Groves, M. | bioRxiv Science

bioRxiv2020

Toward Minimally Invasive Therapeutic Ultrasound: Ultrasound-guided Ablation in Neuro-oncology

IntroductionTo improve patient outcomes (eg, reducing blood loss and infection), practitioners have gravitated toward noninvasive and minimally invasive surgeries (MIS), which demand specialized toolkits. Focused ultrasound, for example, facilitates thermal ablation from a distance, thereby reducing injury to surrounding tissue. Focused ultrasound can often be performed noninvasively; however, it is more difficult to carry out in neuro-oncological tumors, as ultrasound is dramatically attenuated while propagating through the skull. This shortcoming has prompted exploration of MIS options for intracranial placement of focused ultrasound probes, such as within the BrainPath (NICO Corporation, Indianapolis, IN). Herein, we present the design, development, and in vitro testing of an image-guided, focused ultrasound prototype designed for use in MIS procedures. This probe can ablate neuro-oncological lesions despite its small size. Materials & MethodsPreliminary prototypes were iteratively designed, built, and tested. The final prototype consisted of three 8-mm-diameter therapeutic elements guided by an imaging probe. Probe functionality was validated on a series of tissue-mimicking phantoms. ResultsLesions were created in tissue-mimicking phantoms with average dimensions of 2.5x1.2x6.5mm and 3.4x3.25x9.36mm after 10- and 30-second sonification, respectively. 30s sonification with 118W power at 50% duty cycle generated a peak temperature of 68{degrees}C. Each ablation was visualized in real time by the built-in imaging probe. ConclusionWe developed and validated an ultrasound-guided focused ultrasound probe for use in MIS procedures. The dimensional constraints of the prototype were designed to reflect those of BrainPath trocars, which are MIS tools used to create atraumatic access to deep-seated brain pathologies. HIGHLIGHTSO_LIAn ultrasound-guided, focused ultrasound prototype was developed and validated C_LIO_LIThe therapeutic transducer (1.5MHz) consisted of three 8-mm circular elements C_LIO_LIElements were placed on a 9x32mm curved rectangular aperture: 45mm radius curvature C_LIO_LIFunctionality was examined on tissue-mimicking phantoms C_LIO_LI2.5x1.2x6.5mm and 3.4x3.25x9.36mm lesions were seen for 10 and 30s sonification C_LI

bioengineering↗

bioRxiv2019

Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy

BICD2 is a key component of the dynein/dynactin motor complex. Autosomal dominant mutations in BICD2 cause Spinal Muscular Atrophy Lower Extremity Predominant 2 (SMALED2), a developmental disease of motor neurons. In this study we sought to examine the motor neuron phenotype of conditional Bicd2-/- mice. Bicd2-/- mice show a significant reduction in the number of motor axons of the L4 ventral root compared to wild type mice. Muscle-specific knockout of Bicd2, but not motor neuron-specific Bicd2 loss, results in a reduction in L4 ventral axons comparable to global Bicd2-/- mice. Rab6, a small GTPase required for the sorting of secretory vesicles from the TGN to the plasma membrane is a major binding partner of BICD2. We therefore examined the secretory pathway in SMALED2 patient fibroblasts and demonstrated impaired flow of constitutive secretory cargoes. Together, these data indicate that BICD2 loss from muscles is a major driver of non-cell autonomous pathology with important implications for future therapeutic approaches to SMALED2. SummaryMissense mutations in the cargo adaptor protein BICD2 cause SMALED2, a developmental disease of motor neurons. In this study, the authors show that BICD2 mutations cause motor neuron loss by a non-cell autonomous mechanism determining a disabling impairment of muscle function.

neuroscience↗