Improving Segmentation of Objects with Varying Sizes in Biomedical Images using Instance-wise and Center-of-Instance Segmentation Loss Function

In this paper, we propose a novel two-component loss for biomedical image segmentation tasks called the Instance-wise and Center-of-Instance (ICI) loss, a loss function that addresses the instance imbalance problem commonly encountered when using pixel-wise loss functions such as the Dice loss. The Instance-wise component improves the detection of small instances or ``blobs" in image datasets with both large and small instances. The Center-of-Instance component improves the overall detection accuracy. We compared the ICI loss with two existing losses, the Dice loss and the blob loss, in the task of stroke lesion segmentation using the ATLAS R2.0 challenge dataset from MICCAI 2022. Compared to the other losses, the ICI loss provided a better balanced segmentation, and significantly outperformed the Dice loss with an improvement of $1.7-3.7\%$ and the blob loss by $0.6-5.0\%$ in terms of the Dice similarity coefficient on both validation and test set, suggesting that the ICI loss is a potential solution to the instance imbalance problem.Comment: conferenc

Implicit neural representations for joint decomposition and registration of gene expression images in the marmoset brain

We propose a novel image registration method based on implicit neural representations that addresses the challenging problem of registering a pair of brain images with similar anatomical structures, but where one image contains additional features or artifacts that are not present in the other image. To demonstrate its effectiveness, we use 2D microscopy $\textit{in situ}$ hybridization gene expression images of the marmoset brain. Accurately quantifying gene expression requires image registration to a brain template, which is difficult due to the diversity of patterns causing variations in visible anatomical brain structures. Our approach uses implicit networks in combination with an image exclusion loss to jointly perform the registration and decompose the image into a support and residual image. The support image aligns well with the template, while the residual image captures individual image characteristics that diverge from the template. In experiments, our method provided excellent results and outperformed other registration techniques.Comment: 11 page

Real-time intravital multiphoton microscopy to visualize focused ultrasound and microbubble treatments to increase blood-brain barrier permeability

The blood-brain barrier (BBB) is a key challenge for the successful delivery of drugs to the brain. Ultrasound exposure in the presence of microbubbles has emerged as an effective method to transiently and locally increase the permeability of the BBB, facilitating para- and transcellular transport of drugs across the BBB. Imaging the vasculature during ultrasound-microbubble treatment will provide valuable and novel insights on the mechanisms and dynamics of ultrasound-microbubble treatments in the brain. Here, we present an experimental procedure for intravital multiphoton microscopy using a cranial window aligned with a ring transducer and a 20x objective lens. This set-up enables high spatial and temporal resolution imaging of the brain during ultrasound-microbubble treatments. Optical access to the brain is obtained via an open-skull cranial window. Briefly, a 3-4 mm diameter piece of the skull is removed, and the exposed area of the brain is sealed with a glass coverslip. A 0.82 MHz ring transducer, which is attached to a second glass coverslip, is mounted on top. Agarose (1% w/v) is used between the coverslip of the transducer and the coverslip covering the cranial window to prevent air bubbles, which impede ultrasound propagation. When sterile surgery procedures and anti-inflammatory measures are taken, ultrasound-microbubble treatments and imaging sessions can be performed repeatedly over several weeks. Fluorescent dextran conjugates are injected intravenously to visualize the vasculature and quantify ultrasound-microbubble induced effects (e.g., leakage kinetics, vascular changes). This paper describes the cranial window placement, ring transducer placement, imaging procedure, common troubleshooting steps, as well as advantages and limitations of the method.publishedVersio

Imaging Immune Functions Induced by Focused Ultrasound and Microbubble Treatments to Increase Blood-brain Barrier Permeability

Treatment of neurological diseases is limited by the blood-brain barrier (BBB). The BBB controls the exchange of compounds between the brain parenchyma and systemic circulation. One method to bypass the BBB is to use focused ultrasound (FUS). FUS, used in conjunction with preformed microbubbles (MBs), can transiently enhance BBB permeability by increasing transcellular and paracellular transport across the brain endothelium. While FUS+MB BBB treatments have been shown to be an effective method to deliver agents to the brain, the use FUS+MB BBB alone, without additional therapeutics, have also been observed to result in various downstream effects, including the reduction of β-amyloid (Aβ) plaque load in animal models of Alzheimer’s disease. The characteristics of this induced clearance response have yet to be fully elucidated. In this thesis, the time course of the effects of FUS+MB BBB and induced recruitment of peripheral immune cells are investigated using two-photon fluorescence microscopy. Thermal effects of two-photon fluorescence microscopy were assessed to evaluate whether experimental parameters affected the brain milieu. Brain temperatures were moderately hypothermic following cranial window implantation and increased linearly with laser power during imaging. Temporal characteristics of induced Aβ plaque load clearance were investigated by monitoring the size of Aβ plaques following one FUS+MB BBB treatment in the TgCRND8 mouse model of Alzheimer’s disease. Aβ plaque reduction was observed between 2 to 14 days following treatment, and repeated biweekly treatments significantly reduced plaque load. The efficiency of plaque clearance suggested the involvement of peripheral phagocytic immune cells. Blood flow perturbations were observed immediately before and after the onset of sonication, and motile cells were recruited intravascularly within seconds following increase in BBB permeability. Neutrophils were identified to be one of the participating cell types. FUS+MB treated brain hemispheres harboured significantly more neutrophils compared to the contralateral hemispheres, and to control animals. However, the participation of neutrophils in clearing Aβ plaques may be transient, as neutrophil counts in treated brain tissue were not significantly different from control animals following biweekly FUS+MB treatments. The characteristics of immune functions provided in this thesis further inform understanding of biological responses induced by FUS+MB BBB treatments.Ph.D.2021-05-30 00:00:0

Exploring the performance of implicit neural representations for brain image registration

Abstract Pairwise image registration is a necessary prerequisite for brain image comparison and data integration in neuroscience and radiology. In this work, we explore the efficacy of implicit neural representations (INRs) in improving the performance of brain image registration in magnetic resonance imaging. In this setting, INRs serve as a continuous and coordinate based approximation of the deformation field obtained through a multi-layer perceptron. Previous research has demonstrated that sinusoidal representation networks (SIRENs) surpass ReLU models in performance. In this study, we first broaden the range of activation functions to further investigate the registration performance of implicit networks equipped with activation functions that exhibit diverse oscillatory properties. Specifically, in addition to the SIRENs and ReLU, we evaluate activation functions based on snake, sine+, chirp and Morlet wavelet functions. Second, we conduct experiments to relate the hyper-parameters of the models to registration performance. Third, we propose and assess various techniques, including cycle consistency loss, ensembles and cascades of implicit networks, as well as a combined image fusion and registration objective, to enhance the performance of implicit registration networks beyond the standard approach. The investigated implicit methods are compared to the VoxelMorph convolutional neural network and to the symmetric image normalization (SyN) registration algorithm from the Advanced Normalization Tools (ANTs). Our findings not only highlight the remarkable capabilities of implicit networks in addressing pairwise image registration challenges, but also showcase their potential as a powerful and versatile off-the-shelf tool in the fields of neuroscience and radiology

Real-time intravital multiphoton microscopy to visualize focused ultrasound and microbubble treatments to increase blood-brain barrier permeability

The blood-brain barrier (BBB) is a key challenge for the successful delivery of drugs to the brain. Ultrasound exposure in the presence of microbubbles has emerged as an effective method to transiently and locally increase the permeability of the BBB, facilitating para- and transcellular transport of drugs across the BBB. Imaging the vasculature during ultrasound-microbubble treatment will provide valuable and novel insights on the mechanisms and dynamics of ultrasound-microbubble treatments in the brain. Here, we present an experimental procedure for intravital multiphoton microscopy using a cranial window aligned with a ring transducer and a 20x objective lens. This set-up enables high spatial and temporal resolution imaging of the brain during ultrasound-microbubble treatments. Optical access to the brain is obtained via an open-skull cranial window. Briefly, a 3-4 mm diameter piece of the skull is removed, and the exposed area of the brain is sealed with a glass coverslip. A 0.82 MHz ring transducer, which is attached to a second glass coverslip, is mounted on top. Agarose (1% w/v) is used between the coverslip of the transducer and the coverslip covering the cranial window to prevent air bubbles, which impede ultrasound propagation. When sterile surgery procedures and anti-inflammatory measures are taken, ultrasound-microbubble treatments and imaging sessions can be performed repeatedly over several weeks. Fluorescent dextran conjugates are injected intravenously to visualize the vasculature and quantify ultrasound-microbubble induced effects (e.g., leakage kinetics, vascular changes). This paper describes the cranial window placement, ring transducer placement, imaging procedure, common troubleshooting steps, as well as advantages and limitations of the method

The Brain/MINDS Marmoset Connectivity Resource: an open access platform for cellular-level tracing and tractography in the primate brain

The primate brain has unique anatomical characteristics, which translate into advanced cognitive, sensory and motor abilities. Thus, it is important that we gain insight on its structure, to provide a solid basis for models that will clarify function. Here we report on the implementation and features of the Brain/MINDS Marmoset Connectivity Resource (BMCR), a new open-access platform that provides access to high-resolution anterograde neuronal tracer data in the marmoset brain, integrated to retrograde tracer and tractography data. Unlike other existing image explorers, the BMCR allows visualization of data from different individuals and modalities in a common reference space. This feature, allied to an unprecedented high resolution, enables analyses of features such as reciprocity, directionality and spatial segregation of connections. The present release of the BMCR focuses on the prefrontal cortex, a uniquely developed region of the primate brain which is linked to advanced cognition, including the results of 52 anterograde and 164 retrograde tracer injections in the cortex of the marmoset. Moreover, the inclusion of tractography data from diffusion MRI allows systematic analyses of this non-invasive modality against gold-standard cellular connectivity data, enabling detection of false positives and negatives, which provide a basis for future development of tractography. This paper introduces the BMCR image pre-processing pipeline and resources, which include new tools for exploring and reviewing the data

The Brain/MINDS Marmoset Connectivity Resource: an open access platform for cellular-level tracing and tractography in the primate brain

The Brain/MINDS Marmoset Connectivity Resource (BMCR) offers access to integrated anterograde neuronal tracer data in the marmoset brain, complemented by retrograde tracer and tractography data. The current release of the BMCR primarily focuses on the prefrontal cortex, incorporating the results of 52 anterograde tracer injections performed on the marmoset's cortex. It also includes tractography data from diffusion MRI, backlit images to reveal features of brain myelination, Nissl-stained images, and tools for mapping to and from the image spaces used in other marmoset brain projects