Electrical impedance tomography of human brain function.

Electroencephalography (EEG) has been used for over 70 years to record the electrical signals of the brain. Electrical impedance tomography (EIT) is a more recent imaging technique which when applied to brain function and structure has the potential to provide a rapid portable bedside neuroimaging device. The purpose of this work has been to investigate several applications of EIT and EEG in the imaging of brain function. EEG does not always give the required spatial information, especially if the current generator is in the deep brain structures such as the hypothalamus. Dipole source localisation has become a common research tool that can be used estimate the current sources that are responsible for the EEG signals recorded on the scalp. Using this method, the accuracy and ease of use for four commercially available headnets was assessed. No headnet performed better at localisation, with all localising one dipole well, and two or three dipoles poorly. EIT has the potential to image the impedance changes that occur during neuronal depolarisation. Modelling work has been carried out to predict the size of these impedance changes and this thesis presents some work carried out in an attempt to record these changes in human subjects. The levels of noise at present are too great to record the impedance changes, but suggestion for improving the signal to noise ratio are given. Previous work on EIT and fMRI studies has shown that there are changes in blood volume (and as a result changes in impedance) after interictal spike activity. The impedance changes relating to the blood flow response to interictal epileptiform activity were recorded using EEG-correlated continuous EIT acquisition from scalp electrodes from patients on telemetry. Despite averaging up to 900 spikes, there was no recordable change in impedance after the interictal activity. Bioimpedance changes also occur due to pathological conditions. Multifrequcncy HIT makes use of the differences in impedance properties between healthy and ischaemic or tumour tissue, in an attempt to image these conditions. Data were collected from patients with tumours and other conditions and healthy volunteers, and the raw data and images compared. No differences were seen in the raw data between the different patients groups thought changes were seen in individual patients. . These results will inform the design of an EIT system which operates at a lower frequency band where the largest changes in impedance are seen

Minimally invasive therapies for the brain using magnetic particles

Delivering a therapy with precision, while reducing off target effects is key to the success of any novel therapeutic intervention. This is of most relevance in the brain, where the preservation of surrounding healthy tissue is crucial in reducing the risk of cognitive impairment and improving patient prognosis. Our scientific understanding of the brain would also benefit from minimally invasive investigations of specific cell types so that they may be observed in their most natural physiological environment. Magnetic particles based techniques have the potential to deliver cellular precision in a minimally invasive manner. When inside the body, Magnetic particles can be actuated remotely using externally applied magnetic fields while their position can be detected non-invasively using MRI. The magnetic forces applied to the particles however, rapidly decline with increasing distance from the magnetic source. It is therefore critical to understand the amount of force needed for a particular application. The properties of the magnetic particle such as the size, shape and magnetic content, as well as the properties of the applied magnetic field, can then be tailored to that application. The aim of this thesis was to develop magnetic particle based techniques for precise manipulation of cells in the brain. Two different approaches were explored, utilising the versatile nature of magnetic actuation for two different applications. The first approach uses magnetic nanoparticles to mechanically stimulate a specific cell type. Magnetic particles conjugated with the antibody ACSA-1 would selectively bind to astrocytes to evoke the controlled release of ATP and induce a calcium flux which are used for communication with neighbouring cells. This approach allows for the investigation into the role of astrocytes in localised brain regions using a naturally occurring actuation process (mechanical force) without effecting their natural environment. The second approach uses a millimetre sized magnetic particle which can be navigated through the brain and ablate localised regions of cells using a magnetic resonance imaging system. The magnetic particle causes a distinct contrast in MRI images, allowing for precise detection of its location so that it may be iteratively guided along a pre-determined path to avoid eloquent brain regions. Once at the desired location, an alternating magnetic field can be applied causing the magnetic particle to heat and deliver controllable, well defined regions of cell death. The forces needed for cell stimulation are orders of magnitude less than the forces needed to guide particles through the brain. Chapters 4 and 5 use external magnets to deliver forces in the piconewton range. While stimulation was demonstrated in small animals, scaling up this technique to human proportions remains a challenge. Chapters 6 and 7 use a preclinical MRI system to generate forces in the millinewton range, allowing the particle to be moved several centimetres through the brain within a typical surgical timescale. When inside the scanner, an alternating magnetic field causes the particle to heat rapidly, enabling the potential for multiple ablations within a single surgery. For clinical translation of this technique, MRI scanners would require a dedicated propulsion gradient set and heating coil

The Estimation and Correction of Rigid Motion in Helical Computed Tomography

X-ray CT is a tomographic imaging tool used in medicine and industry. Although technological developments have significantly improved the performance of CT systems, the accuracy of images produced by state-of-the-art scanners is still often limited by artefacts due to object motion. To tackle this problem, a number of motion estimation and compensation methods have been proposed. However, no methods with the demonstrated ability to correct for rigid motion in helical CT scans appear to exist. The primary aims of this thesis were to develop and evaluate effective methods for the estimation and correction of arbitrary six degree-of-freedom rigid motion in helical CT. As a first step, a method was developed to accurately estimate object motion during CT scanning with an optical tracking system, which provided sub-millimetre positional accuracy. Subsequently a motion correction method, which is analogous to a method previously developed for SPECT, was adapted to CT. The principle is to restore projection consistency by modifying the source-detector orbit in response to the measured object motion and reconstruct from the modified orbit with an iterative reconstruction algorithm. The feasibility of this method was demonstrated with a rapidly moving brain phantom, and the efficacy of correcting for a range of human head motions acquired from healthy volunteers was evaluated in simulations. The methods developed were found to provide accurate and artefact-free motion corrected images with most types of head motion likely to be encountered in clinical CT imaging, provided that the motion was accurately known. The method was also applied to CT data acquired on a hybrid PET/CT scanner demonstrating its versatility. Its clinical value may be significant by reducing the need for repeat scans (and repeat radiation doses), anesthesia and sedation in patient groups prone to motion, including young children

Developing A Novel Theranostic Nano-Platform For Simultaneous Multimodal Imaging And Radionuclide Therapy

The aim of this project was to develop and evaluate a theranostic nano-platform to enable Radionuclide Therapy (RNT) and multimodal imaging to improve the therapy and diagnosis of lymph node metastases. The work presented in this thesis consists of four main studies. First, Feraheme (FH) and two other superparamagnetic iron-oxide nanoparticles (SPIONs) were radiolabelled with radioisotopes commonly used in the clinic (89Zr, 177Lu and 90Y) for imaging and therapy utilising a novel chelate-free technique, which produced a high radiochemical yield and purity (up to 98%). FH nanoparticles were successfully radiolabelled with 90Y and 177Lu which was the first experimental demonstration that the HIR technique can be extended to radiolabel FH with these isotopes. In the second study, a series of phantom experiments were performed and results demonstrated that 89Zr-FH is a novel nanotechnology for simultaneous PET/MR imaging providing the capability of integrating the spatial resolution and tissue contrast provided by MR imaging with the high sensitivity of PET. An additional phantom study demonstrated the ability to image 177Lu-FH using Single Photon Emission Computed Tomography. The third study was a proof of concept for 90Y RNT. Results revealed that in RNT, the kinetics of DNA double strand break (DSB) induction, repair and misrepair must be considered when deriving radiobiological parameters. The fourth study, a Monte Carlo simulation study, was performed to study the subcellular mechanisms of dose delivery of the radionuclide 223Ra when treating metastases. These simulations showed that indirect cell damage may play an important role in RNT with alpha emitters due to the stochastic nature of alpha particle energy deposition. In conclusion, these results open a pathway towards a novel nuclear nanoplatform for multimodal imaging and RNT of lymph node metastases

Assessing the impact of motion on treatment planning during stereotactic body radiotherapy of lung cancer

Cancer is a leading cause of death in Australia and approximately 52% of cancer patients will require radiotherapy at some stage in their treatment. In recent years, stereotactic radiotherapy has emerged as an increasingly common treatment modality for small lesions in various sites of the human body.  To facilitate the investigation into the effects of imaging small mobile lesions, a see-saw 4D-CT phantom was developed. This phantom was used to investigate phase-binning artifacts that can be present when assigning an insufficient number of phases to 4D-CT data. The interplay between a lesion’s size and its amplitude, and the effects this relationship has on 4D-CT data was also investigated. An upgrade to a commercially available respiratory motion phantom was also pursued in order to replicate patient motion recorded with the Varian RPM system. Monte Carlo methods were used to determine the impact of motion on PET data by incorporating a computational moving phantom (XCAT) with a full Monte Carlo model of a commercially available PET scanner. To assess the impact of motion on treatment planning and dose calculation, two treatment planning scenarios were simulated using Monte Carlo. The traditional method of calculating dose on an average intensity projection from 4D-CT was compared to 4D dose calculation, in which tumour motion data from 4D-CT is explicitly incorporated into the treatment plan. Monte Carlo methods are also employed to evaluate the degree of underdosage at the periphery of lung lesions arising from electronic disequilibrium associated with density changes.  It was found that small lesions typically seen in SBRT of lung cancer require extra care when considering treatment planning, motion mitigation, and treatment delivery. The upgraded QUASAR phantom allows for patient specific verification of SBRT/SABR treatment plans to be conducted and was found to replicate patient motion accurately. Respiratory analysis software presented in this work enables detailed statistics of a patient’s respiratory characteristics to be evaluated. The number of phase-bins required to mitigate banding artifacts in 4D-CT projections is quantified in a simple equation for sinusoidal motion. It was also found that for lesion with diameters greater than 2.0 cm and amplitudes less than 4.0 cm, ten phase-bins are adequate to negate all banding artifacts in projection images.  Experimental and Monte Carlo simulations of PET and 4D-PET revealed that motion greater than 1.0 cm resulted in a reduction in apparent activity that increased with motion amplitude. A Dose Reduction Factor (DRF) metric was developed using Monte Carlo simulation which is defined as the ratio of the average dose to the periphery of the lesion to the dose in the central portion. The mean DRF was found to be 0.97 and 0.92 for 6 MV and 15 MV photon beams respectively, for lesion sizes ranging from 10 – 50 mm. The dynamic scenario was simulated with 4D dose calculation methods of registering and adding the dose distributions in each phase-bin from 4D-CT. The dose-volume distributions compared well with 3D (AIP) methods if multiple beams were used and the amplitude of motion was less than 3.0 cm.  

Positron Emission Tomography for the dose monitoring of intra-fractionally moving Targets in ion beam therapy

Ion beam therapy (IBT) is a promising treatment option in radiotherapy. The characteristic physical and biological properties of light ion beams allow for the delivery of highly tumour conformal dose distributions. Related to the sparing of surrounding healthy tissue and nearby organs at risk, it is feasible to escalate the dose in the tumour volume to reach higher tumour control and survival rates. Remarkable clinical outcome was achieved with IBT for radio-resistant, deep-seated, static and well fixated tumour entities. Presumably, more patients could benefit from the advantages of IBT if it would be available for more frequent tumour sites. Those located in the thorax and upper abdominal region are commonly subjected to intra-fractional, respiration related motion. Different motion compensated dose delivery techniques have been developed for active field shaping with scanned pencil beams and are at least available under experimental conditions at the GSI Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany. High standards for quality assurance are required in IBT to ensure a safe and precise dose application. Both underdosage in the tumour and overdosage in the normal tissue might endanger the treatment success. Since minor unexpected anatomical changes e.g. related to patient mispositioning, tumour shrinkage or tissue swelling could already lead to remarkable deviations between planned and delivered dose distribution, a valuable dose monitoring system is desired for IBT. So far, positron emission tomography (PET) is the only in vivo, in situ and non-invasive qualitative dose monitoring method applied under clinical conditions. It makes use of the tissue autoactivation by nuclear fragmentation reactions occurring along the beam path. Among others, +-emitting nuclides are generated and decay according to their half-life under the emission of a positron. The subsequent positron-electron annihilation creates two 511 keV photons which are emitted in opposite direction and can be detected as coincidence event by a dedicated PET scanner. The induced three-dimensional (3D) +- activity distribution in the patient can be reconstructed from the measured coincidences. Conclusions about the delivered dose distribution can be drawn indirectly from a comparison between two +-activity distributions: the measured one and an expected one generated by a Monte-Carlo simulation. This workflow has been proven to be valuable for the dose monitoring in IBT when it was applied for about 440 patients, mainly suffering from deep-seated head and neck tumours that have been treated with 12C ions at GSI. In the presence of intra-fractional target motion, the conventional 3D PET data processing will result in an inaccurate representation of the +-activity distribution in the patient. Fourdimensional, time-resolved (4D) reconstruction algorithms adapted to the special geometry of in-beam PET scanners allow to compensate for the motion related blurring artefacts. Within this thesis, a 4D maximum likelihood expectation maximization (MLEM) reconstruction algorithm has been implemented for the double-head scanner Bastei installed at GSI. The proper functionality of the algorithm and its superior performance in terms of suppressing motion related blurring artefacts compared to an already applied co-registration approach has been demonstrated by a comparative simulation study and by dedicated measurements with moving radioactive sources and irradiated targets. Dedicated phantoms mainly made up of polymethyl methacrylate (PMMA) and a motion table for regular one-dimensional (1D) motion patterns have been designed and manufactured for the experiments. Furthermore, the general applicability of the 4D MLEM algorithm for more complex motion patterns has been demonstrated by the successful reduction of motion artefacts from a measurement with rotating (two-dimensional moving) radioactive sources. For 1D cos2 and cos4 motion, it has been clearly illustrated by systematic point source measurements that the motion influence can be better compensated with the same number of motion phases if amplitudesorted instead of time-sorted phases are utilized. In any case, with an appropriate parameter selection to obtain a mean residual motion per phase of about half of the size of a PET crystal size, acceptable results have been achieved. Additionally, it has been validated that the 4D MLEM algorithm allows to reliably access the relevant parameters (particle range and lateral field position and gradients) for a dose verification in intra-fractionally moving targets even from the intrinsically low counting statistics of IBT-PET data. To evaluate the measured +-activity distribution, it should be compared to a simulated one that is expected from the moving target irradiation. Thus, a 4D version of the simulation software is required. It has to emulate the generation of +-emitters under consideration of the intra-fractional motion, their decay at motion state dependent coordinates and to create listmode data streams from the simulated coincidences. Such a revised and extended version that has been compiled for the special geometry of the Bastei PET scanner is presented within this thesis. The therapy control system provides information about the exact progress of the motion compensated dose delivery. This information and the intra-fractional target motion needs to be taken into account for simulating realistic +-activity distributions. A dedicated preclinical phantom simulation study has been performed to demonstrate the correct functionality of the 4D simulation program and the necessity of the additional, motionrelated input parameters. Different to the data evaluation for static targets, additional effort is required to avoid a potential misleading interpretation of the 4D measured and simulated +-activity distributions in the presence of deficient motion mitigation or data processing. It is presented that in the presence of treatment errors the results from the simulation might be in accordance to the measurement although the planned and delivered dose distribution are different. In contrast to that, deviations may occur between both distributions which are not related to anatomical changes but to deficient 4D data processing. Recommendations are given in this thesis to optimize the 4D IBT-PET workflow and to prevent the observer from a mis-interpretation of the dose monitoring data. In summary, the thesis contributes on a large scale to a potential future application of the IBT-PET monitoring for intra-fractionally moving target volumes by providing the required reconstruction and simulation algorithms. Systematic examinations with more realistic, multi-directional and irregular motion patterns are required for further improvements. For a final rating of the expectable benefit from a 4D IBT-PET dose monitoring, future investigations should include real treatment plans, breathing curves and 4D patient CT images

Scalable strategies for tumour targeting of magnetic carriers and seeds

With the evolving landscape of medical oncology, focus has shifted away from nonspecific cytotoxic treatment strategies toward therapeutic paradigms more characteristic of targeted therapies. These therapies rely on delivery vehicles such as nano-carriers or micro robotic devices to boosts the concentration of therapeutics in a specific targeted site inside the body. The use of externally applied magnetic field is suggested to be a predominant approach for remote localisation of magnetically responsive carriers and devices to the target region that could not be otherwise reached. However, the fast decline of the magnetic fields and gradients with increasing distances from the source is posing a major challenge for its clinical application. The aim of this thesis was to investigate potential magnetic delivery strategies which can circumvent some of the typical limitations of this technique. Two different approaches were explored to this end. The first approach was to characterise the ability of a conventional permanent magnet on targeting individual nano-carriers and develop novel magnetic designs which improve the targeting efficiency. The second approach was evaluating the feasibility of a magnetic resonance imaging system to move a millimetre-sized magnetic particle within the body. Phantom and in vivo magnetic targeting experiments illustrated the significant increase in effective targeting depth when our novel magnetic design was used for targeting nano-carriers compared with conventional magnets. In the later part of the thesis, the proof of concept and characterisation experiments showed that a 3 mm magnetic particle can be moved in ex vivo brain tissue using a magnetic resonance imaging system using clinically relevant gradient strengths. The magnetic systems introduced in this thesis provide the potential to target nano-carriers and millimetre-sized thermoseeds to tumours located at deep regions of human body through vasculature and soft tissue respectively

Techniques for imaging small impedance changes in the human head due to neuronal depolarisation

A new imaging modality is being developed, which may be capable of imaging small impedance changes in the human head due to neuronal depolarization. One way to do this would be by imaging the impedance changes associated with ion channels opening in neuronal membranes in the brain during activity. The results of previous modelling and experimental studies indicated that impedance changes between 0.6%and 1.7% locally in brain grey matter when recorded at DC. This reduces by a further of 10% if measured at the surface of the head, due to distance and the effect of the resistive skull. In principle, this could be measured using Electrical Impedance Tomography (ElT) but it is close to its threshold of detectability. With the inherent limitation in the use of electrodes, this work proposed two new schemes. The first is a magnetic measurement scheme based on recording the magnetic field with Superconducting Quantum Interference Devices (SQUIDs), used in Magnetoencephalography (MEG) as a result of a non-invasive injection of current into the head. This scheme assumes that the skull does not attenuate the magnetic field. The second scheme takes into consideration that the human skull is irregular in shape, with less and varying conductivity as compared to other head tissues. Therefore, a key issue is to know through which electrodes current can be injected in order to obtain high percentage changes in surface potential when there is local conductivity change in the head. This model will enable the prediction of the current density distribution at specific regions in the brain with respect to the varying skull and local conductivities. In the magnetic study, the head was modelled as concentric spheres, and realistic head shapes to mimic the scalp, skull, Cerebrospinal Auid (CSF) and brain using the Finite Element Method (FEM). An impedance change of 1 % in a 2cm-radius spherical volume depicting the physiological change in the brain was modelled as the region of depolarisation. The magnetic field, 1 cm away from the scalp, was estimated on injecting a constant current of 100 µA into the head from diametrically opposed electrodes. However, in the second scheme, only the realistic FEM of the head was used, which included a specific region of interest; the primary visual cortex (V1). The simulated physiological change was the variation in conductivity of V1 when neurons were assumed to be firing during a visual evoked response. A near DC current of 100 µA was driven through possible pairs of 31 electrodes using ElT techniques. For a fixed skull conductivity, the resulting surface potentials were calculated when the whole head remained unperturbed, or when the conductivity of V1 changed by 0.6%, 1 %, and 1.6%. The results of the magnetic measurement predicted that standing magnetic field was about 10pT and the field changed by about 3fT (0.03%) on depolarization. For the second scheme, the greatest mean current density through V1 was 0.020 ± 0.005 µAmm-2, and occurred with injection through two electrodes positioned near the occipital cortex. The corresponding maximum change in potential from baseline was 0.02%. Saline tank experiments confirmed the accuracy of the estimated standing potentials. As the noise density in a typical MEG system in the frequency band is about 7fT/√Hz, it places the change at the limit of detectability due to low signal to noise ratio. This is therefore similar to electrical recording, as in conventional ElT systems, but there may be advantages to MEG in that the magnetic field direcdy traverses the skull and instrumentation errors from the electrode-skin interface will be obviated. This has enabled the estimation of electrode positions most likely to permit recording of changes in human experiments and suggests that the changes, although tiny, may just be discernible from noise

4D offline PET-based treatment verification in ion beam therapy

Due to the accessible sharp dose gradients, external beam radiotherapy with protons and heavier ions enables a highly conformal adaptation of the delivered dose to arbitrarily shaped tumour volumes. However, this high conformity is accompanied by an increased sensitivity to potential uncertainties, e.g., due to changes in the patient anatomy. Additional challenges are imposed by respiratory motion which does not only lead to rapid changes of the patient anatomy, but, in the cased of actively scanned ions beams, also to the formation of dose inhomogeneities. Therefore, it is highly desirable to verify the actual application of the treatment and to detect possible deviations with respect to the planned irradiation. At present, the only clinically implemented approach for a close-in-time verification of single treatment fractions is based on detecting the distribution of β+-emitter formed in nuclear fragmentation reactions during the irradiation by means of positron emission tomography (PET). For this purpose, a commercial PET/CT (computed tomography) scanner has been installed directly next to the treatment rooms at the Heidelberg Ion-Beam Therapy Center (HIT). Up to present, the application of this treatment verification technique is, however, still limited to static target volumes. This thesis aimed at investigating the feasibility and performance of PET-based treatment verification under consideration of organ motion. In experimental irradiation studies with moving phantoms, not only the practicability of PET-based treatment monitoring for moving targets, using a commercial PET/CT device, could be shown for the first time, but also the potential of this technique to detect motion-related deviations from the planned treatment with sub-millimetre accuracy. The first application to four exemplary hepato-cellular carcinoma patient cases under substantially more challenging clinical conditions indicated potential for improvement by taking organ motion into consideration, particularly for patients exhibiting motion amplitudes of above 1cm and a sufficiently large number of detected true coincidences during their post-irradiation PET scan. Despite the application of an optimised PET image reconstruction scheme, as retrieved from a dedicated phantom imaging study in the scope of this work, the small number of counts and the resulting high level of image noise were identified as a major limiting factor for the detection of motion-induced dose inhomogeneities within the patient. Moreover, the biological washout modelling of the irradiation-induced isotopes proved to be not sufficiently accurate and thereby impede a quantitative analysis of measured and simulated data under consideration of target motion. In future, improvements are particularly foreseen through dedicated noise-robust time-resolved (4D) image reconstruction algorithms, an improved tracking of the organ motion, e.g., by ultrasound (US) imaging, as implemented for the first time in 4D PET imaging in the scope of this work, as well as by patient-specific washout models