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  • Journal article
    Chan TG, O'Neill E, Habjan C, Cornelissen Bet al., 2020,

    Combination Strategies to Improve Targeted Radionuclide Therapy

    , JOURNAL OF NUCLEAR MEDICINE, Vol: 61, Pages: 1544-1552, ISSN: 0161-5505
  • Journal article
    Morse SV, Boltersdorf T, Chan TG, Gavins FNE, Choi JJ, Long NJet al., 2020,

    In vivo delivery of a fluorescent FPR2/ALX-targeted probe using focused ultrasound and microbubbles to image activated microglia

    , RSC Chemical Biology, Vol: 1, Pages: 385-389, ISSN: 2633-0679

    To image activated microglia, a small-molecule FPR2/ALX-targeted fluorescent probe was locally delivered into the brain using focused ultrasound and microbubbles. The probe did not co-localise with neurons or astrocytes but accumulated in activated microglia, making this a potential imaging tool for future drug discovery programs focused on neurological disorders.

  • Journal article
    Vilar R, Torres Huerta A, Chan TG, White AJPet al., 2020,

    Molecular recognition of bisphosphonate-based drugs by di-zinc receptors in aqueous solution and on gold nanoparticles

    , Dalton Transactions, Vol: 49, Pages: 5939-5948, ISSN: 1477-9226

    Metal-based anion receptors have several important applications in sensing, separation and transport of negatively charged species. Amongst these receptors, di-zinc(II) complexes are of particular interest for the recognition of oxoanions, in particular phosphate derivatives. Herein we report the synthesis of a di-zinc(II) receptor and show that it has high affinity and selectivity for bisphosphonates such as alendronate and etidronate – which are used to treat a number of skeletal disorders as well as showing interesting anticancer properties. The binding mode of the di-zinc(II) receptor with alendronate and etidronate has been unambiguously established by single crystal X-ray crystallography. In addition, by modifying the backbone of the receptor, we show that the drug-loaded receptor can be attached onto gold nanoparticles as potential drug-delivery vehicles.

  • Journal article
    Morse SV, Boltersdorf T, Harriss BI, Chan TG, Baxan N, Hee Seok J, Pouliopoulos AN, Choi J, Long NJet al., 2020,

    Neuron labeling with rhodamine-conjugated Gd-based MRI contrast agents delivered to the brain via focused ultrasound

    , Theranostics, Vol: 10, Pages: 2659-2674, ISSN: 1838-7640

    Gadolinium-based magnetic resonance imaging contrast agents can provide information regarding neuronal function, provided that these agents can cross the neuronal cell membrane. Such contrast agents are normally restricted to extracellular domains, however, by attaching cationic fluorescent dyes, they can be made cell-permeable and allow for both optical and magnetic resonance detection. To reach neurons, these agents also need to cross the blood-brain barrier. Focused ultrasound combined with microbubbles has been shown to enhance the permeability of this barrier, allowing molecules into the brain non-invasively, locally and transiently. The goal of this study was to investigate whether combining fluorescent rhodamine with a gadolinium complex would form a dual-modal contrast agent that could label neurons in vivo when delivered to the mouse brain with focused ultrasound and microbubbles.Methods: Gadolinium complexes were combined with a fluorescent, cationic rhodamine unit to form probes with fluorescence and relaxivity properties suitable for in vivo applications. The left hemisphere of female C57bl/6 mice (8-10 weeks old; 19.07 ± 1.56 g; n = 16) was treated with ultrasound (centre frequency: 1 MHz, peak-negative pressure: 0.35 MPa, pulse length: 10 ms, repetition frequency: 0.5 Hz) while intravenously injecting SonoVue microbubbles and either the 1 kDa Gd(rhodamine-pip-DO3A) complex or a conventionally-used lysine-fixable Texas Red® 3 kDa dextran. The opposite right hemisphere was used as a non-treated control region. Brains were then extracted and either sectioned and imaged via fluorescence or confocal microscopy or imaged using a 9.4 T magnetic resonance imaging scanner. Brain slices were stained for neurons (NeuN), microglia (Iba1) and astrocytes (GFAP) to investigate the cellular localization of the probes.Results: Rhodamine fluorescence was detected in the left hemisphere of all ultrasound treated mice, while none was detected in the right contr

  • Journal article
    Morse SV, Pouliopoulos AN, Chan TG, Copping MJ, Lin J, Long NJ, Choi JJet al., 2019,

    Rapid short-pulse ultrasound delivers drugs uniformly across the murine blood-brain barrier with negligible disruption

    , Radiology, Vol: 291, Pages: 459-466, ISSN: 0033-8419

    Background Previous work has demonstrated that drugs can be delivered across the blood-brain barrier by exposing circulating microbubbles to a sequence of long ultrasound pulses. Although this sequence has successfully delivered drugs to the brain, concerns remain regarding potentially harmful effects from disrupting the brain vasculature. Purpose To determine whether a low-energy, rapid, short-pulse ultrasound sequence can efficiently and safely deliver drugs to the murine brain. Materials and Methods Twenty-eight female wild-type mice underwent focused ultrasound treatment after injections of microbubbles and a labeled model drug, while three control mice were not treated (May-November 2017). The left hippocampus of 14 mice was exposed to low-energy short pulses (1 MHz; five cycles; peak negative pressure, 0.35 MPa) of ultrasound emitted at a rapid rate (1.25 kHz) in bursts (0.5 Hz), and another 14 mice were exposed to standard long pulses (10 msec, 0.5 Hz) containing 150 times more acoustic energy. Mice were humanely killed at 0 (n = 5), 10 (n = 3), or 20 minutes (n = 3) after ultrasound treatment. Hematoxylin-eosin (H-E) staining was performed on three mice. The delivered drug dose and distribution were quantified with the normalized optical density and coefficient of variation. Safety was assessed by H-E staining, the amount of albumin released, and the duration of permeability change in the blood-brain barrier. Statistical analysis was performed by using the Student t test. Results The rapid short-pulse sequence delivered drugs uniformly throughout the parenchyma. The acoustic energy emitted from the microbubbles also predicted the delivered dose (r = 0.97). Disruption in the blood-brain barrier lasted less than 10 minutes and 3.4-fold less albumin was released into the brain than with long pulses. No vascular or tissue damage from rapid short-pulse exposure was observable using H-E staining. Conclusion The rapid short-pulse ultrasound sequence is a minimally

  • Journal article
    Quicke P, Song C, McKimm EJ, Milosevic MM, Howe CL, Neil M, Schultz SR, Antic SD, Foust AJ, Knopfel Tet al., 2019,

    Single-neuron level one-photon voltage imaging with sparsely targeted genetically encoded voltage indicators

    , Frontiers in Cellular Neuroscience, Vol: 13, ISSN: 1662-5102

    Voltage imaging of many neurons simultaneously at single-cell resolution is hampered by the difficulty of detecting small voltage signals from overlapping neuronal processes in neural tissue. Recent advances in genetically encoded voltage indicator (GEVI) imaging have shown single-cell resolution optical voltage recordings in intact tissue through imaging naturally sparse cell classes, sparse viral expression, soma restricted expression, advanced optical systems, or a combination of these. Widespread sparse and strong transgenic GEVI expression would enable straightforward optical access to a densely occurring cell type, such as cortical pyramidal cells. Here we demonstrate that a recently described sparse transgenic expression strategy can enable single-cell resolution voltage imaging of cortical pyramidal cells in intact brain tissue without restricting expression to the soma. We also quantify the functional crosstalk in brain tissue and discuss optimal imaging rates to inform future GEVI experimental design.

  • Journal article
    Lubba CT, Le Guen Y, Jarvis S, Jones N, Cork S, Eftekhar A, Schultz Set al., 2019,

    PyPNS: multiscale simulation of a peripheral nerve in Python

    , Neuroinformatics, Vol: 17, Pages: 63-81, ISSN: 1539-2791

    Bioelectronic Medicines that modulate the activity patterns on peripheral nerves have promise as a new way of treating diverse medical conditions from epilepsy to rheumatism. Progress in the field builds upon time consuming and expensive experiments in living organisms. To reduce experimentation load and allow for a faster, more detailed analysis of peripheral nerve stimulation and recording, computational models incorporating experimental insights will be of great help.We present a peripheral nerve simulator that combines biophysical axon models and numerically solved and idealised extracellular space models in one environment. We modeled the extracellular space as a three-dimensional resistive continuum governed by the electro-quasistatic approximation of the Maxwell equations. Potential distributions were precomputed in finite element models for different media (homogeneous, nerve in saline, nerve in cuff) and imported into our simulator. Axons, on the other hand, were modeled more abstractly as one-dimensional chains of compartments. Unmyelinated fibres were based on the Hodgkin- Huxley model; for myelinated fibres, we adapted the model proposed by McIntyre et al. in 2002 to smaller diameters. To obtain realistic axon shapes, an iterative algorithm positioned fibres along the nerve with a variable tortuosity fit to imaged trajectories. We validated our model with data from the stimulated rat vagus nerve. Simulation results predicted that tortuosity alters recorded signal shapes and increases stimulation thresholds. The model we developed can easily be adapted to different nerves, and may be of use for Bioelectronic Medicine research in the future.

  • Journal article
    Quicke P, Reynolds S, Neil M, Knopfel T, Schultz S, Foust AJet al., 2018,

    High speed functional imaging with source localized multifocal two-photon microscopy

    , Biomedical Optics Express, Vol: 9, Pages: 3678-3693, ISSN: 2156-7085

    Multifocal two-photon microscopy (MTPM) increases imaging speed over single-focus scanning by parallelizing fluorescence excitation. The imaged fluorescence’s susceptibility to crosstalk, however, severely degrades contrast in scattering tissue. Here we present a source-localized MTPM scheme optimized for high speed functional fluorescence imaging in scattering mammalian brain tissue. A rastered line array of beamlets excites fluorescence imaged with a complementary metal-oxide-semiconductor (CMOS) camera. We mitigate scattering-induced crosstalk by temporally oversampling the rastered image, generating grouped images with structured illumination, and applying Richardson-Lucy deconvolution to reassign scattered photons. Single images are then retrieved with a maximum intensity projection through the deconvolved image groups. This method increased image contrast at depths up to 112 μm in scattering brain tissue and reduced functional crosstalk between pixels during neuronal calcium imaging. Source-localization did not affect signal-to-noise ratio (SNR) in densely labeled tissue under our experimental conditions. SNR decreased at low frame rates in sparsely labeled tissue, with no effect at frame rates above 50 Hz. Our non-descanned source-localized MTPM system enables high SNR, 100 Hz capture of fluorescence transients in scattering brain, increasing the scope of MTPM to faster and smaller functional signals.

  • Journal article
    Chan T, Morse S, Copping M, Choi J, Vilar Compte Ret al., 2018,

    Targeted delivery of DNA-Au nanoparticles across the blood-brain barrier using focused ultrasound

    , ChemMedChem, Vol: 13, Pages: 1311-1314, ISSN: 1860-7187

    Nanoparticles have been widely studied as versatile platforms for in vivo imaging and therapy. However, their use to image and/or treat the brain is limited, as they are often unable to cross the blood–brain barrier (BBB). To overcome this problem, herein we report the use of focused ultrasound in vivo to successfully deliver DNA‐coated gold nanoparticles to specific locations in the brains of mice.

  • Journal article
    Dall'Orso S, Steinweg J, Allievi AG, Edwards AD, Burdet E, Arichi Tet al., 2018,

    Somatotopic mapping of the developing sensorimotor cortex in the preterm human brain

    , Cerebral Cortex, Vol: 28, Pages: 2507-2515, ISSN: 1047-3211

    In the mature mammalian brain, the primary somatosensory and motor cortices are known to be spatially organized such that neural activity relating to specific body parts can be somatopically mapped onto an anatomical "homunculus". This organization creates an internal body representation which is fundamental for precise motor control, spatial awareness and social interaction. Although it is unknown when this organization develops in humans, animal studies suggest that it may emerge even before the time of normal birth. We therefore characterized the somatotopic organization of the primary sensorimotor cortices using functional MRI and a set of custom-made robotic tools in 35 healthy preterm infants aged from 31 + 6 to 36 + 3 weeks postmenstrual age. Functional responses induced by somatosensory stimulation of the wrists, ankles, and mouth had a distinct spatial organization as seen in the characteristic mature homunculus map. In comparison to the ankle, activation related to wrist stimulation was significantly larger and more commonly involved additional areas including the supplementary motor area and ipsilateral sensorimotor cortex. These results are in keeping with early intrinsic determination of a somatotopic map within the primary sensorimotor cortices. This may explain why acquired brain injury in this region during the preterm period cannot be compensated for by cortical reorganization and therefore can lead to long-lasting motor and sensory impairment.

  • Conference paper
    Morse SV, Pouliopoulos AN, Chan T, Lin J, Copping M, Long NJ, Choi JJet al., 2017,

    Rapid short-pulse (RaSP) sequences improve the distribution of drug delivery to the brain in vivo

    , IEEE UFFC, Publisher: IEEE, ISSN: 1948-5719

    Focused ultrasound and microbubbles have been shown to locally and noninvasively open the blood-brain barrier. Despite encouraging results in human patients, several performance and safety features, such as poor drug distribution, high drug accumulation along vessels and small sites of red blood cell extravasation, have been unavoidable. We have recently developed a new ultrasound sequence - rapid short-pulse (RaSP) sequence - designed to suppress these adverse features by promoting safer modes of cavitation activity throughout capillaries. In our RaSP sequences, low-pressure short ultrasonic pulses are emitted at kHz pulse repetition frequencies (PRF) and grouped into bursts. We have shown in vitro that RaSP sequences prolong microbubble lifetime and increase their mobility, enhancing the distribution of acoustic cavitation activity. Here we evaluate the ability of RaSP sequences to improve the in vivo performance and safety of ultrasound-mediated drug delivery to the brain.

  • Journal article
    Quicke P, Barnes SJ, Knöpfel T, 2017,

    Imaging of Brain Slices with a Genetically Encoded Voltage Indicator.

    , Methods Mol Biol, Vol: 1563, Pages: 73-84

    Functional fluorescence microscopy of brain slices using voltage sensitive fluorescent proteins (VSFPs) allows large scale electrophysiological monitoring of neuronal excitation and inhibition. We describe the equipment and techniques needed to successfully record functional responses optical voltage signals from cells expressing a voltage indicator such as VSFP Butterfly 1.2. We also discuss the advantages of voltage imaging and the challenges it presents.

  • Journal article
    Schultz SR, Copeland CS, Foust AJ, Quicke P, Schuck Ret al., 2016,

    Advances in two-photon scanning and scanless microscopy technologies for functional neural circuit imaging

    , Proceedings of the IEEE, Vol: 105, Pages: 139-157, ISSN: 0018-9219

    Recent years have seen substantial developments in technology for imaging neural circuits, raising the prospect of large-scale imaging studies of neural populations involved in information processing, with the potential to lead to step changes in our understanding of brain function and dysfunction. In this paper, we will review some key recent advances: improved fluorophores for single-cell resolution functional neuroimaging using a two-photon microscope; improved approaches to the problem of scanning active circuits; and the prospect of scanless microscopes which overcome some of the bandwidth limitations of current imaging techniques. These advances in technology for experimental neuroscience have in themselves led to technical challenges, such as the need for the development of novel signal processing and data analysis tools in order to make the most of the new experimental tools. We review recent work in some active topics, such as region of interest segmentation algorithms capable of demixing overlapping signals, and new highly accurate algorithms for calcium transient detection. These advances motivate the development of new data analysis tools capable of dealing with spatial or spatiotemporal patterns of neural activity that scale well with pattern size.

  • Conference paper
    Schuck R, Quicke P, Hwang JK, Annecchino L, Schultz SRet al., 2015,

    Rapid three dimensional two photon neural population scanning

    , 37th Annual International IEEE EMBS Conference of the IEEE Engineering in Medicine and Biology Society, Publisher: IEEE, Pages: 5867-5870, ISSN: 1557-170X

    Recording the activity of neural populationsat high sampling rates is a fundamental requirement forunderstanding computation in neural circuits. Two photonmicroscopy provides one promising approach towards this.However, neural circuits are three dimensional, and functionalimaging in two dimensions fails to capture the 3D natureof neural dynamics. Electrically tunable lenses (ETLs) providea simple and cheap method to extend laser scanningmicroscopy into the relatively unexploited third dimension.We have therefore incorporated them into our Adaptive SpiralScanning (SSA) algorithm, which calculates kinematicallyefficient scanning strategies using radially modulated spiralpaths. We characterised the response of the ETL, incorporatedits dynamics using MATLAB models of the SSA algorithmand tested the models on populations of Izhikevich neuronsof varying size and density. From this, we show that ouralgorithms can theoretically at least achieve sampling rates of36.2Hz compared to 21.6Hz previously reported for 3D scanningtechniques.

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