Purpose In current intraoperative MRI (IMRI) methods, an iterative approach is used to aim trajectory guides at intracerebral targets: image MR‐visible features, determine current aim by fitting model to image, manipulate device, repeat. Infrequent updates are produced by such methods, compared to rapid optically tracked stereotaxy used in the operating room. Our goal was to develop a real‐time interactive IMRI method for aiming. Methods The current trajectory was computed from two points along the guide's central axis, rather than by imaging the entire device. These points were determined by correlating one‐dimensional spokes from a radial sequence with the known cross‐sectional projection of the guide. The real‐time platform RTHawk was utilized to control MR sequences and data acquisition. On‐screen updates were viewed by the operator while simultaneously manipulating the guide to align it with the planned trajectory. Accuracy was quantitated in a phantom, and in vivo validation was demonstrated in nonhuman primates undergoing preclinical gene () and cell () delivery surgeries. Results Updates were produced at 5 Hz In 10 phantom experiments at a depth of 48 mm, the cannula tip was placed with radial error of (min, mean, max) = (0.16, 0.29, 0.68) mm. Successful in vivo delivery of payloads to all 14 targets was demonstrated across nine surgeries with depths of (min, mean, max) = (33.3, 37.9, 42.5) mm. Conclusion A real‐time interactive update rate was achieved, reducing operator fatigue without compromising accuracy. Qualitative interpretation of images during aiming was rendered unnecessary by objectively computing device alignment.

BACKGROUND:An early-life anxious temperament (AT) is a risk factor for the development of anxiety, depression, and comorbid substance abuse. We validated a nonhuman primate model of early-life AT and identified the dorsal amygdala as a core component of AT's neural circuit. Here, we combine RNA sequencing, viral-vector gene manipulation, functional brain imaging, and behavioral phenotyping to uncover AT's molecular substrates. METHODS:In response to potential threat, AT and brain metabolism were assessed in 46 young rhesus monkeys. We identified AT-related transcripts using RNA-sequencing data from dorsal amygdala tissue (including central nucleus of the amygdala [Ce] and dorsal regions of the basal nucleus). Based on the results, we overexpressed the neurotrophin-3 gene, NTF3, in the dorsal amygdala using intraoperative magnetic resonance imaging-guided surgery (n = 5 per group). RESULTS:This discovery-based approach identified AT-related alterations in the expression of well-established and novel genes, including an inverse association between NTRK3 expression and AT. NTRK3 is an interesting target because it is a relatively unexplored neurotrophic factor that modulates intracellular neuroplasticity pathways. Overexpression of the transcript for NTRK3's endogenous ligand, NTF3, in the dorsal amygdala resulted in reduced AT and altered function in AT's neural circuit. CONCLUSIONS:Together, these data implicate neurotrophin-3/NTRK3 signaling in the dorsal amygdala in mediating primate anxiety. More generally, this approach provides an important step toward understanding the molecular underpinnings of early-life AT and will be useful in guiding the development of treatments to prevent the development of stress-related psychopathology.

Abstract INTRODUCTION The spatial and temporal resolution limits of functional MRI (fMRI) brain mapping provide primarily correlative information on brain connectivity. Determining how one region causally modulates and mediates activity in other regions remains difficult with fMRI. We demonstrate a simple means to add causality in resting state functional connectivity MRI (rs-fcMRI) using techniques developed first for convection-enhanced delivery (CED) of therapeutics. Here we use CED to guide and monitor pharmacologic alteration of a local brain region in anaesthetized Rhesus monkeys while monitoring rs-fcMRI signal changes. METHODS Pre-surgical MRI was used to determine skull locations for craniotomies for installation of NavigusTMbrain ports in two untrained monkeys slated for euthanasia. The ports were aligned in real–time to provide trajectories aimed at the central nucleus of the amygdala (CeA). Fused silica catheters were then inserted into the CeA where 24 mg of muscimol (inhibitory agent) was infused in 24 ml of buffered solution under pressure over 12 minutes, first on the right side and then on the left side. rs-fcMRI studies were done for 45 minutes before and after the unilateral infusion and then after the bilateral infusion. RESULTS Catheters were successfully aligned and inserted into the CeA targets with sub-mm accuracy. T2-weighted imaging detected the enhanced T2 from the infusion’s buffer. Pre-infusion rs-fcMRI provides results consistent with prior studies, which have shown that the CeA is most strongly connected to the contralateral CeA. This connectivity was significantly reduced following both unilateral and bilateral injections of muscimol into the CeA, demonstrating the effectiveness of the muscimol infusions. Conditional Grainger Causality (CGC) analysis shows unexpected new connectivity after the unilateral infusion. Upon the bilateral infusion, global effective connectivity in the region is reduced. CONCLUSION Expected and unexpected changes in resting state functional connectivity resulted from unilateral and bilateral infusions of inhibitory agents.

BACKGROUND:Nonhuman primate models are critical for understanding mechanisms underlying human psychopathology. We established a nonhuman primate model of anxious temperament (AT) for studying the early-life risk to develop anxiety and depression. Studies have identified the central nucleus of the amygdala (Ce) as an essential component of AT's neural substrates. Corticotropin-releasing factor (CRF) is expressed in the Ce, has a role in stress, and is linked to psychopathology. Here, in young rhesus monkeys, we combined viral vector technology with assessments of anxiety and multimodal neuroimaging to understand the consequences of chronically increased CRF in the Ce region.METHODS:Using real-time intraoperative magnetic resonance imaging-guided convection-enhanced delivery, five monkeys received bilateral dorsal amygdala Ce-region infusions of adeno-associated virus serotype 2 containing the CRF construct. Their cagemates served as unoperated control subjects. AT, regional brain metabolism, resting functional magnetic resonance imaging, and diffusion tensor imaging were assessed before and 2 months after viral infusions.RESULTS:Dorsal amygdala CRF overexpression significantly increased AT and metabolism within the dorsal amygdala. Additionally, we observed changes in metabolism in other AT-related regions, as well as in measures of functional and structural connectivity.CONCLUSIONS:This study provides a translational roadmap that is important for understanding human psychopathology by combining molecular manipulations used in rodents with behavioral phenotyping and multimodal neuroimaging measures used in humans. The results indicate that chronic CRF overexpression in primates not only increases AT but also affects metabolism and connectivity within components of AT's neural circuitry.

Induced pluripotent stem cell (iPSC)-derived neurons represent an opportunity for cell replacement strategies for neurodegenerative disorders such as Parkinson's disease (PD). Improvement in cell graft targeting, distribution, and density can be key for disease modification. We have previously developed a trajectory guide system for real-time intraoperative magnetic resonance imaging (RT-IMRI) delivery of infusates, such as viral vector suspensions for gene therapy strategies. Intracerebral delivery of iPSC-derived neurons presents different challenges than viral vectors, including limited cell survival if cells are kept at room temperature for prolonged periods of time, precipitation and aggregation of cells in the cannula, and obstruction during injection, which must be solved for successful application of this delivery approach. To develop procedures suitable for RT-IMRI cell delivery, we first performed in vitro studies to tailor the delivery hardware (e.g., cannula) and defined a range of parameters to be applied (e.g., maximal time span allowable between cell loading in the system and intracerebral injection) to ensure cell survival. Then we performed an in vivo study to evaluate the feasibility of applying the system to nonhuman primates. Our results demonstrate that the RT-IMRI delivery system provides valuable guidance, monitoring, and visualization during intracerebral cell delivery that are compatible with cell survival.

The University of Wisconsin-Madison Snowmobile Team has designed and constructed a clean and quiet, high performance snowmobile for entry in the 2015 SAE International Clean Snowmobile Challenge. Built on a 2013 Ski-doo MXZ chassis, the design features a Rotax 600cc ACE port fuel-injected turbocharged four-stroke engine equipped to operate efficiently on gasoline and alcohol based fuel blends. The engine has been customized with a Woodward control system which allows for full engine optimization with complete flex-fuel iso-butanol capabilities. An electronic throttle body and mass airflow sensor are used in conjunction with a heated wide-band oxygen sensor to enable closed-loop fuel control. Utilizing a 3-way catalyst designed by Continetal Emitec GmbH, this sled reduces NOX, HC, and CO emissions by up to 95%. Optimized intake and exhaust camshafts were developed to optimize Miller cycle operation. An external wastegate, electronic boost control, and charge air cooler have been fitted to enable complete control of the turbocharger. A variable geometry intake manifold was implemented to account for the cylinder air-filling imbalance caused by a 270 degree crankshaft. With all of the modifications, the clean turbocharged Rotax ACE is capable of a power output of 45 kW and utilizes a catalytic muffler system to reduce sound levels to 69 dB(A) using SAE test procedure J192. The lightweight combination of the MXZ chassis and revolutionary ACE engine results in a rider-friendly package that meets the criteria to succeed at the Clean Snowmobile Challenge and is desirable to snowmobile consumers.

PurposeTo develop and demonstrate the feasibility of a new formulation for quantitative perfusion modeling in the liver using interrupted DCE-MRI data acquired during multiple sequential breathholds.Materials and MethodsA new mathematical formulation to estimate quantitative perfusion parameters using interrupted data was developed. Using this method, we investigated whether a second degree-of-freedom in the tissue residue function (TRF) improves quality-of-fit criteria when applied to a dual-input single-compartment perfusion model. We subsequently estimated hepatic perfusion parameters using DCE-MRI data from 12 healthy volunteers and 9 cirrhotic patients with a history of hepatocellular carcinoma (HCC); and examined the utility of these estimates in differentiating between healthy liver, cirrhotic liver, and HCC.ResultsQuality-of-fit criteria in all groups were improved using a Weibull TRF (2 degrees-of-freedom) versus an exponential TRF (1 degree-of-freedom), indicating nearer concordance of source DCE-MRI data with the Weibull model. Using the Weibull TRF, arterial fraction was greater in cirrhotic versus normal liver (39 23% versus 15 +/- 14%, P = 0.07). Mean transit time (20.6 +/- 4.1 s versus 9.8 +/- 3.5 s, P = 0.01) and arterial fraction (39 +/- 23% versus 73 +/- 14%, P = 0.04) were both significantly different between cirrhotic liver and HCC, while differences in total perfusion approached significance.ConclusionThis work demonstrates the feasibility of estimating hepatic perfusion parameters using interrupted data acquired during sequential breathholds. J. Magn. Reson. Imaging 2014;39:853-865. (c) 2013 Wiley Periodicals, Inc.

PurposeDetection, characterization, and monitoring the treatment of hepatocellular carcinomas (HCC) in patients with cirrhosis is challenging because of their variable and rapid arterial enhancement. Multiphase dynamic contrast‐enhanced MRI is used clinically for HCC assessment; however, the method suffers from limited temporal resolution and difficulty in coordinating imaging and breath‐hold timing within a narrow temporal window of interest. In this article, a volumetric, high‐spatial resolution, and high‐temporal resolution dynamic contrast‐enhanced liver imaging method for improved detection and characterization of HCC is demonstrated.MethodsA time‐resolved three‐dimensional radial acquisition with iterative sensitivity‐encoding reconstruction images the entire abdomen and thorax with high spatial and temporal resolution, using real‐time three‐dimensional fluoroscopy to match the breath hold to contrast arrival. The sequence was tested on 17 subjects, including eight patients with HCC or other hypervascular focal lesions.ResultsThis technique was successful in acquiring volumetric imaging of the entire liver with 2.1‐mm isotropic spatial and true 4‐s temporal resolution.ConclusionThis technique may be suitable for detecting, characterizing, and monitoring the treatment of HCC. It also holds significant potential for perfusion modeling, which may provide a noninvasive means to rapidly determine the efficacy of chemotherapeutic agents in these tumors over the entire liver volume. Magn Reson Med 71:934–941, 2014. © 2013 Wiley Periodicals, Inc.

Radial trajectories facilitate high‐resolution balanced steady state free precession (bSSFP) because the efficient gradients provide more time to extend the trajectory in k‐space. A number of radial bSSFP methods that support fat–water separation have been developed; however, most of these methods require an environment with limited B0 inhomogeneity. In this work, high‐resolution bSSFP with fat–water separation is achieved in more challenging B0 environments by combining a 3D radial trajectory with the IDEAL chemical species separation method. A method to maintain very high resolution within the timing constraints of bSSFP and IDEAL is described using a dual‐pass pulse sequence. The sampling of a unique set of radial lines at each echo time is investigated as a means to circumvent the longer scan time that IDEAL incurs as a multiecho acquisition. The manifestation of undersampling artifacts in this trajectory and their effect on chemical species separation are investigated in comparison to the case in which each echo samples the same set of radial lines. This new bSSFP method achieves 0.63 mm isotropic resolution in a 5‐min scan and is demonstrated in difficult in vivo imaging environments, including the breast and a knee with ACL reconstruction hardware at 1.5 T. Magn Reson Med 71:95–104, 2014. © 2013 Wiley Periodicals, Inc.

Background Convection enhanced delivery (CED) is emerging as a promising infusion toolto facilitate delivery of therapeutic agents into the brain via mechanically controlled pumps. Infusion protocols and catheter design have an important impact on delivery. CED is a valid alternative for systemic administration of agents in clinical trials for cell and gene therapies. Where gel and ex vivo models are not sufficient in modeling the disease, in vivo models allow researchers to better understand the underlying mechanisms of neuron degeneration, which is helpful in finding novel approaches to control the process or reverse the progression. Determining the risks, benefits, and efficacy of new gene therapies introduced via CED will pave a way to enter human clinical trial. Purpose The objective of this study is to compare volume distribution (Vd)/ volume infused (Vi) ratios and backflow measurements following CED infusions in ex vivo versus in vivo non-human primate brain tissue, based on infusion protocols developed in vitro. Methods In ex vivo infusions, the first brain received 2 infusions using a balloon catheter at rates of 1 μL/min and 2 μL/min for 30 minutes. The second and third brains received infusions using a valve-tip (VT) catheter at 1 μL/min for 30 minutes. The fourth brain received a total of 45 μL infused at a rate of 1 μL/min for 15 minutes followed by 2 μL/min for 15 minutes. Imaging was performed (SPGR FA34) every 3 minutes. In the in vivo group, 4 subjects received a total of 8 infusions of 50 μL. Subjects 1 and 2 received infusions at 1.0 μL/min using a VT catheter in the left hemisphere and a smart-flow (SF) catheter in the right hemisphere. Subjects 3 and 4 each received 1 infusion in the left and right hemisphere at 1.0 μL/min. Results MRI calculations of Vd/Vi did not significantly differ from those obtained on post-mortem pathology. The mean measured Vd/Vi of in vivo (5.23 + /-1.67) compared to ex vivo (2.17 + /-1.39) demonstrated a significantly larger Vd/Vi for in vivo by 2.4 times (p = 0.0017). Conclusion We detected higher ratios in the in vivo subjects than in ex vivo. This difference could be explained by the extra cellular space volume fraction. Studies evaluating backflow and morphology use in vivo tissue as a medium are recommended. Further investigation is warranted to evaluate the role blood pressure and heart rate may play in human CED clinical trials.

Backflow variability shows importance of MR monitoring of CED infusions Ethan K. Brodsky, Benjamin Grabow, Martin L. Brady, Raghu Raghavan, Chris D. Ross, and Walter F. Block Medical Physics, University of Wisconsin, Madison, WI, United States, Biomedical Engineering, University of Wisconsin, Madison, WI, United States, Therataxis, LLC, Baltimore, MD, United States, Engineering Resources Group, Inc., Pembroke Pines, FL, United States

Background: Delivery of multiple collinear payloads utilizing convection-enhanced delivery (CED) has historically been performed by retraction of a needle or catheter from the most distal delivery site. Few studies have addressed end-infusion morphology and associated payload reflux in stacked and collinear infusions, and studies comparing the advancement with the retraction mode are lacking. Objective: To compare advancement versus retraction mode infusion results. Methods: Infusion cloud pairs were created with the advancement and retraction technique in agarose gel using both open end-port SmartFlow™ (SF) and valve tip (VT) catheter infusion systems. Backflow, radius of infusion, and morphology were assessed. Results: Infusions with the SF catheter, in contrast to the VT catheter, exhibited significantly more backflow in retraction mode at the shallow infusion site. Infusion morphology differed with the second infusion after retraction: the infusate at the proximal site first filling the channel left by the retraction and then being convected into gel in a pronouncedly non-spherical shape during the second infusion. Conclusions: Significant differences in cloud morphology were noted with respect to external catheter geometry with retraction versus penetration between infusions in an agarose gel model of the brain. Further study is warranted to determine optimal protocols for human clinical trials employing CED with multiple collinear payloads.

The University of Wisconsin-Madison Snowmobile Team has designed and constructed a clean and quiet, high performance snowmobile for entry in the 2012 Society of Automotive Engineers’ Clean Snowmobile Challenge. Built on a 2011 Polaris Rush ProR chassis, this machine features a Weber AG 750 cc port fuel-injected turbocharged four-stroke engine equipped with a flex-fuel sensor and Woodward control system which allows for full engine optimization using a range of fuels from E0 to E85. An electronic throttle body and a closed-loop oxygen sensor are used to control fuel-injection. Utilizing a 3-way catalyst customized for this engine by W.C. Heraeus-GmbH, this sled reduces carbon monoxide (CO) and hydrocarbons+oxides of nitrogen (HC+NOx) emissions by up to 98% to an average specific mass of 12.04, and 0.17 g/kW-hr respectively. Equipped with a specialized camshaft with low valve overlap, Wisconsin reduced both engine-out emissions and fuel consumption by approximately 10%. With all of the modifications, the clean turbocharged MPE 750 is capable of a power output of 65 kW and utilizes a custom catalytic muffler system to reduce sound levels to 71 dBa using SAE test procedure J192. The entire engine and muffler system is packaged in a manner that builds on the snowmobile’s aggressive OEM appearance. The reduced weight of the revolutionary Pro-Ride chassis in conjunction with other lightweight components results in a rider-friendly package that meets the criteria to succeed at the Clean Snowmobile Challenge and is desirable to the snowmobiling public.

Non‐Cartesian imaging sequences and navigational methods can be more sensitive to scanner imperfections that have little impact on conventional clinical sequences, an issue which has repeatedly complicated the commercialization of these techniques by frustrating transitions to multicenter evaluations. One such imperfection is phase errors caused by resonant frequency shifts from eddy currents induced in the cryostat by time‐varying gradients, a phenomenon known as B0 eddy currents. These phase errors can have a substantial impact on sequences that use ramp sampling, bipolar gradients, and readouts at varying azimuthal angles. We present a method for measuring and correcting phase errors from B0 eddy currents and examine the results on two different scanner models. This technique yields significant improvements in image quality for high‐resolution joint imaging on certain scanners. This result suggests that correcting short‐time B0 eddy currents that do not affect conventional clinical sequences may simplify the adoption of non‐Cartesian methods. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.

pictured of 1, 2, 3, 4, 5 μL/min and end of infusion, from left to right. Infusion morphology begins as the desired, roughly spherical distribution at low flow rates then transitions to significant backflow at higher flow rates. Real-time monitoring for systematic investigation of catheter design and infusion protocol effect on CED performance Benjamin Grabow, Raghu Raghavan, Martin Brady, Ken Kubota, Chris Ross, Samuel Hurley, Ethan Brodsky, James Raschke, Andy Alexander, and Walter Block Medical Physics, University of Wisconsin, Madison, WI, United States, Therataxis LLC, Baltimore, MD, United States, Kinetics Foundation, Los Altos, CA, United States, Engineering Resources Group, Inc, Hialeah, FL, United States

Convection-enhanced delivery (CED) is an advanced infusion technique used to deliver therapeutic agents into the brain. CED has shown promise in recent clinical trials. Independent verification of published parameters is warranted with benchmark testing of published parameters in applicable models such as gel phantoms, ex vivo tissue and in vivo non-human animal models to effectively inform planned and future clinical therapies. In the current study, specific performance characteristics of two CED infusion catheter systems, such as backflow, infusion cloud morphology, volume of distribution (mm3) versus the infused volume (mm3) (Vd/Vi) ratios, rate of infusion (µl min−1) and pressure (mmHg), were examined to ensure published performance standards for the ERG valve-tip (VT) catheter. We tested the hypothesis that the ERG VT catheter with an infusion protocol of a steady 1 µl min−1 functionality is comparable to the newly FDA approved MRI Interventions Smart Flow (SF) catheter with the UCSF infusion protocol in an agarose gel model. In the gel phantom models, no significant difference was found in performance parameters between the VT and SF catheter. We report, for the first time, such benchmark characteristics in CED between these two otherwise similar single-end port VT with stylet and end-port non-stylet infusion systems. Results of the current study in agarose gel models suggest that the performance of the VT catheter is comparable to the SF catheter and warrants further investigation as a tool in the armamentarium of CED techniques for eventual clinical use and application.