Michael D. Mills

Functional Redundancy of Ventral Spinal Locomotor Pathways

Identification of long tracts responsible for the initiation of spontaneous locomotion is critical for spinal cord injury (SCI) repair strategies. Pathways derived from the mesencephalic locomotor region and pontomedullary medial reticular formation responsible for fictive locomotion in decerebrate preparations project to the thoracolumbar levels of the spinal cord via reticulospinal axons in the ventrolateral funiculus (VLF). However, white matter regions critical for spontaneous over-ground locomotion remain unclear because cats, monkeys, and humans display varying degrees of locomotor recovery after ventral SCIs. We studied the contributions of myelinated tracts in the VLF and ventral columns (VC) to spontaneous over-ground locomotion in the adult rat using demyelinating lesions. Animals received ethidium bromide plus photon irradiation producing discrete demyelinating lesions sufficient to stop axonal conduction in the VLF, VC, VLF–VC, or complete ventral white matter (CV). Behavior [open-field Basso, Beattie, and Bresnahan (BBB) scores and grid walking] and transcranial magnetic motor-evoked potentials (tcMMEP) were studied at 1, 2, and 4 weeks after lesion. VLF lesions resulted in complete loss or severe attenuation of tcMMEPs, with mean BBB scores of 18.0, and no grid walking deficits. VC lesions produced behavior similar to VLF-lesioned animals but did not significantly affect tcMMEPs. VC–VLF and CV lesions resulted in complete loss of tcMMEP signals with mean BBB scores of 12.7 and 6.5, respectively. Our data support a diffuse arrangement of axons within the ventral white matter that may comprise a system of multiple descending pathways subserving spontaneous over-ground locomotion in the intact animal.

Both dorsal and ventral spinal cord pathways contribute to overground locomotion in the adult rat.

Identification of long tracts responsible for spontaneous locomotion is critical for spinal cord injury (SCI) repair strategies. We recently demonstrated that extensive demyelination of adult rat thoracic ventral columns, ventromedial, and ventrolateral white matter produces persistent, significant open-field hindlimb locomotor deficits. Locomotor movements resulting from stimulation of the pontomedullary locomotor region are inhibited by dorsolateral funiculus (DLF) lesions suggesting that important pathways for locomotion may also exist in the dorsal white matter. However, dorsal hemisections that interrupt dorsal columns/dorsal corticospinal tract (DC/CST) and DLF pathways do not produce persistent, severe locomotor deficits in the adult rat. We studied the contributions of myelinated tracts in the DLF and DC/CST to overground locomotion following complete conduction blockade of axons in the ventrolateral funiculus (VLF), a region important for locomotor movements and for transcranial magnetic motor-evoked potentials (tcMMEP). Animals received ethidium bromide plus photon irradiation to produce discrete demyelinating lesions sufficient to stop axonal conduction in the VLF, combined VLF + DLF, or combined VLF + DC/CST. Open-field BBB scores and tcMMEPs were studied at 1, 2, 3, and 4 weeks postlesion. VLF lesions resulted in mean BBB scores of 17 at 4 weeks. VLF + DC/CST and VLF + DLF lesions resulted in mean BBB scores of 15.9 and 11.1, respectively. TcMMEPs were absent in all lesion types confirming VLF conduction blockade throughout the study. Our data indicate that significant contributions to locomotion from myelinated pathways within the rat DLF can be revealed when combined with simultaneous compromise of the VLF.

Schwann cell-like differentiation by adult oligodendrocyte precursor cells following engraftment into the demyelinated spinal cord is BMP-dependent

The development of remyelinating strategies designed to enhance recruitment and differentiation of endogenous precursor cells available to a site of demyelination in the adult spinal cord will require a fundamental understanding of the potential for adult spinal cord precursor cells to remyelinate as well as an insight into epigenetic cues that regulate their mobilization and differentiation. The ability of embryonic and postnatal neural precursor cell transplants to remyelinate the adult central nervous system is well documented, while no transplantation studies to date have examined the remyelinating potential of adult spinal‐cord‐derived oligodendrocyte precursor cells (adult OPCs). In the present study, we demonstrate that, when transplanted subacutely into spinal ethidium bromide/X‐irradiated (EB‐X) lesions, adult OPCs display a limited capacity for oligodendrocyte remyelination. Interestingly, the glia‐free environment of EB lesions promotes engrafted adult OPCs to differentiate primarily into cells with immunophenotypic and ultrastructural characteristics of myelinating Schwann cells (SCs). Astrocytes modulate this potential, as evidenced by the demonstration that SC‐like differentiation is blocked when adult OPCs are co‐transplanted with astrocytes. We further show that inhibition of bone morphogenetic protein (BMP) signaling through noggin overexpression by engrafted adult OPCs is sufficient to block SC‐like differentiation within EB‐X lesions. Present data suggest that the macroglial‐free environment of acute EB lesions in the ventrolateral funiculus is inhibitory to adult spinal cord‐derived OPC differentiation into remyelinating oligodendrocytes, while the presence of BMPs and absence of noggin promotes SC‐like differentiation, thereby unmasking a surprising lineage fate for these cells.

Commissioning of a mobile electron accelerator for intraoperative radiotherapy

Radiation performance characteristics of a dedicated intraoperative accelerator were determined to prepare the unit for clinical use. The linear accelerator uses standing wave X‐band technology (wavelength approximately 3 centimeters) in order to minimize the mass of the accelerator. The injector design, smaller accelerator components, and low electron beam currents minimize radiation leakage. The unit may be used in a standard operating room without additional shielding. The mass of the accelerator gantry is 1250 Kg (weight approximately 2750 lbs) and the unit is transportable between operating rooms. Nominal electron energies are 4, 6, 9, and 12 MeV, and operate at selectable dose rates of 2.5 or 10 Gray per minute. Dmax depths in water for a 10 cm applicator are 0.7, 1.3, 1.7, and 2.0 for these energies, respectively. The depths of 80% dose are 1.2, 2.1, 3.1, and 3.9 cm, respectively. Absolute calibration using the American Association of Physicists in Medicine TG‐51 protocol was performed for all electron energies using the 10 cm applicator. Applicator sizes ranged from 3 to 10 cm diameter for flat applicators, and 3 to 6 cm diameter for 30° beveled applicators. Output factors were determined for all energies relative to the 10 cm flat applicator. Central axis depth dose profiles and isodose plots were determined for every applicator and energy combination. A quality assurance protocol, performed each day before patient treatment, was developed for output and energy constancy. PACS number(s): 87.53.–j, 87.52.–g

Shielding assessment of a mobile electron accelerator for intra-operative radiotherapy

The purpose of this investigation is to measure, characterize and report stray photon leakage and scatter radiation measurements from the Mobetron, an intra‐operative electron linear accelerator designed for use in an operating room environment. The study is needed due to recent changes to the shielding design of the Mobetron, and also to provide specific information that may be required by regulation in various jurisdictions. An analysis is performed on a number of manufactured units to determine an average 3D stray photon radiation map. This information provides a basis for determining patient‐based load restrictions and/or additional shielding for the operating room. The data presented evaluates the number of procedures for which the Mobetron may be safely operated in a typical unshielded operating room. PACS number: 87.53.‐j; 87.56.‐v

State of the JACMP: Thoughts on our transition and a fond farewell to Multimed

As I write this Editorial on October 25, I realize it will be the last document submitted through the Public Knowledge Project (PKP) system and published by Multimed. Beginning October 26, we will accept submissions and resubmissions within the Wiley/Electronic Journal Press systems through the links provided in the Announcements and in the Section Editor/Author/Reviewer corresponding emails. We intend to keep the PKP system live through December 31, but it will be closed down on January 1 and replaced by the new Wiley/EJP site. Please help us by completing any reviews that you may have been asked to do. By December 31 we must not have any articles left in the PKP system. Sometime ago, I was asked to write a support letter for Multimed to be used in a packet to prospective clients. This is what came to mind (some information is updated):

VOLUMETRIC MODULATED ARC THERAPY (VMAT) TREATMENT PLANNING FOR SUPERFICIAL TUMORS

The physicians planning objective is often a uniform dose distribution throughout the planning target volume (PTV), including superficial PTVs on or near the surface of a patients body. Varians Eclipse treatment planning system uses a progressive resolution optimizer (PRO), version 8.2.23, for RapidArc dynamic multileaf collimator volumetric modulated arc therapy planning. Because the PRO is a fast optimizer, optimization convergence errors (OCEs) produce dose nonuniformity in the superficial area of the PTV. We present a postsurgical cranial case demonstrating the recursive method our clinic uses to produce RapidArc treatment plans. The initial RapidArc treatment plan generated using one 360 degrees arc resulted in substantial dose nonuniformity in the superficial section of the PTV. We demonstrate the use of multiple arcs to produce improved dose uniformity in this region. We also compare the results of this superficial dose compensation method to the results of a recursive method of dose correction that we developed in-house to correct optimization convergence errors in static intensity-modulated radiation therapy treatment plans. The results show that up to 4 arcs may be necessary to provide uniform dose to the surface of the PTV with the current version of the PRO.

Algorithm for correcting optimization convergence errors in Eclipse

IMRT plans generated in Eclipse use a fast algorithm to evaluate dose for optimization and a more accurate algorithm for a final dose calculation, the Analytical Anisotropic Algorithm. The use of a fast optimization algorithm introduces optimization convergence errors into an IMRT plan. Eclipse has a feature where optimization may be performed on top of an existing base plan. This feature allows for the possibility of arriving at a recursive solution to optimization that relies on the accuracy of the final dose calculation algorithm and not the optimizer algorithm. When an IMRT plan is used as a base plan for a second optimization, the second optimization can compensate for heterogeneity and modulator errors in the original base plan. Plans with the same field arrangement as the initial base plan may be added together by adding the initial plan optimal fluence to the dose correcting plan optimal fluence. A simple procedure to correct for optimization errors is presented that may be implemented in the Eclipse treatment planning system, along with an Excel spreadsheet to add optimized fluence maps together. PACS number: 87.53.Bn, 87.56.By

Geometry function of a linear brachytherapy source

An equation is derived for the TG43 geometry function, G(r,θ), of a linear brachytherapy source in terms of its active length. This equation is validated by comparison to published values. It is then used to calculate values of the geometry function for the Model 200 103Pd seed, which is a segmented linear source. PACS number(s): 87.53.–j

Radiation shielding design of a new tomotherapy facility

It is expected that intensity modulated radiation therapy (IMRT) and image guided radiation therapy (IGRT) will replace a large portion of radiation therapy treatments currently performed with conventional MLC-based 3D conformal techniques. IGRT may become the standard of treatment in the future for prostate and head and neck cancer. Many established facilities may convert existing vaults to perform this treatment method using new or upgraded equipment. In the future, more facilities undoubtedly will be considering de novo designs for their treatment vaults. A reevaluation of the design principles used in conventional vault design is of benefit to those considering this approach with a new tomotherapy facility. This is made more imperative as the design of the TomoTherapy system is unique in several aspects and does not fit well into the formalism of NCRP 49 for a conventional linear accelerator.