Small Animal Magnetic Resonance Imaging Research Articles

Potential treatment approaches for malignant peritoneal mesothelioma: in vivo and in vitro experimental study of natural killer cell immunotherapy.

Malignant peritoneal mesothelioma (MPM) is a rare primary malignant tumor with an extremely poor prognosis that currently lacks effective treatment options. This study investigated the in vitro and in vivo efficacy of natural killer (NK) cells for treatment of MPM. An in vitro study was conducted to assess the cytotoxicity of NK cells from umbilical cord blood to MPM cells with the use of a high-content imaging analysis system, the Cell Counting Kit-8 assay, and Wright-Giemsa staining. The level of NK cell effector molecule expression was detected by flow cytometry and enzyme-linked immunosorbent assays. The ability of NK cells to kill MPM cells was determined based on live cell imaging, transmission electron microscopy, and scanning electron microscopy. An in vivo study was conducted to assess the efficacy and safety of NK cell therapy based on the experimental peritoneal cancer index, small animal magnetic resonance imaging, and conventional histopathologic, cytologic, and hematologic studies. NK cells effectively killed MPM cells through the release of effector molecules (granzyme B, perforin, interferon-γ, and tumor necrosis factor-α) in a dose- and density-dependent manner. The NK cell killing process potentially involved four dynamic steps: chemotaxis; hitting; adhesion; and penetration. NK cells significantly reduced the tumor burden, diminished ascites production, and extended survival with no significant hematologic toxicity or organ damage in NOG mice. NK cell immunotherapy inhibited proliferation of MPM cells in vitro and in vivo with a good safety profile.

Automated quality control of small animal MR neuroimaging data

Abstract Magnetic resonance imaging (MRI) is a valuable tool for studying brain structure and function in animal and clinical studies. With the growth of public MRI repositories, access to data has finally become easier. However, filtering large datasets for potential poor-quality outliers can be a challenge. We present AIDAqc, a machine-learning-assisted automated Python-based command-line tool for small animal MRI quality assessment. Quality control features include signal-to-noise ratio (SNR), temporal SNR, and motion. All features are automatically calculated and no regions of interest are needed. Automated outlier detection for a given dataset combines the interquartile range and the machine-learning methods one-class support vector machine, isolation forest, local outlier factor, and elliptic envelope. To evaluate the reliability of individual quality control metrics, a simulation of noise (Gaussian, salt and pepper, speckle) and motion was performed. In outlier detection, single scans with induced artifacts were successfully identified by AIDAqc. AIDAqc was challenged in a large heterogeneous dataset collected from 19 international laboratories, including data from mice, rats, rabbits, hamsters, and gerbils, obtained with different hardware and at different field strengths. The results show that the manual inter-rater agreement (mean Fleiss Kappa score 0.17) is low when identifying poor-quality data. A direct comparison of AIDAqc results, therefore, showed only low-to-moderate concordance. In a manual post hoc validation of AIDAqc output, precision was high (>70%). The outlier data can have a significant impact on further postprocessing, as shown in representative functional and structural connectivity analysis. In summary, this pipeline optimized for small animal MRI provides researchers with a valuable tool to efficiently and effectively assess the quality of their MRI data, which is essential for improved reliability and reproducibility.

Implementing a two-stage, shim field-calibrated superconducting shimming method on a 7 T cryogen-free small animal MRI magnet

Ultrahigh field systems (≥ 7 T) can increase the signal-to-noise ratio of magnetic resonance imaging (MRI), improving imaging performance compared to systems with lower fields. However, these enhancements heavily rely on a high B0 magnetic field homogeneity level, which can be achieved through superconducting shimming. This paper presents a novel two-stage superconducting shimming method designed to achieve precise shimming for a 7 T MRI superconducting magnet. In the initial stage, detailed measurements and fittings were conducted to determine the current polarity and the axial or circumferential positions of the shim fields. Subsequently, an optimization strategy was implemented to determine the optimal shim currents with a flexible target field. The second stage involves an iterative process to fine-tune the current of a specific shim coil, identified as having the most significant impact on field homogeneity. The overall fitness of 99.5% underscores the precision in determining the current polarity and position of the shim fields. Significantly, the calibrated shim system substantially improves the peak-to-peak and Root Mean Square Error (RMSE) field homogeneities from 107.42 ppm and 37.00 ppm to 11.12 ppm and 3.26 ppm, respectively, representing improvements of 89.65% and 91.19%. Furthermore, the simulation results of the fine-tuning stage demonstrate additional enhancements in peak-to-peak field homogeneity, to 9.9 ppm by reducing the current of the Z2 shim coil by 51.3 mA. Additionally, the shimmed magnetic field exhibited high time stability, with a maximum variation of only 27 µT observed within 48 h. Thus, the proposed two-stage superconducting shimming framework effectively addresses the challenge of imperfect B0 magnetic fields, enhancing peak-to-peak and RMSE field homogeneity. The stepwise optimized approach also mitigates deviations caused by shim-to-shim coupling, demonstrating its efficacy in achieving precise shimming in ultrahigh-field MRI systems.

Novel Tumor Organoid-Based Mouse Model to Study Image Guided Radiation Therapy of Rectal Cancer After Noninvasive and Precise Endoscopic Implantation

PurposePreoperative (neoadjuvant) radiation therapy (RT) is an essential part of multimodal rectal cancer therapy. Recently, total neoadjuvant therapy (TNT) which combines simultaneous radio-chemotherapy with additional courses of chemotherapy (CTx) has emerged as an effective approach. TNT achieves a pathological complete remission in approximately 30% of resected patients, opening avenues for treatment strategies that avoid radical organ resection. Furthermore, recent studies have demonstrated that anti-PD-1 immunotherapy (IT) can induce clinical complete responses in patients with specific genetic alterations. Overall, there is significant potential to enhance outcomes through intensifying, personalizing, and de-escalating treatment approaches. However, the heterogeneous response rates to RT or TNT and strategies to sensitize patients without specific genetic changes to IT remain poorly understood. Materials and MethodsWe developed a novel orthotopic mouse model of rectal cancer which is based on precisely defined endoscopic injections of tumor organoids that reflect tumor heterogeneity. Subsequently, we employed endoscopic- and computed tomography-guided RT, and validated rectal tumor growth and response rates to therapy using small animal magnetic resonance imaging and endoscopic follow-up. ResultsRectal tumor formation was successfully induced in all mice following two organoid injections. Clinically relevant RT regimens with 5 × 5 Gy significantly delayed clinical signs of tumor progression and significantly improved survival. Consistent with human disease, rectal tumor progression correlated with the development of liver and lung metastases. Notably, longterm survivors after RT showed no evidence of tumor recurrence, as demonstrated by in vivo radiological tumor staging and histopathological examination. ConclusionsOur novel mouse model combines orthotopic tumor growth via non-invasive and precise rectal organoid injection and small animal RT. This model holds significant promise for investigating the impact of tumor cell-intrinsic aspects, genetic alterations of the host, or exogenous factors (e.g., nutrition or microbiota) on RT outcomes. Furthermore, it allows for the exploration of combination therapies involving CTx, IT or novel targeted therapies.

Chanling Gao suppresses colorectal cancer via PI3K/Akt/mTOR pathway modulation and enhances quality of survival.

The Chinese medicine formula Chanling Gao (CLG) exhibits significant tumor inhibitory effects in colorectal cancer (CRC) nude mice. However, the detailed mechanisms remain elusive. CRC in situ nude mouse models were treated with CLG. Small animal magnetic resonance imaging (MRI) tracked tumor progression, and overall health metrics such as food and water intake, body weight, and survival were monitored. Posttreatment, tissues and blood were analyzed for indicators of tumor inhibition and systemic effects. Changes in vital organs were observed via stereoscope and hematoxylin-eosinstaining. Immunohistochemistry quantified HIF-1α and P70S6K1 protein expression in xenografts. Double labeling was used to statistically analyze vascular endothelial growth factor (VEGF) and CD31 neovascularization. Enzyme-linked immunosorbent assay was used to determine the levels of VEGF, MMP-2, MMP-9, IL-6, and IL-10 in serum, tumors, and liver. Western blotting was used to assess the expression of the PI3K/Akt/mTOR signaling pathway-related factors TGF-β1 and smad4 in liver tissues. CLG inhibited tumor growth, improved overall health metrics, and ameliorated abnormal blood cell counts in CRC nude mice. CLG significantly reduced tumor neovascularization and VEGF expression in tumors and blood. It also suppressed HIF-1α, EGFR, p-PI3K, Akt, p-Akt, and p-mTOR expression in tumors while enhancing PTEN oncogene expression. Systemic improvements were noted, with CLG limiting liver metastasis, reducing pro-inflammatory cytokines IL-6 and IL-10 in liver tissues, decreasing MMP-2 in blood and MMP-2 and MMP-9 in tumors, and inhibiting TGF-β1 expression in liver tissues. CLG can enhance survival quality and inhibit tumor growth in CRC nude mice, likely through the regulation of the PI3K/Akt/mTOR signaling pathway.

Intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancy

IntroductionConventional morphologic and volumetric assessment of treatment response is not suitable for adequately assessing responses to targeted cancer therapy. The aim of this study was to evaluate changes in tumor composition after targeted therapy in murine models of breast cancer with differing degrees of malignancy via non-invasive magnetic resonance imaging (MRI). Materials and methodsMice bearing highly malignant 4T1 tumors or low malignant 67NR tumors were treated with either a combination of two immune checkpoint inhibitors (ICI, anti-PD1 and anti-CTLA-4) or the multi-tyrosine kinase inhibitor sorafenib, following experiments with macrophage-depleting clodronate-loaded liposomes and vessel-stabilizing angiopoietin-1. Mice were imaged on a 9.4 T small animal MRI system with a multiparametric (mp) protocol, comprising T1 and T2 mapping and diffusion-weighted imaging. Tumors were analyzed ex vivo with histology. Results and discussionsAll treatments led to an increase in non-viable areas, but therapy-induced intratumoral changes differed between the two tumor models and the different targeted treatments. While ICI treatment led to intratumoral hemorrhage, sorafenib treatment mainly induced intratumoral necrosis. Treated 4T1 tumors showed increasing and extensive areas of necrosis, in comparison to 67NR tumors with only small, but also increasing, necrotic areas. After either of the applied treatments, intratumoral heterogeneity, was increased in both tumor models, and confirmed ex vivo by histology. Apparent diffusion coefficient with subsequent histogram analysis proved to be the most sensitive MRI sequence. In conclusion, mp MRI enables to assess dedicated therapy-related intratumoral changes and may serve as a biomarker for treatment response assessment.

Miniaturized MR-compatible ultrasound system for real-time monitoring of acoustic effects in mice using high-resolution MRI

Visualization of focused ultrasound in high spatial and temporal resolution is crucial for accurately and precisely targeting brain regions noninvasively. Magnetic resonance imaging (MRI) is the most widely used noninvasive tool for whole-brain imaging. However, focused ultrasound studies employing high-resolution (> 9.4 T) MRI in small animals are limited by the small size of the radiofrequency (RF) volume coil and the noise sensitivity of the image to external systems such as bulky ultrasound transducers. This technical note reports a miniaturized ultrasound transducer system packaged directly above a mouse brain for monitoring ultrasound-induced effects using high-resolution 9.4 T MRI. Our miniaturized system integrates MR-compatible materials with electromagnetic (EM) noise reduction techniques to demonstrate echo-planar imaging (EPI) signal changes in the mouse brain at various ultrasound acoustic intensities. The proposed ultrasound-MRI system will enable extensive research in the expanding field of ultrasound therapeutics.

Assessment of Transarterial Chemoembolization Using Super-resolution Ultrasound Imaging and a Rat Model of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly prevalent form of liver cancer diagnosed annually in 600,000 people worldwide. A common treatment is transarterial chemoembolization (TACE), which interrupts the blood supply of oxygen and nutrients to the tumor mass. The need for repeat TACE treatments may be assessed in the weeks after therapy with contrast-enhanced ultrasound (CEUS) imaging. Although the spatial resolution of traditional CEUS has been restricted by the diffraction limit of ultrasound (US), this physical barrier has been overcome by a recent innovation known as super-resolution US (SRUS) imaging. In short, SRUS enhances the visible details of smaller microvascular structures on the 10 to 100 µm scale, which unlocks a host of new clinical opportunities for US. In this study, a rat model of orthotopic HCC is introduced and TACE treatment response (to a doxorubicin-lipiodol emulsion) is assessed using longitudinal SRUS and magnetic resonance imaging (MRI) performed at 0, 7 and 14 d. Animals were euthanized at 14 d for histological analysis of excised tumor tissue and determination of TACE response, that is, control, partial response or complete response. CEUS imaging was performed using a pre-clinical US system (Vevo 3100, FUJIFILM VisualSonics Inc.) equipped with an MX201 linear array transducer. After administration of a microbubble contrast agent (Definity, Lantheus Medical Imaging), a series of CEUS images were collected at each tissue cross-section as the transducer was mechanically stepped at 100 μm increments. SRUS images were formed at each spatial position, and a microvascular density metric was calculated. Microscale computed tomography (microCT, OI/CT, MILabs) was used to confirm TACE procedure success, and tumor size was monitored using a small animal MRI system (BioSpec 3T, Bruker Corp.). Although there were no differences at baseline (p > 0.15), both microvascular density levels and tumor size measures from the complete responder cases at 14 d were considerably lower and smaller, respectively, than those in the partial responder or control group animals. Histological analysis revealed tumor-to-necrosis levels of 8.4%, 51.1% and 100%, for the control, partial responder and complete responder groups, respectively (p < 0.005). SRUS imaging is a promising modality for assessing early changes in microvascular networks in response to tissue perfusion-altering interventions such as TACE treatment of HCC.

Development of a non-invasive method for testicular toxicity evaluation using a novel compact magnetic resonance imaging system.

In non-clinical animal studies for drug discovery, histopathological evaluation is the most powerful tool to assess testicular toxicity. However, histological analysis is extremely invasive; many experimental animals are needed to evaluate changes in the pathology and anatomy of the testes over time. As an alternative, small animal magnetic resonance imaging (MRI) offers a non-invasive methodology to examine testicular toxicity without radiation. The present study demonstrated the suitability of a new, ready-to-use compact MRI platform using a high-field permanent magnet to assist with the evaluation of testicular toxicity. To validate the utility of the MRI platform, male mice were treated with busulfan (40 mg/kg, intraperitoneal injection). Twenty-eight days after treatment, both testes in busulfan-treated and control mice (n = 6/group) were non-invasively scanned in situ by MRI at 1 tesla. On a T1-weighted 3D gradient-echo MRI sequences (voxel size: 0.23 × 0.23 × 0.50 mm), the total testicular volume in busulfan-treated mice was significantly smaller than in controls. On T1-weighted images, the signal intensity of the testes was significantly higher in busulfan-treated mice than in controls. The mice were sacrificed, and the testes were isolated for histopathological analysis. The weight of the testes in busulfan-treated mice significantly decreased, similar to the results of the non-invasive analysis. Additionally, periodic acid-Schiff stain-positive effusions were observed in the interstitium of the busulfan-treated mouse testes, potentially explaining T1 shortening due to a high concentration of glycoproteinaceous content. The present data demonstrated a rapid evaluation of testicular toxicity in vivo by compact MRI.

7T Small Animal MRI Research for Hepatic Alveolar Echinococcosis.

7T small animal magnetic resonance imaging (MRI) was used to analyze the growth characteristics of hepatic alveolar echinococcosis (HAE). A mouse model of HAE was established by intraperitoneal injection of alveolar Echinococcus tissue suspension. Ten mouse models successfully inoculated by ultrasound screening were selected. The mouse model was scanned with T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and diffusion-weighted imaging (DWI) sequence by 7T small animal MRI. Size, morphology, boundary, signal, and relationship with surrounding tissues of the lesions were recorded as characteristic alterations. Mice were killed at the end of the experiment, and the pathological specimens were taken for routine hematoxylin and eosin staining. Lesions were mainly located in the right lobe of the liver. The multivesicular structure is the characteristic manifestation of this disease. In the liver, lesions invaded the portal vein and were mainly distributed at the hepatic hilum. The left branch of the portal vein was mainly invaded. The mean diameter of the lesions in the left lobe of the liver was larger than in other parts of the liver. The mean diameter of the cystic solid lesions was greater than the multilocular cystic lesions. HAE showed hypointense on T1WI, hyperintense on T2WI, and hypointense on DWI; the marginal zone of the lesion showed hyperintensity on DWI and grew toward the hilum. The MRI features of intraperitoneal lesions were similar to those of intrahepatic lesions. Intraperitoneal lesions increased faster than intrahepatic lesions in the same period. Polyvesicular structure is a characteristic manifestation of hepatic alveolar echinococcosis in mice. The noninvasive monitoring of liver HAE in mice by 7T small animal MRI provides a visual basis for the diagnosis and treatment integration of HAE.

Signal Amplification Pretargeted PET/Fluorescence Imaging Based on Human Serum Albumin-Encapsulated GdF3 Nanoparticles for Diagnosis of Ovarian Cancer.

Different modal imaging techniques could be complementary in tumor diagnosis. Human serum albumin (HSA)-encapsulated GdF3 nanoparticles were developed as T1 magnetic resonance imaging (MRI) contrast agents. However, no significant T1 enhancement in the tumor site of the SKOV3 human ovarian cancer xenograft tumor model was observed within 3 h after injection of tetrazine-modified GdF3@HSA NPs through small-animal MRI. After intravenous injection of 18F (or Cy7)-labeled Reppe anhydride, pretargeted positron emission tomography (PET) (near-infrared (NIR) fluorescence) imaging was used to reveal the pharmacokinetics of GdF3@HSA NPs in the SKOV3 xenograft mouse model to locate the tumor. The probe based on Reppe anhydride achieved rapid ligation with tetrazine-modified GdF3@HSA nanoparticles (NPs), which accumulated in tumor through Reppe anhydride/tetrazine bioorthogonal chemistry. This pretargeting strategy enabled excellent tumor visualization and quantification at an early period after nanoparticle injection (3 h p.i.), while the MRI images with significant T1 enhancement could be obtained until 24 h after injection of Gd-based contrast agents only. In vivo pretargeted multimodal imaging based on the tetrazine/Reppe anhydride system using HSA-encapsulated GdF3 nanoparticles would be beneficial for amplification of the imaging signal in the disease site and enhancing diagnostic efficiency.

Design and construction of an 8-channel transceiver coil array for rat imaging at 9.4 T

Ultra-high field (UHF) small animal magnetic resonance imaging (MRI) is a crucial tool permitting investigation of metabolic diseases and identification of imaging biomarkers suitable for clinical diagnosis and translation. Radiofrequency (RF) coils are critical components in enabling acquisition of high-quality rat abdomen MRI data. However, efficient RF coils with high-channel count, capable of sensitive and accelerated rat abdomen imaging at 9.4 T, are not available commercially. The SNR of the commonly-used 9.4 T birdcage coil is relatively weak, particularly in the peripheral area of the subject. In addition, the birdcage is not readily to perform parallel imaging due to unavailability of the required multiple channels. Consequently, the extended scanning duration may cause unnecessary hazards to the rat. In this work, an 8-channel transceiver coil array was designed and constructed to provide good image quality and large coverage for rat abdomen imaging at 9.4 T. The structure and the performance of the developed array was optimized and evaluated by numerical electromagnetic simulations and bench tests, respectively. The MR imaging experiments in phantoms and rat models were also performed on a Bruker 9.4 T preclinical MRI system to validate the feasibility of the proposed design. The coil array supports a one-dimensional acceleration factor up to R = 4, providing good parallel imaging capabilities. These results demonstrated that the proposed 8-channel transceiver coil array for rat imaging has the ability to obtain high spatial resolution of rat abdomen anatomical structure images at 9.4 T.

Progress in magnetic resonance imaging of autism model mice brain.

Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by social disorder and stereotypical behaviors with an increasing incidence. ASD patients are suffering from varying degrees of mental retardation and language development abnormalities. Magnetic resonance imaging (MRI) is a noninvasive imaging technology to detect brain structural and functional dysfunction in vivo, playing an important role in the early diagnosisbasic research of ASD. High-field, small-animal MRI in basic research of autism model mice has provided a new approach to research the pathogenesis, characteristics, and intervention efficacy in autism. This article reviews MRI studies of mouse models of autism over the past 20 years. Reduced gray matter, abnormal connections of brain networks, and abnormal development of white matter fibers have been demonstrated in these studies, which are present in different proportions in the various mouse models. This provides a more macroscopic view for subsequent research on autism model mice. This article is categorized under: Cognitive Biology > Genes and Environment Neuroscience > Computation Neuroscience > Genes, Molecules, and Cells Neuroscience > Development.

Establishment of a visualized mouse orthotopic model of nasopharyngeal carcinoma.

e18048 Background: Nasopharyngeal carcinoma, one of the most common head and neck tumors, is particularly prevalent in Southeast Asia and is characterized by high rates of metastasis and recurrence. Although mouse orthotopic tumor models are commonly employed in studies investigating the mechanisms underlying tumor development and progression, as well as preclinical treatment, currently no such model exists for nasopharyngeal carcinoma. The aim of the current study is to, therefore, establish an orthotopic murine model for nasopharyngeal carcinoma. Methods: To this end, human nasopharyngeal carcinoma C666-1-luc cells, stably expressing the firefly luciferase gene, were injected subcutaneously into the right axilla of BALB/C nude mice. Four weeks later, the resulting subcutaneous tumors were cut into small blocks and grafted into the nasopharynx of immunodeficient BALB/C nude mice to induce tumor formation. Tumor growth was monitored by bioluminescence imaging and small animal magnetic resonance imaging. The histological and immunological antigen expression associated with orthotopic nasopharyngeal carcinoma were analyzed by tissue section analysis and immunohistochemistry (IHC). Results: The tumor formation rate was over 90%. Fluorescence signal detection, micro-magnetic resonance imaging and hematoxylin and eosin staining revealed the successful growth of tumors in the nasopharynx of nude mice. Moreover, IHC analysis detected positive CK, CK5/6, P40 and P63 expression in the mouse orthotopic tumors, which is consistent with the reported antigen expression in the nasopharyngeal tumors of patients. Conclusions: Hence, we successfully established a mouse orthotopic model of nasopharyngeal carcinoma that is highly reproducible, and simple in operation, with low mortality and high tumor formation rates. Moreover, this model facilitates real-time monitoring of tumor growth via in vivo imaging technology, thus, providing a platform for researching nasopharyngeal carcinoma that is more conducive to preclinical research.

Sex-Dependent Responses to Prebiotic Inulin in Cerebral Blood Flow and Scyllo-Inositol Metabolism in APOE Mice

Abstract Objectives Apolipoprotein E4 (APOE4) is the most potent genetic risk factor for Alzheimer's disease (AD). Early dietary intervention might be critical for preventing AD progression for APOE4 carriers. Here we investigate whether, in APOE4 carriers, a prebiotic inulin diet can preserve cerebral blood flow (CBF) and increase brain scyllo-inositol, a therapeutic compound that has been proved to inhibit amyloid-beta (Aβ) aggregation and alleviate the risk of AD, and whether the responses to inulin are sex-dependent, compared with risk-neutral APOE3 carriers. Methods Four-month-old, asymptomatic APOE3 and APOE4 mice were fed inulin or a cellulose control diet for four months (N = 18/group; Male: Female = 1:1). CBF and scyllo-inositol were measured by magnetic resonance imaging (MRI) and MR spectroscopy, respectively, at the end of the study. We performed a 3-way ANOVA (gene ⋉ diet ⋉ sex) followed by post hoc Tukey's multiple comparisons test using GraphPad Prism. A p &amp;lt; 0.05 was considered statistically significant. Results Inulin increased CBF in the APOE4 male mice in the whole brain (p &amp;lt; 0.001), hippocampus (p = 0.043), cortex (p = 0.016), and thalamus (p &amp;lt; 0.001), but these differences were not found in female mice. In contrast, inulin increased brain scyllo-inositol in APOE4 female mice (p = 0.006), as well as in both sexes in APOE3 mice (male, p &amp;lt; 0.001; female, p &amp;lt; 0.001). Conclusions These findings suggest that the responses to inulin diet are sex- and APOE genotype-dependent in preserving CBF and scyllo-inositol metabolism (markers of brain functionality), indicating a nutrigenetic difference between male and female mice. This study may provide valuable insights into precision nutrition in AD prevention in the future. Funding Sources This research was supported by grants NIH/NIA RF1AG062480 to ALL. The 7T ClinScan small animal MRI scanner was funded by the S10 NIH Shared Instrumentation Program Grant.

The Development of Monolithic Silicon Carbide Intracortical Neural Interfaces for Long-Term Human Implantation

Silicon Carbide (SiC) has been demonstrated as both a bio- and neuro-compatible wide-band-gap semiconductor with a high thermal conductivity and magnetic susceptibility and may be potentially compatible with human brain tissue. Two single-crystal, solid-state forms of SiC have been used to create monolithic intracortical neural implants (INI) without using physiologically exposed metals or polymers, thus eliminating many known reliability challenges in-vivo through a single, homogenous material. Amorphous SiC (a-SiC) was used to insulate 16-channel functional INI and the electrochemical and MRI compatibility (7T) performance were measured. 4H-SiC interfaces were fabricated using homoepitaxy,alternating epitaxial films of n-type and p-type forming an isolating PN junction which prevents substrate leakage current between the 16 adjacent electrodes and traces fabricated which were formed using deep-reactive ion etching (DRIE). 3C-SiC interfaces were fabricated in a similar fashion, but the epitaial conductive layers were grown on on both bulk crystalline (100) silicon and SOI wafers. In both cases a conformal coating of a-SiC was used as the top-side insulator and windows opened using RIE to allow electrochemical interaction. Electrochemical charaterization achieved through electrochemcial impedance spectroscopy (EIS) and cyclic voltammetry (CV) indicates performance on par, or exceeding, that of Pt reference electrodes with the same form fit. While magnetic resonance imaging (MRI) is an essential, non-contact method used to investigate issues with the nervous system, the high field MRI (e.g., 3 T and higher) necessary for proper diagnosis can be a safety issue for patients with INI due to inductive coupling between the powerful electromagnetic fields and the implanted device. This results in having to use lower electromagnetic field power (less than 1.5T), and therefore lower resolution, which hinders diagnostic prognosis for these patients. In this work the MRI compliance of epitaxial, monolithic SiC INI was studied. The specific absorption rate (SAR), induced heating, and image artifacts caused by the portion of the implant within a brain tissue phantom located in a 7 T small animal MRI machine were estimated and measured via finite element method (FEM) and Fourier-based simulations. Both the simulation and experimental results revealed that free-standing 3C-SiC films had no observable image artifacts compared to silicon and platinum reference materials inside the MRI at 7 T while FEM simulations predicted an ~30% SAR reduction for 3C-SiC compared to Pt. These initial simulations and experiments indicate a SiC monolithic INI may effectively reduce MRI induced heating and image artifacts in high field MRI.

Electroacupuncture promotes the repair of neurological function in ischemic stroke rats by inhi-biting cofilin rod formation

To observe the effect of electroacupuncture (EA) on modified neurological severity score (mNSS), cerebral infarction volume, expression of Lim domain kinase-1 (LIMK1) and slingshot homolog-1 (SSH1) proteins, Cofilin rod formation and neural cell apoptosis in rats with ischemic stroke (IS), so as to explore its mechanisms underlying improvement of IS. Male SD rats were randomly divided into normal, model and EA groups, with 13 rats in each group. The IS model was established by occlusion of the middle cerebral artery (MCAO) according to Zea Longa's method. EA was applied to "Quchi" (LI11) and "Zusanli" (ST36) for 30 min, once a day for 7 consecutive days. The behavioral changes of mNSS were observed before and after modeling. The volume of cerebral infarction was measured by using a small animal magnetic resonance imaging. The protein expressions of LIMK1 and SSH1 in the cerebral ischemic tissues were detected by Western blot. The density of Cofilin rod and neural cell apoptosis in cerebral ischemic area were determined by immunofluorescence staining and TUNEL staining, separately. After modeling, the mNSS score, cerebral infarction volume ratio, expression level of SSH1, density of Cofilin rod and the number of apoptotic cells were significantly increased (P<0.01), while the expression level of LIMK1 protein was obviously decreased in the model group relevant to the normal group (P<0.01). After 7 days' treatment, all the increased and decreased levels of the indexes mentioned above were reversed in the EA group relevant to the model group (P<0.01, P<0.05). EA of LI11 and ST36 can improve neurological function and reduce infarction range in MCAO rats, which may be related to its action in regulating the expression of LIMK1 and SSH1, inhibiting the formation of Cofilin rod and reducing apoptosis of neural cells.

Magnetic Resonance Imaging in Tauopathy Animal Models.

The microtubule-associated protein tau plays an important role in tauopathic diseases such as Alzheimer’s disease and primary tauopathies such as progressive supranuclear palsy and corticobasal degeneration. Tauopathy animal models, such as transgenic, knock-in mouse and rat models, recapitulating tauopathy have facilitated the understanding of disease mechanisms. Aberrant accumulation of hyperphosphorylated tau contributes to synaptic deficits, neuroinflammation, and neurodegeneration, leading to cognitive impairment in animal models. Recent advances in molecular imaging using positron emission tomography (PET) and magnetic resonance imaging (MRI) have provided valuable insights into the time course of disease pathophysiology in tauopathy animal models. High-field MRI has been applied for in vivo imaging in animal models of tauopathy, including diffusion tensor imaging for white matter integrity, arterial spin labeling for cerebral blood flow, resting-state functional MRI for functional connectivity, volumetric MRI for neurodegeneration, and MR spectroscopy. In addition, MR contrast agents for non-invasive imaging of tau have been developed recently. Many preclinical MRI indicators offer excellent translational value and provide a blueprint for clinical MRI in the brains of patients with tauopathies. In this review, we summarized the recent advances in using MRI to visualize the pathophysiology of tauopathy in small animals. We discussed the outstanding challenges in brain imaging using MRI in small animals and propose a future outlook for visualizing tau-related alterations in the brains of animal models.

Positron emission tomography-magnetic resonance imaging as a research tool in musculoskeletal conditions.

Compared to positron emission tomography/computed tomography (PET/CT), the uptake of PET- magnetic resonance imaging (MRI) has been slow, even more so in clinical practice compared to the (pre-)clinical research setting. However, for applications in musculoskeletal (MSK) research, the combination of PET and MRI into a single modality offers attractive advantages over other imaging modalities. Most importantly, MRI has exquisite soft-tissue detail without the use of contrast agents or ionizing radiation, superior bone marrow visualization, and an extensive spectrum of distinct multiparametric assessment methods. In the preclinical setting, the introduction of PET inserts for small-animal MRI machines has proven to be a successful concept in bringing this technology to the lab. Initial hurdles in quantification have been mainly overcome in this setting. In parallel, a promising range of radiochemistry techniques has been developed to create multimodality probes that offer the possibility of simultaneously querying different metabolic pathways. Not only will these applications help in elucidating disease mechanisms, but they can also facilitate drug development. The clinical applications of PET/MRI in MSK are still limited, but encouraging initial results with novel radiotracers suggest a high potential for use in various MSK conditions, including osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and inflammation and infection. Further innovations will be required to bring down the cost of PET/MRI to justify a broader clinical implementation, and remaining issues with quality control and standardization also need to be addressed. Nevertheless, PET/MRI is a powerful platform for MSK research with distinct qualities that are not offered by other techniques.

Magnetic Resonance Imaging in Animal Models of Alzheimer's Disease Amyloidosis.

Amyloid-beta (Aβ) plays an important role in the pathogenesis of Alzheimer’s disease. Aberrant Aβ accumulation induces neuroinflammation, cerebrovascular alterations, and synaptic deficits, leading to cognitive impairment. Animal models recapitulating the Aβ pathology, such as transgenic, knock-in mouse and rat models, have facilitated the understanding of disease mechanisms and the development of therapeutics targeting Aβ. There is a rapid advance in high-field MRI in small animals. Versatile high-field magnetic resonance imaging (MRI) sequences, such as diffusion tensor imaging, arterial spin labeling, resting-state functional MRI, anatomical MRI, and MR spectroscopy, as well as contrast agents, have been developed for preclinical imaging in animal models. These tools have enabled high-resolution in vivo structural, functional, and molecular readouts with a whole-brain field of view. MRI has been used to visualize non-invasively the Aβ deposits, synaptic deficits, regional brain atrophy, impairment in white matter integrity, functional connectivity, and cerebrovascular and glymphatic system in animal models of Alzheimer’s disease amyloidosis. Many of the readouts are translational toward clinical MRI applications in patients with Alzheimer’s disease. In this review, we summarize the recent advances in MRI for visualizing the pathophysiology in amyloidosis animal models. We discuss the outstanding challenges in brain imaging using MRI in small animals and propose future outlook in visualizing Aβ-related alterations in the brains of animal models.