NOVEL PHANTOMS AND POST-PROCESSING FOR DIFFUSION SPECTRUM IMAGING

High Angular Resolution Diffusion Imaging (HARDI) techniques, including Diffusion Spectrum Imaging (DSI), have been proposed to resolve crossing and other complex fiber architecture in the human brain white matter. In these methods, directional information of diffusion is inferred from the peaks in the orientation distribution function (ODF). Extensive studies using histology on macaque brain, cat cerebellum, rat hippocampus and optic tracts, and bovine tongue are qualitatively in agreement with the DSI-derived ODFs and tractography. However, there are only two studies in the literature which validated the DSI results using physical phantoms and both these studies were not performed on a clinical MRI scanner. Also, the limited studies which optimized DSI in a clinical setting, did not involve a comparison against physical phantoms. Finally, there is lack of consensus on the necessary pre- and post-processing steps in DSI; and ground truth diffusion fiber phantoms are not yet standardized. Therefore, the aims of this dissertation were to design and construct novel diffusion phantoms, employ post-processing techniques in order to systematically validate and optimize (DSI)-derived fiber ODFs in the crossing regions on a clinical 3T MR scanner, and develop user-friendly software for DSI data reconstruction and analysis. Phantoms with a fixed crossing fiber configuration of two crossing fibers at 90° and 45° respectively along with a phantom with three crossing fibers at 60°, using novel hollow plastic capillaries and novel placeholders, were constructed. T2-weighted MRI results on these phantoms demonstrated high SNR, homogeneous signal, and absence of air bubbles. Also, a technique to deconvolve the response function of an individual peak from the overall ODF was implemented, in addition to other DSI post-processing steps. This technique greatly improved the angular resolution of the otherwise unresolvable peaks in a crossing fiber ODF. The effects of DSI acquisition parameters and SNR on the resultant angular accuracy of DSI on the clinical scanner were studied and quantified using the developed phantoms. With a high angular direction sampling and reasonable levels of SNR, quantification of a crossing region in the 90°, 45° and 60° phantoms resulted in a successful detection of angular information with mean ± SD of 86.93°±2.65°, 44.61°±1.6° and 60.03°±2.21° respectively, while simultaneously enhancing the ODFs in regions containing single fibers. For the applicability of these validated methodologies in DSI, improvement in ODFs and fiber tracking from known crossing fiber regions in normal human subjects were demonstrated; and an in-house software package in MATLAB which streamlines the data reconstruction and post-processing for DSI, with easy to use graphical user interface was developed. In conclusion, the phantoms developed in this dissertation offer a means of providing ground truth for validation of reconstruction and tractography algorithms of various diffusion models (including DSI). Also, the deconvolution methodology (when applied as an additional DSI post-processing step) significantly improved the angular accuracy of the ODFs obtained from DSI, and should be applicable to ODFs obtained from the other high angular resolution diffusion imaging techniques.

Evaluation of PRESAGE® dosimeters for brachytherapy sources and the 3D dosimetry and characterization of the new AgX100 125I seed model

With continuous new improvements in brachytherapy source designs and techniques, method of 3D dosimetry for treatment dose verifications would better ensure accurate patient radiotherapy treatment. This study was aimed to first evaluate the 3D dose distributions of the low-dose rate (LDR) Amersham 6711 OncoseedTM using PRESAGE® dosimeters to establish PRESAGE® as a suitable brachytherapy dosimeter. The new AgX100 125I seed model (Theragenics Corporation) was then characterized using PRESAGE® following the TG-43 protocol. PRESAGE® dosimeters are solid, polyurethane-based, 3D dosimeters doped with radiochromic leuco dyes that produce a linear optical density response to radiation dose. For this project, the radiochromic response in PRESAGE® was captured using optical-CT scanning (632 nm) and the final 3D dose matrix was reconstructed using the MATLAB software. An Amersham 6711 seed with an air-kerma strength of approximately 9 U was used to irradiate two dosimeters to 2 Gy and 11 Gy at 1 cm to evaluate dose rates in the r=1 cm to r=5 cm region. The dosimetry parameters were compared to the values published in the updated AAPM Report No. 51 (TG-43U1). An AgX100 seed with an air-kerma strength of about 6 U was used to irradiate two dosimeters to 3.6 Gy and 12.5 Gy at 1 cm. The dosimetry parameters for the AgX100 were compared to the values measured from previous Monte-Carlo and experimental studies. In general, the measured dose rate constant, anisotropy function, and radial dose function for the Amersham 6711 showed agreements better than 5% compared to consensus values in the r=1 to r=3 cm region. The dose rates and radial dose functions measured for the AgX100 agreed with the MCNPX and TLD-measured values within 3% in the r=1 to r=3 cm region. The measured anisotropy function in PRESAGE® showed relative differences of up to 9% with the MCNPX calculated values. It was determined that post-irradiation optical density change over several days was non-linear in different dose regions, and therefore the dose values in the r=4 to r=5 cm regions had higher uncertainty due to this effect. This study demonstrated that within the radial distance of 3 cm, brachytherapy dosimetry in PRESAGE® can be accurate within 5% as long as irradiation times are within 48 hours.

STUDIES ON CHOLINERGIC FUNCTION AND MEMORY IN MICE (CHOLINOTOXINS, WORKING, REFERENCE MEMORY, RADIAL ARM MAZE)

Considerable evidence suggests that central cholinergic neurons participate in either acquisition, storage or retrieval of information. Experiments were designed to evaluate information processing in mice following either reversible or irreversible impairment in central cholinergic activity. The cholinergic receptor antagonists, atropine and methylatropine were used to reversibly inhibit cholinergic transmission. Irreversible impairment in central cholinergic function was achieved by central administration of the cholinergic-specific neurotoxins, N-ethyl-choline aziridinium (ECA) and N-ethyl-acetylcholine aziridinium (EACA).^ ECA and EACA appear to act by irreversible inhibition of high affinity choline uptake (proposed rate-limiting step in acetylcholine synthesis). Intraventricular administration of ECA or EACA produced persistent reduction in hippocampal choline acetyltransferase activity. Other neuronal systems and brain regions showed no evidence of toxicity.^ Mice treated with either ECA or EACA showed behavioral deficits associated with cholinergic dysfunction. Passive avoidance behavior was significantly impaired by cholinotoxin treatment. Radial arm maze performance was also significantly impaired in cholinotoxin-treated animals. Deficits in radial arm maze performance were transient, however, such that rapid and apparent complete behavioral recovery was seen during retention testing. The centrally active cholinergic receptor antagonist atropine also caused significant impairment in radial arm maze behavior, while equivalent doses of methylatropine were without effect.^ The relative effects of cholinotoxin and receptor antagonist treatment on short-term (working) memory and long-term (reference) memory in radial arm maze behavior were examined. Maze rotation studies indicated that there were at least two different response strategies which could result in accurate maze performance. One strategy involved the use of response algorithms and was considered to be a function of reference memory. Another strategy appeared to be primarily dependent on spatial working memory. However, all behavioral paradigms with multiple trails have reference memory requirements (i.e. information useful over all trials). Performance was similarly affected following either cholinotoxin or anticholinergic treatment, regardless of the response strategy utilized. In addition, rates of behavioral recovery following cholinotoxin treatment were similar between response groups. It was concluded that both cholinotoxin and anticholinergic treatment primarily resulted in impaired reference memory processes. ^