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.

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!

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.

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.

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.

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. 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 also inspire new approaches to create a visual prosthesis for the blind, by creating a direct interface with the visual cortex. 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.

To enable the understanding and repair of complex biological systems, such as the brain, we are creating novel optical tools that enable molecular-resolution maps of such systems, as well as technologies for observing and controlling high-speed physiological dynamics in such systems. First, we have developed a method for imaging specimens with nanoscale precision, by embedding them in a swellable polymer, homogenizing their mechanical properties, and exposing them to water – which causes them to expand manyfold isotropically. This method, which we call expansion microscopy (ExM), enables ordinary microscopes to do nanoscale imaging, in a multiplexed fashion – important, for example, for brain mapping. Second, we have developed a set of genetically-encoded reagents, known as optogenetic tools, that when expressed in specific neurons, enable their electrical activities to be precisely driven or silenced in response to millisecond timescale pulses of light. Finally, we are designing, and evolving, novel reagents, such as fluorescent voltage indicators and somatically targeted calcium indicators, to enable the imaging of fast physiological processes in 3-D with millisecond precision. In this way we aim to enable the systematic mapping, control, and dynamical observation of complex biological systems like the brain. The talk will be simultaneously interpreted English-Spanish) by the Interpreter, Mg. Lourdes Martino. Para permitir la comprensión y reparación de sistemas biológicos complejos, como el cerebro, estamos creando herramientas ópticas novedosas que permiten crear mapas de resolución molecular de dichos sistemas, así como tecnologías para observar y controlar la dinámica fisiológica de alta velocidad en dichos sistemas. Primero, hemos desarrollado un método para obtener imágenes de muestras con precisión a nanoescala, incrustándolas en un polímero hinchable, homogeneizando sus propiedades mecánicas y exponiéndolas al agua, lo que hace que se expandan muchas veces isotrópicamente. Este método, que llamamos microscopía de expansión (ExM), permite que los microscopios ordinarios obtengan imágenes a nanoescala, de forma multiplexada, lo que es importante, por ejemplo, para el mapeo cerebral. En segundo lugar, hemos desarrollado un conjunto de reactivos codificados genéticamente, conocidos como herramientas optogenéticas, que cuando se expresan en neuronas específicas, permiten que sus actividades eléctricas sean activadas o silenciadas con precisión en respuesta a pulsos de luz en una escala de tiempo de milisegundos. Finalmente, estamos diseñando y desarrollando reactivos novedosos, como indicadores de voltaje fluorescentes e indicadores de calcio dirigidos somáticamente, para permitir la obtención de imágenes de procesos fisiológicos rápidos en 3-D con precisión de milisegundos. De esta manera, nuestro objetivo es permitir el mapeo sistemático, el control y la observación dinámica de sistemas biológicos complejos como el cerebro. La conferencia será traducida simultáneamente al español por la intérprete Mg. Lourdes Martino.

Brain-machine interfaces (BMIs) change how the brain sends and receives information from the environment, opening new ways to probe brain function. For instance, motor BMIs allow us to precisely define and manipulate the sensorimotor loop which has enabled new insights into motor control and learning. In this talk, I’ll first present an example study where sensory-motor loop manipulations in BMI allowed us to probe feed-forward and feedback control mechanisms in ways that are not possible in the natural motor system. This study shed light on sensorimotor processing, and in turn led to state-of-the-art neural interface performance. I’ll then survey recent work that highlights the likelihood that BMIs, much like natural motor learning, engages multiple distributed learning mechanisms that can be carefully interrogated with BMI.

Learning is a population phenomenon. Since it is the organized activity of populations of neurons that cause movement, learning a new skill must involve reshaping those population activity patterns. Seeing how the brain does this has been elusive, but a brain-computer interface approach can yield new insight. We presented monkeys with novel BCI mappings that we knew would be difficult for them to learn how to control. Over several days, we observed the emergence of new patterns of neural activity that endowed the animals with the ability to perform better at the BCI task. We speculate that there also exists a direct relationship between new patterns of neural activity and new abilities during natural movements, but it is much harder to see in that setting.