 Ω, and inductance of about 30 nH. We demonstrated the feasibility of micro-magnetic stimulation in rodent experiments, by using the fabricated chip on the sciatic nerve of an anesthetized rat, while measuring the elicited neuromuscular (EMG) responses which suggests the high focality of the micromagnetic stimulation system.

Imaging tools for kidney inflammation could improve care for patients suffering inflammatory kidney diseases by lessening reliance on percutaneous biopsy or biochemical tests alone. During kidney inflammation, infiltration of myeloid immune cells generates a kidney microenvironment that is oxidizing relative to normal kidney. Here, we evaluated whether magnetic resonance imaging (MRI) using the redox-active iron (Fe) complex Fe-PyC3A as an oxidatively activated probe could serve as a marker of kidney inflammation using mouse models of unilateral ischemia-reperfusion injury (IRI) and lupus nephritis (MRL-lpr mice). We imaged unilateral IRI in gp91phox knockout mice, which are deficient in the nicotinamide oxidase II (NOX2) enzyme required for myeloid oxidative burst, as loss of function control, and imaged MRL/MpJ mice as non-kidney involved lupus control. Gadoterate meglumine was used as a non-oxidatively activated control MRI probe. Fe-PyC3A safety was preliminarily examined following a single acute dose. Fe-PyC3A generated significantly greater MRI signal enhancement in the IRI kidney compared to the contralateral kidney in wild-type mice, but the effect was not observed in the NOX2-deficient control. Fe-PyC3A also generated significantly greater kidney enhancement in MRL-lpr mice compared to MRL/MpJ control. Gadoterate meglumine did not differentially enhance the IRI kidney over the contralateral kidney and did not differentially enhance the kidneys of MRL-lpr over MRL/MpJ mice. Fe-PyC3A was well tolerated at the highest dose evaluated, which was a 40-fold greater than required for imaging. Thus, our data indicate that MRI using Fe-PyC3A is specific to an oxidizing kidney environment shaped by activity of myeloid immune cells and support further evaluation of Fe-PyC3A for imaging kidney inflammation.

Trans-Spinal Magnetic Stimulation (TSMS) is emerging as a promising, low-risk, non-invasive alternative to spinal cord stimulation (SCS) in treating refractory chronic neuropathic back and leg pain. TSMS entails the generation of electrical pulses using a magnetic field produced by a coil positioned on the patient’s skin, obviating the need for surgical intervention. Clinical research and trials are continuously needed to assess the effectiveness of TSMS and its potential as a noninvasive option for managing chronic pain.We developed a non-invasive coil allowing for focal TSMS stimulation. The device is based on a new figure-8 ribbon design, ensuring low resistance (R 0 ) and low heating. A system for high-frequency (HF) TSMS pulses (i.e., f=10kHz) was also developed to drive the proposed coil. The coil design was investigated and preliminary tested using the finite element method (FEM) and numerical simulations. Its feasibility was then assessed on rodent experiments using peripheral (i.e., electromyographic-EMG) and central (i.e., brain fMRI) responses to stimulation as endpoints.Numerical simulations showed that action potentials can be generated by TSMS in the peripheral nerves when the coil is driven with high currents (e.g., 10kA). Experimental results revealed that stimulation can penetrate the tissue deeply, reaching the spinal cord and evoking a peripheral nerve response. Changes in the activity of brain areas associated with chronic pain during stimulation were also observed with fMRI.

Electrocorticography (ECoG) is a critical tool in preclinical neuroscience research for studying global network activity. However, integrating ECoG with functional magnetic resonance imaging (fMRI) has posed challenges, due to metal electrode interference with imaging quality and heating around the metallic electrodes. Here, we introduce recent advancements in ECoG grid development that utilize a polymer-thick film on an organic substrate (PTFOS). PTFOS offers notable advantages over traditional ECoG grids. Firstly, it significantly reduces imaging artifacts, ensuring minimal interference with MR image quality when overlaying brain tissue with PTFOS grids. Secondly, during a 30-min fMRI acquisition, the temperature increase associated with PTFOS grids is remarkably low, measuring only 0.4 °C. These findings suggest that utilizing ECoG with PTFOS grids has the potential to enhance the safety and efficacy of neurosurgical procedures. By providing clearer imaging results and mitigating risk factors such as excessive heating during MRI scans, PTFOS-based ECoG grids represent a promising advancement in neurosurgical technology. Furthermore, we describe a cutting-edge open-source system designed for simultaneous electrophysiology and fMRI. This system stands out due to its exceptionally low input noise levels (<0.6 V peak-to-peak), robust electromagnetic compatibility (it is suitable for use in MRI environments up to 9.4 teslas), and the inclusion of user-programmable real-time signal-processing capabilities. The open-platform software is a key feature, enabling researchers to swiftly implement and customize real-time signal-processing algorithms to meet specific experimental needs. This innovative system has been successfully utilized in several rodent EEG/fMRI studies, particularly at magnetic field strengths of 4.7 and 9.4 teslas, focusing on the somatosensory system. These studies have allowed for detailed observation of neural activity and responses within this sensory system, providing insights that are critical for advancing our understanding of neurophysiological processes. The versatility and high performance of our system make it an invaluable tool for researchers aiming to integrate and analyze complex datasets from advanced imaging and electrophysiological recordings, ultimately enhancing the depth and scope of neuroscience research.

BACKGROUND:Diagnosing and monitoring kidney diseases traditionally rely on blood and urine analyses and invasive procedures such as kidney biopsies, the latter offering limited possibilities for longitudinal monitoring and a comprehensive understanding of disease dynamics. Current noninvasive methods lack specificity in capturing intrarenal molecular processes, hindering patient stratification and patient monitoring in clinical practice and clinical trials. SUMMARY:Molecular imaging enables noninvasive and quantitative assessment of physiological and pathological molecular processes. By using specific molecular probes and imaging technologies, e.g., magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, or ultrasound, molecular imaging allows the detection and longitudinal monitoring of disease activity with spatial and temporal resolution of different kidney diseases and disease-specific pathways. Several approaches have already shown promising results in kidneys and exploratory clinical studies, and validation is needed before implementation in clinical practice. KEY MESSAGES:Molecular imaging offers a noninvasive assessment of intrarenal molecular processes, overcoming the limitations of current diagnostic methods. It has the potential to serve as companion diagnostics, not only in clinical trials, aiding in patient stratification and treatment response assessment. By guiding therapeutic interventions, molecular imaging might contribute to the development of targeted therapies for kidney diseases.

Background Gadolinium retention has been observed in organs of patients with normal renal function; however, the biodistribution and speciation of residual gadolinium is not well understood. Purpose To compare the pharmacokinetics, distribution, and speciation of four gadolinium-based contrast agents (GBCAs) in healthy rats using MRI, mass spectrometry, elemental imaging, and electron paramagnetic resonance (EPR) spectroscopy. Materials and Methods In this prospective animal study performed between November 2021 and September 2022, 32 rats received a dose of gadoterate, gadoteridol, gadobutrol, or gadobenate (2.0 mmol/kg) for 10 consecutive days. GBCA-naive rats were used as controls. Three-dimensional T1-weighted ultrashort echo time images and R2* maps of the kidneys were acquired at 3, 17, 34, and 52 days after injection. At 17 and 52 days after injection, gadolinium concentrations in 23 organ, tissue, and fluid specimens were measured with mass spectrometry; gadolinium distribution in the kidneys was evaluated using elemental imaging; and gadolinium speciation in the kidney cortex was assessed using EPR spectroscopy. Data were assessed with analysis of variance, Kruskal-Wallis test, analysis of response profiles, and Pearson correlation analysis. Results For all GBCAs, the kidney cortex exhibited higher gadolinium retention at 17 days after injection than all other specimens tested (mean range, 350-1720 nmol/g vs 0.40-401 nmol/g; P value range, .001-.70), with gadoteridol showing the lowest level of retention. Renal cortex R2* values correlated with gadolinium concentrations measured ex vivo (r = 0.95; P < .001), whereas no associations were found between T1-weighted signal intensity and ex vivo gadolinium concentration (r = 0.38; P = .10). EPR spectroscopy analysis of rat kidney cortex samples showed that all GBCAs were primarily intact at 52 days after injection. Conclusion Compared with other macrocyclic GBCAs, gadoteridol administration led to the lowest level of retention. The highest concentration of gadolinium was retained in the kidney cortex, but T1-weighted MRI was not sensitive for detecting residual gadolinium in this tissue. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Tweedle in this issue.

During fibroproliferation, protein-associated extracellular aldehydes are formed by the oxidation of lysine residues on extracellular matrix proteins to form the aldehyde allysine. Here we report three Mn(II)-based, small molecule magnetic resonance (MR) probes that contain α-effect nucleophiles to target allysine in vivo and report on tissue fibrogenesis. We used a rational design approach to develop turn-on probes with a 4-fold increase in relaxivity upon targeting. The effects of aldehyde condensation rate and hydrolysis kinetics on the performance of the probes to detect tissue fibrogenesis noninvasively in mouse models were evaluated by a systemic aldehyde tracking approach. We showed that for highly reversible ligations, off-rate was a stronger predictor of in vivo efficiency, enabling histologically validated, three-dimensional characterization of pulmonary fibrogenesis throughout the entire lung. The exclusive renal elimination of these probes allowed for rapid imaging of liver fibrosis. Reducing the hydrolysis rate by forming an oxime bond with allysine enabled delayed phase imaging of kidney fibrogenesis. The imaging efficacy of these probes, coupled with their rapid and complete elimination from the body, make them strong candidates for clinical translation.

Background In most CKDs, lysyl oxidase oxidation of collagen forms allysine side chains, which then form stable crosslinks. We hypothesized that MRI with the allysine-targeted probe Gd-oxyamine (OA) could be used to measure this process and noninvasively detect renal fibrosis. Methods Two mouse models were used: hereditary nephritis in Col4a3-deficient mice (Alport model) and a glomerulonephritis model, nephrotoxic nephritis (NTN). MRI measured the difference in kidney relaxation rate, ΔR1, after intravenous Gd-OA administration. Renal tissue was collected for biochemical and histological analysis. Results ΔR1 was increased in the renal cortex of NTN mice and in both the cortex and the medulla of Alport mice. Ex vivo tissue analyses showed increased collagen and Gd-OA levels in fibrotic renal tissues and a high correlation between tissue collagen and ΔR1. Conclusions Magnetic resonance imaging using Gd-OA is potentially a valuable tool for detecting and staging renal fibrogenesis.

We propose a non-invasive Trans Spinal Magnetic Stimulation (TSMS) coil allowing for focal stimulation. The device is based on a new figure-8 ribbon design, ensuring low R0, and low heating. The two coils were designed and studied using the finite element method (FEM) coupled with NEURON and tested for efficacy on rats. The numerical simulations confirmed the generation of the observed action potentials when the coil was driven with 2.8kA.Clinical Relevance— Chronic neuropathic back and leg pain is one of the main indications for spinal cord stimulation in the United States. Chronic low back pain is one of the most common reasons patients seek medical care, and in 2013 resulted in 87.6 billion dollars in healthcare costs in the USA. Patients would most likely prefer a low-risk, non-invasive procedure, such as TSMS, to surgery with a significant rate of complications.

Purpose Idiopathic pulmonary fibrosis (IPF) is a destructive lung disease with a poor prognosis, an unpredictable clinical course, and inadequate therapies. There are currently no measures of disease activity to guide clinicians making treatment decisions. The aim of this study was to develop a PET probe to identify lung fibrogenesis using a pre-clinical model of pulmonary fibrosis, with potential for translation into clinical use to predict disease progression and inform treatment decisions. Methods Eight novel allysine-targeting chelators, PIF-1, PIF-2, …, PIF-8, with different aldehyde-reactive moieties were designed, synthesized, and radiolabeled with gallium-68 or copper-64. PET probe performance was assessed in C57BL/6J male mice 2 weeks after intratracheal bleomycin challenge and in naïve mice by dynamic PET/MR imaging and with biodistribution at 90 min post injection. Lung hydroxyproline and allysine were quantified ex vivo and histological staining for fibrosis and aldehyde was performed. Results In vivo screening of probes identified 68 GaPIF-3 and 68 GaPIF-7 as probes with high uptake in injured lung, high uptake in injured lung versus normal lung, and high uptake in injured lung versus adjacent liver and heart tissue. A crossover, intra-animal PET/MR imaging study of 68 GaPIF-3 and 68 GaPIF-7 confirmed 68 GaPIF-7 as the superior probe. Specificity for fibrogenesis was confirmed in a crossover, intra-animal PET/MR imaging study with 68 GaPIF-7 and a non-binding control compound, 68 GaPIF-Ctrl. Substituting copper-64 for gallium-68 did not affect lung uptake or specificity indicating that either isotope could be used. Conclusion A series of allysine-reactive PET probes with variations in the aldehyde-reactive moiety were evaluated in a pre-clinical model of lung fibrosis. The hydrazine-bearing probe, 68 GaPIF-7, exhibited the highest uptake in fibrogenic lung, low uptake in surrounding liver or heart tissue, and low lung uptake in healthy mice and should be considered for further clinical translation.

Electrical stimulation of the cervical vagus nerve is an emerging treatment field for various central nervous system disorders. Invasive electrical Vagus nerve stimulation (VNS) is an FDA-approved add-on treatment to medication for refractory partial-onset seizures in patients 12 years of age and older. However, only approximately 40-50% of patients experience a marked seizure reduction of 50% or more than seizures before treatment [1]. The effects of VNS on neurotransmitter systems, including the noradrenergic system originating from the locus coeruleus and the serotonergic system from the dorsal raphe nucleus, have been reported in experimental settings. The therapeutic effect of VNS in the brain is linked to the stimulation of large diameter afferent fibers. These large myelinated afferent fibers, terminating in the nucleus tractus solitarius in the brainstem, are assumed to deliver the therapeutic effect through further projections into the other brain areas. Non-selective stimulation results in inadvertent activation of efferent fibers that innervate a wide range of peripheral organs resulting in adverse effects [2] with a rare but severe risk of bradyarrhythmia and asystole.

Background: Non-invasive vagus nerve stimulation (nVNS) using a hand-held stimulator placed on the neck is an FDA-approved treatment for primary headache disorders. The safety of nVNS is unknown in stroke patients. Objective: To assess the safety and feasibility of nVNS for the acute treatment of stroke. Methods: TR-VENUS (clinicaltrials.gov identifier NCT03733431) was a randomized, sham-controlled, open-label, multicenter trial conducted in patients with acute ischemic stroke (IS) or intracerebral hemorrhage (ICH). Patients were randomly assigned to standard-dose nVNS, high-dose nVNS, or sham stimulation. The primary endpoint was a composite safety outcome defined as bradycardia or reduction in mean arterial blood pressure during treatment or progression of neurological or death within 24 h of treatment. The feasibility endpoints were the proportion of eligible subjects receiving nVNS within 6 h of symptom onset and the proportion completing all pre-specified treatment doses. Efficacy assessments included infarct growth from baseline to 24 h after treatment. Results: Sixty-nine patients (61 IS, 8 ICH) completed the study. The composite safety outcome was achieved in 32.0% in sham and 47.7% in nVNS group (p = 0.203). Treatment was initiated in all but two randomized patients. All dosed subjects received 100% of prespecified stimulations. A non-significant reduction in infarct growth was observed in the high-dose nVNS group (184.2% in sham vs. 63.3% in high-dose nVNS; p = 0.109). Conclusions: The results of this study suggest that nVNS may be safe and feasible in the setting of acute stroke. These findings support further development of nVNS as a potential treatment for acute ischemic stroke. (c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Introduction: Non-invasive vagus nerve stimulation (nVNS) reduces infarct volume after transient ischemia in rats. Here, we tested the effect of nVNS in intracerebral hemorrhage (ICH) and permanent ischemic brain injury models. Methods: ICH was induced by whole blood (n=24) or collagenase (n=24) injection into the striatum of adult male and female Wistar rats. 1-hour sham stimulation (n=16) or nVNS (n=32) was initiated 30 minutes after injection. Spontaneous circling, hindlimb retraction, and grasp ability were tested at 24 hours to measure functional deficit. Rats were euthanized 24 hours or one week after injury, and brain tissue was processed for water content analysis (n=24) and histology (n=24), respectively. Permanent ischemia was induced by filament occlusion of the right middle cerebral artery in adult male Wistar rats (n=18). Sham stimulation and nVNS initiated 30 minutes after the induction of ischemia were applied for 1 hour and 3 hours (n=6 per group). Rats were euthanized 24 hours later to measure infarct volume. Results: 1-hour nVNS was associated with a non-significant reduction in hematoma volume in both models of ICH (Fig). Animals treated with nVNS demonstrated better functional outcome at 24 hours after ICH ( p =0.042). There was no difference in brain edema between control and active treatment arms in both models of ICH. 3-hour nVNS reduced infarct volume by 21% in permanent ischemia ( p =0.047, Fig). Conclusion: The results of this study support prior evidence that nVNS may have a therapeutic potential in ischemic stroke. nVNS is currently being evaluated in two clinical studies (NCT03733431 and NCT04050501) for the treatment of acute ischemic stroke. The lack of adverse events in two different models of ICH in this study suggests that nVNS could be safely administered as early as an ambulatory setting before the stroke etiology (ischemic vs. hemorrhagic) has been determined.

Background: This first-in-human randomized, blinded, sham-controlled, multicenter study assessed the safety and feasibility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of ischemic and hemorrhagic stroke. Potential efficacy was also assessed. Methods: Eligible participants admitted to nine clinical sites received standard care for acute stroke and were randomly assigned to low-dose nVNS, sham (2-minute stimulation applied to the skin overlying the vagus nerve every 10 minutes for an hour; 7 stimulations) or high-dose nVNS (2-minute stimulation every 10 minutes during hour 1 and hour 5; 14 stimulations) within 6 hours of stroke onset. Safety endpoints included severe bradycardia (≤50 beats/min) or significant hypotension (≥20-mm Hg reduction in arterial blood pressure) evaluated at 2 and 5 minutes after each stimulation and 30 minutes after the final stimulation. Feasibility was measured as the proportion of eligible patients in whom nVNS could be initiated within 6 hours of stroke onset and the ability to deliver scheduled stimulations per protocol. Efficacy measurements included absolute and relative infarct growth 24 hours poststroke compared to baseline and the proportion of patients with an NIH Stroke Scale (NIHSS) score of ≤4 or a ≥8-point improvement at 24 hours. Results: Sixty-eight patients with ischemic (n=60) or hemorrhagic (n=8) stroke completed the study. Baseline characteristics did not differ between sham (n=24) and nVNS (n=44). No significant bradycardia (2.9% of sham vs 3.1% of nVNS; p =0.965) or hypotension (1.1% of sham vs 2.5% of nVNS; p =0.145) occurred with nVNS. No deaths, acute coronary syndrome, symptomatic intracerebral hemorrhage, or stimulation site reactions were noted. All patients received 100% of intended stimulations per protocol. Clinical efficacy measures were similar between sham and total nVNS. Relative infarct growth, measured by diffusion weighted imaging, in the high dose nVNS group (63.3%) was lower than in the sham group (185.8%; p =0.05). Conclusions: This study suggests that nVNS is safe and feasible for the acute treatment for ischemic and hemorrhagic stroke. Possible efficacy is suggested by a decrease in relative infarct growth.

This study evaluated the effects of non-invasive vagus nerve stimulation (nVNS) on intracerebral hemorrhage (ICH) and permanent ischemic brain injury models.