Biomedical Engineering seminars

Visual restoration after decades of blindness is now becoming possible by means of retinal and cortical prostheses, as well as emerging stem cell and gene therapeutic approaches. After restoring visual perception, however, a key question remains. Are there optimal means and methods for retraining the visual cortex to process visual inputs, and for learning or relearning to “see”? Up to this point, it has been largely assumed that if the sensory loss is visual, then the rehabilitation focus should also be primarily visual. However, the other senses play a key role in visual rehabilitation due to the plastic repurposing of visual cortex during blindness by audition and somatosensation, and also to the reintegration of restored vision with the other senses. I will present multisensory neuroimaging results, cortical thickness changes, as well as behavioral outcomes for patients with Retinitis Pigmentosa (RP), which causes blindness by destroying photoreceptors in the retina. These patients have had their vision partially restored by the implantation of a retinal prosthesis, which electrically stimulates still viable retinal ganglion cells in the eye. Our multisensory and structural neuroimaging and behavioral results suggest a new, holistic concept of visual rehabilitation that leverages rather than neglects audition, somatosensation, and other sensory modalities.

La resonancia magnética nuclear está basada en el fenómeno del magnetismo nuclear que más aplicaciones ha encontrado para el estudio de enfermedades humanas. Usualmente la señal de RM es recibida y transmitida a distancias cercanas al objeto del que se quiere obtener una imagen. Otra alternativa es emitir y recibir la misma señal de manera remota haciendo uso de guías de onda. Este enfoque tiene la ventaja que se puede aplicar a altos campos magnéticos, la absorción de energía es menor, además es posible cubrir mayores regiones de interés y comodidad para el paciente. Por otro lado, sufre de baja calidad de imagen en algunos casos. En esta ocasión hablaremos de nuestra experiencia haciendo uso de este enfoque empleando una guía de ondas abierta y metamateriales tanto para sistemas clínicos como preclínicos de IRM.

On Thursday February 15th, we will host Victoria Peterson and Julian Neumann. Victoria will tell us about “Spatial filtering to enhance signal processing in invasive neurophysiology”. Besides his scientific presentation on “Closed-loop deep brain stimulation as a neuroprosthetic of dopaminergic circuits – Current evidence and future opportunities”, Julian will give us a glimpse at the person behind the science. The talks will be followed by a shared discussion. Note: The talks will exceptionally be held at 10 ET / 4PM CET. You can register via talks.stimulatingbrains.org to receive the (free) Zoom link!

Sound waves can be used to modify brain activity safely and transiently with unprecedented precision even deep in the brain - unlike traditional brain stimulation methods. In a series of studies in humans and non-human primates, I will show that Transcranial Ultrasound Stimulation (TUS) can have medium- to long-lasting effects. Multiple read-outs allow us to conclude that TUS can perturb neuronal tissues up to 2h after intervention, including changes in local and distributed brain network configurations, behavioural changes, task-related neuronal changes and chemical changes in the sonicated focal volume. Combined with multiple neuroimaging techniques (resting state functional Magnetic Resonance Imaging [rsfMRI], Spectroscopy [MRS] and task-related fMRI changes), this talk will focus on recent human TUS studies.

On Friday, August 31st we will host Stephanie Cernera & Doris Wang! Stephanie Cernera, PhD, is a postdoctoral research fellow in the Starr lab at University of California San Francisco. She will tell us about “Personalized chronic adaptive deep brain stimulation outperforms conventional stimulation in Parkinson’s Disease”. Doris Wang, MD, PhD, is a neurosurgeon and assistant professor at the University of California San Francisco. Apart from her scientific presentation about “Adaptive Deep Brain Stimulation to Treat Gait Disorders in Parkinson’s Disease”, she will give us a glimpse at the “Person behind the science”. The talks will be followed by a shared discussion. You can register via talks.stimulatingbrains.org to receive the (free) Zoom link!

Myopia is predicted to affect 50% of all people worldwide by 2050, and is a risk factor for significant, potentially blinding ocular pathologies, such as retinal detachment and glaucoma. Thus, there is significant motivation to better understand the process of myopigenesis and to develop effective anti-myopigenic treatments. In nearly all cases of human myopia, scleral remodeling is an obligate step in the axial elongation that characterizes the condition. Here I will describe the development of a biomechanical assay based on transient unconfined compression of scleral samples. By treating the scleral as a poroelastic material, one can determine scleral biomechanical properties from extremely small samples, such as obtained from the mouse eye. These properties provide proxy measures of scleral remodeling, and have allowed us to identify all-trans retinoic acid (atRA) as a myopigenic stimulus in mice. I will also describe nascent collaborative work on modeling the transport of atRA in the eye.

The eye is a multi-component biological system, where mechanics, optics, transport phenomena and chemical reactions are strictly interlaced, characterized by the typical bio-variability in sizes and material properties. The eye’s response to external action is patient-specific and it can be predicted only by a customized approach, that accounts for the multiple physics and for the intrinsic microstructure of the tissues, developed with the aid of forefront means of computational biomechanics. Our activity in the last years has been devoted to the development of a comprehensive model of the cornea that aims at being entirely patient-specific. While the geometrical aspects are fully under control, given the sophisticated diagnostic machinery able to provide a fully three-dimensional images of the eye, the major difficulties are related to the characterization of the tissues, which require the setup of in-vivo tests to complement the well documented results of in-vitro tests. The interpretation of in-vivo tests is very complex, since the entire structure of the eye is involved and the characterization of the single tissue is not trivial. The availability of micromechanical models constructed from detailed images of the eye represents an important support for the characterization of the corneal tissues, especially in the case of pathologic conditions. In this presentation I will provide an overview of the research developed in our group in terms of computational models and experimental approaches developed for the human cornea.

Computational imaging seeks to achieve novel capabilities and overcome conventional limitations by combining optics and algorithms. In this seminar, I will discuss two computational imaging technologies developed in Boston University Computational Imaging Systems lab, including Intensity Diffraction Tomography and Computational Miniature Mesoscope. In our intensity diffraction tomography system, we demonstrate 3D quantitative phase imaging on a simple LED array microscope. We develop both single-scattering and multiple-scattering models to image complex biological samples. In our Computational Miniature Mesoscope, we demonstrate single-shot 3D high-resolution fluorescence imaging across a wide field-of-view in a miniaturized platform. We develop methods to characterize 3D spatially varying aberrations and physical simulator-based deep learning strategies to achieve fast and accurate reconstructions. Broadly, I will discuss how synergies between novel optical instrumentation, physical modeling, and model- and learning-based computational algorithms can push the limits in biomedical microscopy and neural imaging.

Neural computations occurring simultaneously in multiple cerebral cortical regions are critical for mediating behaviors. Progress has been made in understanding how neural activity in specific cortical regions contributes to behavior. However, there is a lack of tools that allow simultaneous monitoring and perturbing neural activity from multiple cortical regions. We have engineered a suite of technologies to enable easy, robust access to much of the dorsal cortex of mice for optical and electrophysiological recordings. First, I will describe microsurgery robots that can programmed to perform delicate microsurgical procedures such as large bilateral craniotomies across the cortex and skull thinning in a semi-automated fashion. Next, I will describe digitally designed, morphologically realistic, transparent polymer skulls that allow long-term (+300 days) optical access. These polymer skulls allow mesoscopic imaging, as well as cellular and subcellular resolution two-photon imaging of neural structures up to 600 µm deep. We next engineered a widefield, miniaturized, head-mounted fluorescence microscope that is compatible with transparent polymer skull preparations. With a field of view of 8 × 10 mm2 and weighing less than 4 g, the ‘mini-mScope’ can image most of the mouse dorsal cortex with resolutions ranging from 39 to 56 µm. We used the mini-mScope to record mesoscale calcium activity across the dorsal cortex during sensory-evoked stimuli, open field behaviors, social interactions and transitions from wakefulness to sleep.

Visual restoration is certainly the greatest challenge for brain-machine interfaces with the high pixel number and high refreshing rate. In the recent year, we brought retinal prostheses and optogenetic therapy up to successful clinical trials. Concerning visual restoration at the cortical level, prostheses have shown efficacy for limited periods of time and limited pixel numbers. We are investigating the potential of sonogenetics to develop a non-contact brain machine interface allowing long-lasting activation of the visual cortex. The presentation will introduce our genetic-based brain machine interfaces for visual restoration at the retinal and cortical levels.

We have been developing Brain-Computer Interface (BCI) using electrocorticography (ECoG) [1] , which is recorded by electrodes implanted on brain surface, and magnetoencephalography (MEG) [2] , which records the cortical activities non-invasively, for the clinical applications. The invasive BCI using ECoG has been applied for severely paralyzed patient to restore the communication and motor function. The non-invasive BCI using MEG has been applied as a neurofeedback tool to modulate some pathological neural activities to treat some neuropsychiatric disorders. Although these techniques have been developed for clinical application, BCI is also an important tool to investigate neural function. For example, motor BCI records some neural activities in a part of the motor cortex to generate some movements of external devices. Although our motor system consists of complex system including motor cortex, basal ganglia, cerebellum, spinal cord and muscles, the BCI affords us to simplify the motor system with exactly known inputs, outputs and the relation of them. We can investigate the motor system by manipulating the parameters in BCI system. Recently, we are developing some BCIs to visualize and manipulate our perception and mental imagery. Although these BCI has been developed for clinical application, the BCI will be useful to understand our neural system to generate the perception and imagery. In this talk, I will introduce our study of phantom limb pain [3] , that is controlled by MEG-BCI, and the development of a communication BCI using ECoG [4] , that enable the subject to visualize the contents of their mental imagery. And I would like to discuss how much we can control our cortical activities that represent our perception and mental imagery. These examples demonstrate that BCI is a promising tool to visualize and manipulate the perception and imagery and to understand our consciousness. References 1. Yanagisawa, T., Hirata, M., Saitoh, Y., Kishima, H., Matsushita, K., Goto, T., Fukuma, R., Yokoi, H., Kamitani, Y., and Yoshimine, T. (2012). Electrocorticographic control of a prosthetic arm in paralyzed patients. AnnNeurol 71, 353-361. 2. Yanagisawa, T., Fukuma, R., Seymour, B., Hosomi, K., Kishima, H., Shimizu, T., Yokoi, H., Hirata, M., Yoshimine, T., Kamitani, Y., et al. (2016). Induced sensorimotor brain plasticity controls pain in phantom limb patients. Nature communications 7, 13209. 3. Yanagisawa, T., Fukuma, R., Seymour, B., Tanaka, M., Hosomi, K., Yamashita, O., Kishima, H., Kamitani, Y., and Saitoh, Y. (2020). BCI training to move a virtual hand reduces phantom limb pain: A randomized crossover trial. Neurology 95, e417-e426. 4. Ryohei Fukuma, Takufumi Yanagisawa, Shinji Nishimoto, Hidenori Sugano, Kentaro Tamura, Shota Yamamoto, Yasushi Iimura, Yuya Fujita, Satoru Oshino, Naoki Tani, Naoko Koide-Majima, Yukiyasu Kamitani, Haruhiko Kishima (2022). Voluntary control of semantic neural representations by imagery with conflicting visual stimulation. arXiv arXiv:2112.01223.

My research uses electrophysiological techniques to evaluate normal retinal function, dysfunction caused by blinding retinal diseases and the restoration of function using a variety of therapeutic strategies. We can use our understanding or normal retinal function and disease-related changes to construct optimal therapeutic strategies and evaluate how they ameliorate the effects of disease. Retinitis pigmentosa (RP) is a family of blinding eye diseases caused by photoreceptor degeneration. The absence of the cells that for this primary signal leads to blindness. My interest in RP involves the evaluation of therapies to restore vision: replacing degenerated photoreceptors either with: (1) new stem or other embryonic cells, manipulated to become photoreceptors or (2) prosthetics devices that replace the photoreceptor signal with an electronic signal to light. Glaucoma is caused by increased intraocular pressure and leads to ganglion cell death, which eliminates the link between the retinal output and central visual processing. We are parsing out of the effects of increased intraocular pressure and aging on ganglion cells. Congenital Stationary Night Blindness (CSNB) is a family of diseases in which signaling is eliminated between rod photoreceptors and their postsynaptic targets, rod bipolar cells. This deafferents the retinal circuit that is responsible for vision under dim lighting. My interest in CSNB involves understanding the basic interplay between excitation and inhibition in the retinal circuit and its normal development. Because of the targeted nature of this disease, we are hopeful that a gene therapy approach can be developed to restore night vision. My work utilizes rodent disease models whose mutations mimic those found in human patients. While molecular manipulation of rodents is a fairly common approach, we have recently developed a mutant NIH miniature swine model of a common form of autosomal dominant RP (Pro23His rhodopsin mutation) in collaboration with the National Swine Resource Research Center at University of Missouri. More genetically modified mini-swine models are in the pipeline to examine other retinal diseases.

Restoring hand function is a top priority for individuals with tetraplegia. This challenge motivates considerable research on brain-computer interfaces (BCIs), which bypass damaged neural pathways to control paralyzed or prosthetic limbs. Here, we demonstrate the BCI control of a prosthetic hand using intracortical recordings from the posterior parietal cortex (PPC). As part of an ongoing clinical trial, two participants with cervical spinal cord injury were each implanted with a 96-channel array in the left PPC. Across four sessions each, we recorded neural activity while they attempted to press individual fingers of the contralateral (right) hand. Single neurons modulated selectively for different finger movements. Offline, we accurately classified finger movements from neural firing rates using linear discriminant analysis (LDA) with cross-validation (accuracy = 90%; chance = 17%). Finally, the participants used the neural classifier online to control all five fingers of a BCI hand. Online control accuracy (86%; chance = 17%) exceeded previous state-of-the-art finger BCIs. Furthermore, offline, we could classify both flexion and extension of the right fingers, as well as flexion of all ten fingers. Our results indicate that neural recordings from PPC can be used to control prosthetic fingers, which may help contribute to a hand restoration strategy for people with tetraplegia.

Brain microstructure plays a key role in driving the transport of drug molecules directly administered to the brain tissue as in Convection-Enhanced Delivery procedures. This study reports the first systematic attempt to characterize the cytoarchitecture of commissural, long association and projection fiber, namely: the corpus callosum, the fornix and the corona radiata. Ovine samples from three different subjects have been imaged using scanning electron microscope combined with focused ion beam milling. Particular focus has been given to the axons. For each tract, a 3D reconstruction of relatively large volumes (including a significant number of axons) has been performed. Namely, outer axonal ellipticity, outer axonal cross-sectional area and its relative perimeter have been measured. This study [1] provides useful insight into the fibrous organization of the tissue that can be described as composite material presenting elliptical tortuous tubular fibers, leading to a workflow to enable accurate simulations of drug delivery which include well-resolved microstructural features. As a demonstration of the use of these imaging and reconstruction techniques, our research analyses the hydraulic permeability of two white matter (WM) areas (corpus callosum and fornix) whose three-dimensional microstructure was reconstructed starting from the acquisition of the electron microscopy images. Considering that the white matter structure is mainly composed of elongated and parallel axons we computed the permeability along the parallel and perpendicular directions using computational fluid dynamics [2]. The results show a statistically significant difference between parallel and perpendicular permeability, with a ratio about 2 in both the white matter structures analysed, thus demonstrating their anisotropic behaviour. This is in line with the experimental results obtained using perfusion of brain matter [3]. Moreover, we find a significant difference between permeability in corpus callosum and fornix, which suggests that also the white matter heterogeneity should be considered when modelling drug transport in the brain. Our findings, that demonstrate and quantify the anisotropic and heterogeneous character of the white matter, represent a fundamental contribution not only for drug delivery modelling but also for shedding light on the interstitial transport mechanisms in the extracellular space. These and many other discoveries will be discussed during the talk." "1. https://www.researchsquare.com/article/rs-686577/v1, 2. https://www.pnas.org/content/118/36/e2105328118, 3. https://ieeexplore.ieee.org/abstract/document/9198110

I will discuss the mechanisms that determine whether a weak visual stimulus will reach consciousness or not. If the stimulus is simple, early visual cortex acts as a relay station that sends the information to higher visual areas. If the stimulus arrives at a minimal strength, it will be stored in working memory and can be reported. However, during more complex visual perceptions, which for example depend on the segregation of a figure from the background, early visual cortex’ role goes beyond a simply relay. It now acts as a cognitive blackboard and conscious perception depends on it. Our results inspire new approaches to create a visual prosthesis for the blind, by creating a direct interface with the visual brain. I will discuss how high-channel-number interfaces with the visual cortex might be used to restore a rudimentary form of vision in blind individuals.

The human gut microbiome has emerged as a key player in the bidirectional communication of the gut-brain axis, affecting various aspects of homeostasis and pathophysiology. Until recently, the majority of studies that seek to explore the mechanisms underlying the microbiome-gut-brain axis cross-talk relied almost exclusively on animal models, and particularly gnotobiotic mice. Despite the great progress made with these models, various limitations, including ethical considerations and interspecies differences that limit the translatability of data to human systems, pushed researchers to seek for alternatives. Over the past decades, the field of in vitro modelling of tissues has experienced tremendous growth, thanks to advances in 3D cell biology, materials, science and bioengineering, pushing further the borders of our ability to more faithfully emulate the in vivo situation. Organ-on-chip technology and bioengineered tissues have emerged as highly promising alternatives to animal models for a wide range of applications. In this talk I’ll discuss our progress towards generating a complete platform of the human microbiota-gut-brain axis with integrated monitoring and sensing capabilities. Bringing together principles of materials science, tissue engineering, 3D cell biology and bioelectronics, we are building advanced models of the GI and the BBB /NVU, with real-time and label-free monitoring units adapted in the model architecture, towards a robust and more physiologically relevant human in vitro model, aiming to i) elucidate the role of microbiota in the gut-brain axis communication, ii) to study how diet and impaired microbiota profiles affect various (patho-)physiologies, and iii) to test personalised medicine approaches for disease modelling and drug testing.