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The functional roles of the Caudate nucleus (Cd) are well known. Selective Cd lesions can be found in neurological disorders. However, little is known about the dynamics of the behavioral changes during progressive Cd ablation. Current stereotactic radiosurgery technologies allow the progressive ablation of a brain region with limited adverse effects in surrounding normal tissues. This could be of high interest for the study of the modified behavioral functions in relation with the degree of impairment of the brain structures. Using hypofractionated stereotactic radiotherapy combined with synchrotron microbeam radiation, we investigated, during one year after irradiation, the effects of unilateral radio-ablation of the right Cd on the behavior of Yucatan minipigs. The right Cd was irradiated to a minimal dose of 35.5 Gy delivered in three fractions. MRI-based morphological brain integrity and behavioral functions, i.e. locomotion, motivation/hedonism were assessed. We detected a progressive radio-necrosis leading to a quasi-total ablation one year after irradiation, with an additional alteration of surrounding areas. Transitory changes in the motivation/hedonism were firstly detected, then on locomotion, suggesting the influence of different compensatory mechanisms depending on the functions related to Cd and possibly some surrounding areas. We concluded that early behavioral changes related to eating functions are relevant markers for the early detection of ongoing lesions occurring in Cd-related neurological disorders.

Purpose: Intrastriatal neural transplantation using multiple grafts is an experimental approach to the treatment of Huntington's disease (HD). Brain atrophy makes stereotactic plans in these patients a tedious procedure with a risk of suboptimal spatial distribution of the grafts in transplantation procedures. Here we present a self-developed software to optimize the surgical stereotactic planning for bilateral neurotransplantation procedures. It allows close to symmetrical distribution of the stereotactic coordinates in relation to the mid-commissural point (MCP), proposing automatically the planning coordinates for the first transplanted hemisphere and mirrored coordinates to be used in the contra-lateral hemisphere., Methods: Twenty-two consecutive HD patients underwent bilateral stereotactic striatal transplantation. Two caudate nucleus and four putaminal tracks were planned bilaterally. For the second, contra-lateral transplantation, the coordinates were mirrored in order to determine contralateral targets and trajectories. Intra-individual comparison between software given coordinates and finally used coordinates was performed., Results: No statistical significance was found comparing a) the differences between coordinates proposed by the software and the final coordinates and b) the distribution of the transplantation sites in relation to the midline for the right vs. left hemisphere. No intra- or postoperative transplantation-related adverse events occurred., Conclusions: The use of model-based and mirrored coordinates allowed optimal spatial distribution of the grafts. Minor changes were required comparing right to left coordinates giving proof-of principle. The initial use of the software suggests that it may be useful in experimental transplantation trials where neural cell grafts are to be implanted into predefined target sites in the human brain, whether unilateral or bilateral.

Gold nanoparticles are excellent intracellular markers in X-ray imaging. Having shown previously the suitability of gold nanoparticles to detect small groups of cells with the synchrotron-based computed tomography (CT) technique both ex vivo and in vivo, it is now demonstrated that even single-cell resolution can be obtained in the brain at least ex vivo. Working in a small animal model of malignant brain tumour, the image quality obtained with different imaging modalities was compared. To generate the brain tumour, 1 × 10(5) C6 glioma cells were loaded with gold nanoparticles and implanted in the right cerebral hemisphere of an adult rat. Raw data were acquired with absorption X-ray CT followed by a local tomography technique based on synchrotron X-ray absorption yielding single-cell resolution. The reconstructed synchrotron X-ray images were compared with images obtained by small animal magnetic resonance imaging. The presence of gold nanoparticles in the tumour tissue was verified in histological sections.

Purpose: Synchrotron microbeam radiation therapy (MRT) is a radiosurgery concept in the preclinical stage, developed mainly for brain tumor treatment. Experimental studies suggest that with MRT a better therapeutic index can be obtained than with homogenous field radiotherapy, but the underlying cellular mechanisms need further understanding. The aim of this study was to investigate the dynamics of radiation-induced bystander effects (RIBE) in rats after exposing one brain hemisphere to either MRT or homogenous synchrotron radiation (HSR)., Materials and Methods: Healthy and tumor-bearing Wistar rats were exposed to doses of 17.5, 35, 70 or 350 Gy, applied either as MRT or HSR to the right cerebral hemisphere. Rats were euthanized at 4, 8 and 12 hours after irradiation to assess the release of bystander signals. Brains and urinary bladders were dissected, and explants for bystander clonogenic reporter assays were set up., Results: Clonogenic survival showed that RIBE occurred in both the non-irradiated brain hemisphere and in bladder of normal and tumor-bearing rats, while the irradiated hemisphere showed the direct effects of radiation., Conclusion: The RIBE observed in our reporter cells shows that both MRT and HSR yield a demonstrable abscopal effect after high doses of irradiation; presumably as part of a systemic response.

Purpose: To further evaluate the use of microbeam irradiation (MBI) as a potential means of non-invasive brain tumor treatment by investigating the induction of a bystander effect in non-irradiated tissue., Methods: Adult rats were irradiated with 35 or 350 Gy at the European Synchotron Research Facility (ESRF), using homogenous (broad beam) irradiation (HI) or a high energy microbeam delivered to the right brain hemisphere only. The proteome of the frontal lobes were then analyzed using two-dimensional electrophoresis (2-DE) and mass spectrometry., Results: HI resulted in proteomic responses indicative of tumourigenesis; increased albumin, aconitase and triosphosphate isomerase (TPI), and decreased dihydrolipoyldehydrogenase (DLD). The MBI bystander effect proteomic changes were indicative of reactive oxygen species mediated apoptosis; reduced TPI, prohibitin and tubulin and increased glial fibrillary acidic protein (GFAP). These potentially anti-tumourigenic apoptotic proteomic changes are also associated with neurodegeneration. However the bystander effect also increased heat shock protein (HSP) 71 turnover. HSP 71 is known to protect against all of the neurological disorders characterized by the bystander effect proteome changes., Conclusions: These results indicate that the collective interaction of these MBI-induced bystander effect proteins and their mediation by HSP 71, may confer a protective effect which now warrants additional experimental attention.

The ability to perform cell tracking using x-ray computed tomography combined with gold nanoparticles has been demonstrated recently on ex vivo samples using different malignant and nonmalignant cell lines. Here we proved the concept of the method for in vivo assessment in a small-animal model of malignant brain tumors. The limitations of the method due to radiation dose constraints were investigated using Monte Carlo simulations. Taking into consideration different x-ray entrance doses and the spatial resolution, the visibility of the cell clusters was evaluated. The results of the experiments conducted on mice implanted with F98 tumor cells confirmed the prediction of the Monte Carlo calculations. Small clusters of cells exogenously loaded with gold nanoparticles could be visualized using our in vivo method., From the Clinical Editor: This article discusses the use of CT-based detection of gold nanoparticle loaded cells of interest in small-animal models of malignant brain tumors, where small clusters of cells loaded with gold nanoparticles could be visualized., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: In order to improve image quality in a simultaneous fMRI-EEG study with patients suffering from the involuntary movements typical for Huntington's disease, the aim was to develop a technique for immobilizing the heads of our patients inside an MRI head coil., Methods: We modified a mask technique previously used for reliable repositioning in temporally fractionated radiotherapy. The mask was tested in three patients with Huntington's disease, acquiring structural and functional MR images with simultaneous EEG with and without the mask., Results: Image as well as EEG signal quality were significantly improved in patients wearing the mask. However, the image quality with mask was comparable to acquisitions from patients without movement disorders only in patients with light to moderate dyskinesia. Although image quality was also significantly improved in a patient suffering from severe dyskinesia with quasi-continuous involuntary movements, the quality of both the MR images as well as the EEG signal was lower than what would be expected in a healthy control person., Conclusion: We have succeeded in developing a mask that fits into the MRI head coil, does not disturb the MRI signal, and significantly improves both fMRI and EEG signal quality.

We have conducted the first in-vivo experiments in pencilbeam irradiation, a new synchrotron radiation technique based on the principle of microbeam irradiation, a concept of spatially fractionated high-dose irradiation. In an animal model of adult C57 BL/6J mice we have determined technical and physiological limitations with the present technical setup of the technique. Fifty-eight animals were distributed in eleven experimental groups, ten groups receiving whole brain radiotherapy with arrays of 50 µm wide beams. We have tested peak doses ranging between 172 Gy and 2,298 Gy at 3 mm depth. Animals in five groups received whole brain radiotherapy with a center-to-center (ctc) distance of 200 µm and a peak-to-valley ratio (PVDR) of ∼ 100, in the other five groups the ctc was 400 µm (PVDR ∼ 400). Motor and memory abilities were assessed during a six months observation period following irradiation. The lower dose limit, determined by the technical equipment, was at 172 Gy. The LD50 was about 1,164 Gy for a ctc of 200 µm and higher than 2,298 Gy for a ctc of 400 µm. Age-dependent loss in motor and memory performance was seen in all groups. Better overall performance (close to that of healthy controls) was seen in the groups irradiated with a ctc of 400 µm.

Abstract: Glioblastoma multiforme (GBM) is a highly malignant human brain tumour for which no cure is available at present. Numerous clinical studies as well as animal experiments are under way with the goal being to understand tumour biology and develop potential therapeutic approaches. C6 cell glioma in the adult rat is a frequently used and well accepted animal model for the malignant human glial tumour. By combining standard analytical methods such as histology and immunohistochemistry with Fourier Transform Infrared (FTIR) microspectroscopic imaging and multivariate statistical approaches, we are developing a novel approach to tumour diagnosis which allows us to obtain information about the structure and composition of tumour tissues that could not be obtained easily with either method alone. We have used a “Stingray” FTIR imaging spectrometer to analyse and compare the compositions of coronal brain tissue sections of a tumour-bearing animal and those from a healthy animal. We have found that the tumour tissue has a characteristic chemical signature, which distinguishes it from tumour-free brain tissue. The physical-chemical differences, determined by image and spectral comparison are consistent with changes in total protein absorbance, phosphodiester absorbance and physical dispersive artefacts. The results indicate that FTIR imaging analysis could become a valuable analytic method in brain tumour research and possibly in the diagnosis of human brain tumours. [Copyright &y& Elsevier]