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Objectives: Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive targeted tissue ablation technique that can be applied to the nervous system. Diffusion weighted imaging (DWI) can visualize and evaluate nervous system microstructure. Tractography algorithms can reconstruct fiber bundles which can be used for treatment navigation and diffusion tensor imaging (DTI) metrics permit the quantitative assessment of nerve microstructure in vivo. There is a need for imaging tools to aid in the visualization and quantitative assessment of treatment-related nerve changes in MRgFUS. We present a method of peripheral nerve tract reconstruction and use DTI metrics to evaluate the MRgFUS treatment effect.Materials and Methods: MRgFUS was applied bilaterally to the sciatic nerves in 6 piglets (12 nerves total). T1-weighted and diffusion images were acquired before and after treatment. Tensor-based and constrained spherical deconvolution (CSD) tractography algorithms were used to reconstruct the nerves. DTI metrics of fractional anisotropy (FA), and mean (MD), axial (AD), and radial diffusivities (RD) were measured to assess acute (in vivo via MR thermometry. Histological data was collected for lesion assessment.Results: The sciatic nerves were successfully reconstructed in all subjects. Tract disruption was observed after treatment using both CSD and tensor models. DTI metrics in the targeted nerve segments showed significantly decreased FA and increased MD, AD, and RD. Transducer output power was positively correlated with lesion volume and temperature and negatively correlated with MD, AD, and RD. No correlations were observed between FA and other measured parameters.Conclusions: DWI and tractography are effective tools for visualizing peripheral nerve segments for targeting in non-invasive surgical methods and for assessing the microstructural changes that occur following MRgFUS treatment.

OBJECTIVE While intraventricular hemorrhage (IVH) is associated with posthemorrhagic ventricular dilation (PHVD), not all infants affected by high-grade IVH develop PHVD. The authors aimed to determine clot-associated predictors of PHVD in a porcine model by varying the amount and rate of direct intraventricular injection of whole autologous blood. METHODS Seven 1-week-old piglets underwent craniectomy and injection of autologous blood into the right lateral ventricle. They survived for a maximum of 28 days. MRI was performed prior to injection, immediately postoperatively, and every 7 days thereafter. T1-weighted, T2-weighted, and susceptibility-weighted imaging (SWI) sequences were used to segment ventricular and clot volumes. Spearman correlations were used to determine the relationship between blood and clot volumes and ventricular volumes over time. RESULTS The maximum ventricular volume was up to 12 times that of baseline. One animal developed acute hydrocephalus on day 4. All other animals survived until planned endpoints. The interaction between volume of blood injected and duration of injection was significantly associated with clot volume on the postoperative scan (p = 0.003) but not the amount of blood injected alone (p = 0.38). Initial postoperative and day 7 clot volumes, but not volume of blood injected, were correlated with maximum (p = 0.007 and 0.014) and terminal (p = 0.014 and 0.036) ventricular volumes. Initial postoperative ventricular volume was correlated with maximum and terminal ventricular volume (p = 0.007 and p = 0.014). CONCLUSIONS Initial postoperative, maximum, and terminal ventricular dilations were associated with the amount of clot formed, rather than the amount of blood injected. This supports the hypothesis that PHVD is determined by clot burden rather than the presence of blood products and allows further testing of early clot lysis to minimize PHVD risk.

Intraventricular hemorrhage (IVH) affects approximately 50% of premature births where 50% further develop post-hemorrhagic ventricular dilation (PHVD). Patients face significant impact to long-term development if PHVD is not managed. Unfortunately, there is no accepted treatment to remove the thrombus caused by IVH. This paper describes an acute and chronic IVH model for use with magnetic resonance-guided focused ultrasound (MRgFUS) thrombolysis. A total of 12 pigs (~ 1 month in age) were used in the model (eight acute and four chronic). A pre-operative brain MRI was obtained for ventricular targeting. 1.25 cm3/kg of autologous blood was injected through a burr hole lateral to the midline and anterior of the coronal suture at a rate of 0.6 cm3/min. A craniotomy was performed to simulate a “fontanelle”. Post-operative MRI was used to calculate the clot volume. Chronic piglets were recovered, monitored daily with a neurological scoring system (NSS), and MRI scanned for 21 days. The clot injection was well tolerated. The average clot size was 3987 mm3 (median = 4330 mm, standard deviation = 739 mm3). Postmortem examination validated the presence of the clot. In the chronic animals, there was an increase in ventricular volume of 30%. Transient neurological impairment immediately followed clot injection and with onset of hydrocephalus in the chronic animals. This model establishes a measurable and targetable IVH clot in an MRI-based neonatal porcine model. The progressive post-hemorrhagic ventricular dilation in the chronic model is a potential alterable outcome from MRgFUS thrombolysis.

Objectives: The application of magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of neurological conditions has been of increasing interest. Conventional MR imaging can provide structural information about the effect of MRgFUS, where differences in ablated tissue can be seen, but it lacks information about the status of the cellular environment or neural microstructure. We investigate in vivo acute changes in water diffusion and white matter tracts in the brain of a piglet model after MRgFUS treatment using diffusion-weighted imaging (DWI) with histological verification of treatment-related changes. Methods: MRgFUS was used to treat the anterior body of the fornix in four piglets. T1 and diffusion-weighted images were collected before and after treatment. Mean diffusion-weighted imaging (MDWI) images were generated to measure lesion volumes via signal intensity thresholds. Histological data were collected for volume comparison and assessment of treatment effect. DWI metric maps of fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were generated for quantitative assessment. Fornix-related fiber tracts were generated before and after treatment for qualitative assessment. Results: The volume of treated tissue measured via MDWI did not differ significantly from histological measurements, and both were significantly larger than the treatment cell volume. Diffusion metrics in the treatment region were significantly decreased following MRgFUS treatment, with the peak change seen at the lesion core and decreasing radially. Histological analysis confirmed an area of coagulative necrosis in the targeted region with sharp demarcation zone with surrounding brain. Tractography from the lesion core and the fornix revealed fiber disruptions following treatment. Conclusions: Diffusion maps and fiber tractography are an effective method for assessing lesion volumes and microstructural changes in vivo following MRgFUS treatment. This study demonstrates that DWI has the potential to advance MRgFUS by providing convenient in vivo microstructural lesion and fiber tractography assessment after treatment.

OBJECTIVE Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) is a potential noninvasive therapy for fetal conditions. In utero MRgHIFU delivery and proton resonance frequency shift (PRFS) thermometry monitoring will control accuracy of HIFU ablation and confirm in situ tissue heating in a rabbit model. METHODS High-resolution 3T MR images were acquired in late-gestation rabbits (approximately 30 days, n = 5). HIFU sonications, using magnetic resonance (MR) thermometry as a guide, were delivered to achieve necrosis in relevant fetal targets. Thermometry, posttreatment magnetic resonance imaging (MRI), and follow-up histology confirmed ablation. RESULTS Placentas (n = 14) were treated with 127 ± 34 Wac; thermometry-indicated temperatures reached 67°C. Lungs (n = 8) were treated with 85 ± 15 Wac and reached 73°C, livers (n = 6) with 80 ± 15 Wac and reached 74°C, and kidneys (n = 5) with 100 Wac and reached 66°C. Histological changes showed focal areas of necrosis with circumferential hemorrhage and/or vasodilation, which transitioned abruptly to healthy tissue. CONCLUSION MRgHIFU therapy can effectively target and thermally treat specific in utero organs in this acute fetal rabbit model. PRFS gives in situ temperature control of therapy on tissues. Conceivably, MRgHIFU therapy may be applicable to specific fetal organ anomalies clinically and has the potential to improve the overall fetal outcome over traditional invasive surgical procedures.

An increasing number of applications use the postnatal piglet model in neuroimaging studies, however, these are based primarily on T1 weighted image templates. There is a growing need for a multimodal structural brain template for a comprehensive depiction of the piglet brain, particularly given the growing applications of diffusion weighted imaging for characterizing tissue microstructures and white matter organization. In this study, we present the first multimodal piglet structural brain template which includes a T1 weighted image with tissue segmentation probability maps, diffusion weighted metric templates with multiple diffusivity maps, and population-based whole-brain fiber tracts for postnatal piglets. These maps provide information about the integrity of white matter that is not available in T1 images alone. The availability of this diffusion weighted metric template will contribute to the structural imaging analysis of the postnatal piglet brain, especially models that are designed for the study of white matter diseases. Furthermore, the population-based whole-brain fiber tracts permit researchers to visualize the white matter connections in the piglet brain across subjects, guiding the delineation of a specific white matter region for structural analysis where current diffusion data is lacking. Researchers are able to augment the tracts by merging tracts from their own data to the population-based fiber tracts and thus improve the confidence of the population-wise fiber distribution.

This study determined the effect of chronic intrauterine hypoxia on collagen deposition in the fetal sheep heart. Moderate or severe hypoxia was induced by placental embolization in chronically catheterized fetal sheep for 15 days starting at gestational day 116 ± 2 (term ∼147 days). The fetal right and left ventricle were evaluated for collagen content using a Sirius red dye and for changes in signaling components of pathways involved in collagen synthesis and remodeling using quantitative polymerase chain reaction and Western blot. In severely hypoxic fetuses (n = 6), there was a two-fold increase (P < 0.05) in the percentage staining for collagen in the right ventricle, compared with control (n = 6), whereas collagen content was not altered in the moderate group (n = 4). Procollagen I and III mRNA levels were increased in the right ventricle, two-fold (P < 0.05) and three-fold (P < 0.05), respectively, in the severe group relative to control. These changes were paralleled by a two-fold increase (P < 0.05) in mRNA levels of the pro-fibrotic cytokine, transforming growth factor β (TGF-β1), in the right ventricle. In the right ventricle, the mRNA levels of matrix metalloproteinase 2 (MMP-2) and its activator, membrane-type MMP (MTI-MMP) were increased five-fold (P = 0.06) and three-fold (P < 0.05), respectively, relative to control. Protein levels of TGF-β were increased in the left ventricle (P < 0.05). Thus, up-regulated collagen synthesis leading to increased collagen content occurs in the chronically hypoxic fetal heart and may contribute to the right ventricular diastolic and systolic dysfunction reported in human intrauterine growth restriction fetuses.

This study examined perturbed aortic development and subsequent wall stiffening as a link to later cardiovascular disease. Placental insufficiency was induced in pregnant guinea pigs at midgestation by uterine artery ligation. Near term, fetuses were killed and defined as normal birth weight (NBW), low birth weight (LBW), and intrauterine growth restricted (IUGR). Offspring were classified according to birth weight and killed in adulthood. Collagen and elastin content of aortas were analyzed using Sirius red and orcein staining, respectively. Immunofluorescence was used for detection of α-actin and nonmuscle myosin heavy chain (MHC-B), a marker of synthetic-type vascular smooth muscle cells (VSMCs). Ex vivo generation of length-tension curves was performed with aortic rings from adult offspring. Relative elastic fiber content was decreased by 10% in LBW and 14% in IUGR compared with NBW fetuses. In adulthood, relative elastic fiber content was 51% lower in LBW vs. NBW, and the number of elastic laminae adjusted for wall thickness was 25% lower in LBW ( P < 0.01). The percent area stained for MHC-B was sixfold higher in LBW vs. NBW fetuses ( P < 0.0001) and threefold higher in LBW vs. NBW adult offspring ( P < 0.05). The increase in MHC-B in LBW offspring concurred with a 41% increase in total collagen content and a 33 and 56% increase in relative and total α-actin content, respectively ( P < 0.05). Thus aortic wall stiffening in adulthood can be traced to altered matrix composition established under suboptimal intrauterine conditions that is amplified postnatally by the activity of synthetic VSMCs.