Browsing by Author "Robinson, Jacob T."

Now showing 1 - 20 of 36
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    A microfluidic-induced C. elegans sleep state
    (Springer Nature, 2019) Gonzales, Daniel L.; Zhou, Jasmine; Fan, Bo; Robinson, Jacob T.
    An important feature of animal behavior is the ability to switch rapidly between activity states, however, how the brain regulates these spontaneous transitions based on the animal’s perceived environment is not well understood. Here we show a C. elegans sleep-like state on a scalable platform that enables simultaneous control of multiple environmental factors including temperature, mechanical stress, and food availability. This brief quiescent state, which we refer to as microfluidic-induced sleep, occurs spontaneously in microfluidic chambers, which allows us to track animal movement and perform whole-brain imaging. With these capabilities, we establish that microfluidic-induced sleep meets the behavioral requirements of C. elegans sleep and depends on multiple factors, such as satiety and temperature. Additionally, we show that C. elegans sleep can be induced through mechanosensory pathways. Together, these results establish a model system for studying how animals process multiple sensory pathways to regulate behavioral states.
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    A wireless millimetric magnetoelectric implant for the endovascular stimulation of peripheral nerves
    (Springer Nature, 2022) Chen, Joshua C.; Kan, Peter; Yu, Zhanghao; Alrashdan, Fatima; Garcia, Roberto; Singer, Amanda; Lai, C.S. Edwin; Avants, Ben; Crosby, Scott; Li, Zhongxi; Wang, Boshuo; Felicella, Michelle M.; Robledo, Ariadna; Peterchev, Angel V.; Goetz, Stefan M.; Hartgerink, Jeffrey D.; Sheth, Sunil A.; Yang, Kaiyuan; Robinson, Jacob T.; Applied Physics Program
    Implantable bioelectronic devices for the simulation of peripheral nerves could be used to treat disorders that are resistant to traditional pharmacological therapies. However, for many nerve targets, this requires invasive surgeries and the implantation of bulky devices (about a few centimetres in at least one dimension). Here we report the design and in vivo proof-of-concept testing of an endovascular wireless and battery-free millimetric implant for the stimulation of specific peripheral nerves that are difficult to reach via traditional surgeries. The device can be delivered through a percutaneous catheter and leverages magnetoelectric materials to receive data and power through tissue via a digitally programmable 1 mm × 0.8 mm system-on-a-chip. Implantation of the device directly on top of the sciatic nerve in rats and near a femoral artery in pigs (with a stimulation lead introduced into a blood vessel through a catheter) allowed for wireless stimulation of the animals’ sciatic and femoral nerves. Minimally invasive magnetoelectric implants may allow for the stimulation of nerves without the need for open surgery or the implantation of battery-powered pulse generators.
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    Characterizations of two-photon absorption process induced by defects in aluminum nitride using Z-scan method
    (IOP Publishing, 2024) Zhou, Jingan; Li, Tao; Zhao, Xuan; Zhang, Xiang; Doumani, Jacques; Xu, Mingfei; He, Ziyi; Luo, Shisong; Mei, Zhaobo; Chang, Cheng; Robinson, Jacob T.; Ajayan, Pulickel M.; Kono, Junichiro; Zhao, Yuji; Smalley-Curl Institute
    In this work, we reported two-photon absorption (TPA) measurements for aluminum vacancies in Aluminum nitride single crystals. We measured the linear transmission and identified the defect levels. Using the Z-scan method, we measured the TPA coefficients of the transitions between defect levels from 380 nm to 735 nm. The transition occurs between the aluminum vacancies defect levels. Furthermore, the power dependence shows good linear fitting, confirming the TPA mechanism. These results will be helpful for the design and fabrication of ultra-low loss waveguides and integrated photonics in the ultraviolet spectral range.
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    Deep imaging in scattering media with selective plane illumination microscopy
    (SPIE, 2016) Pediredla, Adithya Kumar; Zhang, Shizheng; Avants, Ben; Ye, Fan; Nagayama, Shin; Chen, Ziying; Kemere, Caleb; Robinson, Jacob T.; Veeraraghavan, Ashok
    In most biological tissues, light scattering due to small differences in refractive index limits the depth of optical imaging systems. Two-photon microscopy (2PM), which significantly reduces the scattering of the excitation light, has emerged as the most common method to image deep within scattering biological tissue. This technique, however, requires high-power pulsed lasers that are both expensive and difficult to integrate into compact portable systems. Using a combination of theoretical and experimental techniques, we show that if the excitation path length can be minimized, selective plane illumination microscopy (SPIM) can image nearly as deep as 2PM without the need for a high-powered pulsed laser. Compared to other single-photon imaging techniques like epifluorescence and confocal microscopy, SPIM can image more than twice as deep in scattering media (∼10 times the mean scattering length). These results suggest that SPIM has the potential to provide deep imaging in scattering media in situations in which 2PM systems would be too large or costly.
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    Deep learning extended depth-of-field microscope for fast and slide-free histology
    (PNAS, 2020) Jin, Lingbo; Tang, Yubo; Wu, Yicheng; Coole, Jackson B.; Tan, Melody T.; Zhao, Xuan; Badaoui, Hawraa; Robinson, Jacob T.; Williams, Michelle D.; Gillenwater, Ann M.; Richards-Kortum, Rebecca R.; Veeraraghavan, Ashok
    Microscopic evaluation of resected tissue plays a central role in the surgical management of cancer. Because optical microscopes have a limited depth-of-field (DOF), resected tissue is either frozen or preserved with chemical fixatives, sliced into thin sections placed on microscope slides, stained, and imaged to determine whether surgical margins are free of tumor cells—a costly and time- and labor-intensive procedure. Here, we introduce a deep-learning extended DOF (DeepDOF) microscope to quickly image large areas of freshly resected tissue to provide histologic-quality images of surgical margins without physical sectioning. The DeepDOF microscope consists of a conventional fluorescence microscope with the simple addition of an inexpensive (less than $10) phase mask inserted in the pupil plane to encode the light field and enhance the depth-invariance of the point-spread function. When used with a jointly optimized image-reconstruction algorithm, diffraction-limited optical performance to resolve subcellular features can be maintained while significantly extending the DOF (200 µm). Data from resected oral surgical specimens show that the DeepDOF microscope can consistently visualize nuclear morphology and other important diagnostic features across highly irregular resected tissue surfaces without serial refocusing. With the capability to quickly scan intact samples with subcellular detail, the DeepDOF microscope can improve tissue sampling during intraoperative tumor-margin assessment, while offering an affordable tool to provide histological information from resected tissue specimens in resource-limited settings.
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    DeepDOF-SE: affordable deep-learning microscopy platform for slide-free histology
    (Springer Nature, 2024) Jin, Lingbo; Tang, Yubo; Coole, Jackson B.; Tan, Melody T.; Zhao, Xuan; Badaoui, Hawraa; Robinson, Jacob T.; Williams, Michelle D.; Vigneswaran, Nadarajah; Gillenwater, Ann M.; Richards-Kortum, Rebecca R.; Veeraraghavan, Ashok
    Histopathology plays a critical role in the diagnosis and surgical management of cancer. However, access to histopathology services, especially frozen section pathology during surgery, is limited in resource-constrained settings because preparing slides from resected tissue is time-consuming, labor-intensive, and requires expensive infrastructure. Here, we report a deep-learning-enabled microscope, named DeepDOF-SE, to rapidly scan intact tissue at cellular resolution without the need for physical sectioning. Three key features jointly make DeepDOF-SE practical. First, tissue specimens are stained directly with inexpensive vital fluorescent dyes and optically sectioned with ultra-violet excitation that localizes fluorescent emission to a thin surface layer. Second, a deep-learning algorithm extends the depth-of-field, allowing rapid acquisition of in-focus images from large areas of tissue even when the tissue surface is highly irregular. Finally, a semi-supervised generative adversarial network virtually stains DeepDOF-SE fluorescence images with hematoxylin-and-eosin appearance, facilitating image interpretation by pathologists without significant additional training. We developed the DeepDOF-SE platform using a data-driven approach and validated its performance by imaging surgical resections of suspected oral tumors. Our results show that DeepDOF-SE provides histological information of diagnostic importance, offering a rapid and affordable slide-free histology platform for intraoperative tumor margin assessment and in low-resource settings.
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    Developing Genetically Encoded Voltage Indicators for in vivo Neuroimaging
    (2023-08-09) Lu, Helen; Robinson, Jacob T.; St-Pierre, François
    A fundamental goal of neuroscience is to decipher the neural activities underlying behaviors in vivo. Among existing tools for neural recording, genetically encoded voltage indicators (GEVIs) — protein-based fluorescent indicators whose brightness is directly modulated by membrane potential — hold the most promise for large-scale measuring of neural activities with cell-type specificity, subcellular spatial resolution, and sub-millisecond temporal resolution. However, current GEVIs have limited utility in vivo due to their suboptimal performance, especially under two-photon microscopy (2PM), a desired method for deep-tissue imaging. To address these limitations, we started from building a high-throughput screening platform that can evaluate all key metrics of a GEVI under one-photon illumination. Directed evolution on this platform led to JEDI-1P, a green-emitting GEVI optimized for widefield voltage imaging. With improved brightness, kinetics, sensitivity and photostability, JEDI-1P empowered chronic pan-cortical voltage imaging and robust detection of rapid voltage signals in behaving mice. Next, we sought to optimize GEVI for deep tissue imaging by extending the screening platform with a two-photon resonant scanning system. Using this 2P screening platform, we identified JEDI-2P, whose brightness, sensitivity and photostability under 2PM were all significantly improved over its parental indicator. We showed that JEDI-2P can capture voltage responses to visual stimuli in the amacrine cells of isolated mouse retina and the axonal projections of Drosophila interneurons. With excellent 2P photostability, JEDI-2P enabled prolonged continuous recording from individual cortical neurons in awake behaving mice with both resonant-scanning 2PM and ULoVE random-access microscopy. In particular, we highlighted that the improved sensitivity and brightness of JEDI-2P allowed the first high-fidelity voltage recording from mice Layer 5 cortical neurons as well as robust recordings of pairwise voltage correlations during behavior. Taken together, JEDI-2P fills the vacancy of a GEVI optimized for 2P applications and paves the way for long-term studying of deep brain neural activities. Finally, to enable all-optical electrophysiology and multi-spectral imaging under two-photon microscopy, we designed a red-emitting voltage indicator from scratch. After rationally engineering the interface between the chromophore and the voltage-sensing domain, we identified VADER1, the first red-emitting GEVI that has demonstrated the capability to resolve single action potentials in mice under two-photon illumination. We anticipate the expanded GEVI toolbox will enable high-throughput and real-time recording of action potentials from the genetically specified group of neurons in live animals, thereby helping interpret the computation mechanism of neural circuits with unprecedented spatiotemporal resolution.
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    Distributed sensor and actuator networks for closed-loop bioelectronic medicine
    (Elsevier, 2021) Bhave, Gauri; Chen, Joshua C.; Singer, Amanda; Sharma, Aditi; Robinson, Jacob T.
    Designing implantable bioelectronic systems that continuously monitor physiological functions and simultaneously provide personalized therapeutic solutions for patients remains a persistent challenge across many applications ranging from neural systems to bioelectronic organs. Closed-loop systems typically consist of three functional blocks, namely, sensors, signal processors and actuators. An effective system, that can provide the necessary therapeutics, tailored to individual physiological factors requires a distributed network of sensors and actuators. While significant progress has been made, closed-loop systems still face many challenges before they can truly be considered as long-term solutions for many diseases. In this review, we consider three important criteria where materials play a critical role to enable implantable closed-loop systems: Specificity, Biocompatibility and Connectivity. We look at the progress made in each of these fields with respect to a specific application and outline the challenges in creating bioelectronic technologies for the future.
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    Engineering Deep Brain Stimulation as a Treatment for Parkinson's Disease: from Models to Materials
    (2014-04-25) Summerson, Samantha Rose; Aazhang, Behnaam; Kemere, Caleb T.; Baraniuk, Richard G.; Cox, Steven J.; Robinson, Jacob T.
    This thesis analyzes deep brain stimulation (DBS) as a treatment for the motor symptoms of Parkinson's disease (PD) at multiple levels. Although this treatment is currently used on human patients, little is understood about the mechanism of action which allows patients to experience therapeutic benefits. The work here investigates efficacy of DBS in computational and experimental manners in order to enhance the understanding of the effects on neural activity and behavior. First, I examine computational models of the nuclei within the motor circuit of the brain and used these models to test novel electrical stimulation signal designs. I show that irregular spacing of stimulation pulses allows for increased variability in neuronal firing rate responses within the basal ganglia. Also, I develop a model of the stimulation-frequency-dependent nature of antidromic spiking induced in the motor cortex as a result of DBS. Second, I use the hemi-Parkinsonian rat model to demonstrate motor and cognitive behavioral effects of DBS in the globus pallidus internus (GPi). The work validates this animal model for translational research on DBS of the GPi and demonstrates results consistent with reports for DBS of the subthalamic nucleus (STN) in the same model. Additionally I study recorded neural activity in the motor cortex while stimulating the STN in order to characterize the corresponding changes in neural activity. I found that regular and irregular stimulation patterns both decrease Parkinsonian entropic noise in the output layer of the motor cortex, with irregular stimulation having the greatest benefit towards reducing this noise. Third, I consider a new material for its biocompatibility and applicability as a material for stimulating electrodes. In the rat model that I previously validated, I verify that behavioral results using a stimulating electrode made from carbon nanotube fibers (CNTf) match results from previous experiments using standard platinum iridium (PtIr) electrodes. Additionally, it is shown that CNTf electrodes produce lower inflammation, gliosis and damage to the blood brain barrier. Together, all three aspects of the work demonstrate significant contributions to the functionality and engineering of DBS as a neuromodulation therapy for PD.
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    Evaluation of Aerosol Particle Leak and Standard Surgical Mask Fit With 3 Elastomeric Harness Designs
    (American Medical Association, 2022) Ingabire, Jeannette; McKenney, Hannah; Sebesta, Charles; Badhiwala, Krishna; Kemere, Caleb; Kapur, Sahil; Robinson, Jacob T.
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    Flexible sensors for high-quality recording and human-computer interface
    (2022-12-01) Fan, Bo; Robinson, Jacob T.
    Human-computer interfaces have been widely developed to bridge the gap in information transmission and enable the interaction between humans and computers. It provides unique opportunities to understand, augment, assist and repair the cognitive, sensory, and motor functions. Due to the soft nature of human skin and tissues, the conventional rigid human-computer interfaces face challenges in biocompatibility, wearability, comfortability, and high signal-to-noise (SNR) ratio for long-term and stable recording. Flexible devices are emerging. The flexible human-machine interface requires fundamental research in materials, mechanism, device design, and fabrication. This work focuses on developing flexible devices for human-computer interfaces which collect high-quality physical and physiological signals from animals. We have developed low impedance flexible electronic devices for high SNR recording in the motor cortex of rats: With a simple direct sputtering method, we can reduce the impedance of flexible Pt microelectrodes by 5-9-fold and reduce the thermal noise from both in vitro and in vivo recording. We also demonstrated that in addition to the surface area, the shape also affects the total impedance. We then further investigated how the design and materials of the electrodes affect the impedance, which is important for balancing the electrode sizes and recording SNR. We discovered that for materials associated with a diffusion-limited process, in small electrodes with a radius of fewer than 10 microns, the impedance transitions from area-dependent to perimeter-dependent. This indicates that when pushing for small electrodes, materials that have interactions with diffusion species in the electrolyte should be preferred. Finally, similar fabrication techniques for flexible microelectrodes can be applied to flexible photonic devices for temperature monitoring. We designed a micro-ring-resonator (MRR) based temperature sensor and demonstrated that the flexible temperature sensor doubled the temperature sensitivity compared to the conventional silicon-based MRR temperature sensor, which opens opportunities for biomedical applications in wearable devices or high sensitivity temperature monitoring. In summary, this work reports a novel method for wafer-scale low-impedance microelectrodes fabrication and provides insights into flexible device design, mechanism, and materials for high-quality recording and human-computer interfaces.
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    Generalized method to design phase masks for 3D super-resolution microscopy
    (Optical Society of America, 2019) Wang, Wenxiao; Ye, Fan; Shen, Hao; Moringo, Nicholas A.; Dutta, Chayan; Robinson, Jacob T.; Landes, Christy F.
    Point spread function (PSF) engineering by phase modulation is a novel approach to three-dimensional (3D) super-resolution microscopy, with different point spread functions being proposed for specific applications. It is often not easy to achieve the desired shape of engineered point spread functions because it is challenging to determine the correct phase mask. Additionally, a phase mask can either encode 3D space information or additional time information, but not both simultaneously. A robust algorithm for recovering a phase mask to generate arbitrary point spread functions is needed. In this work, a generalized phase mask design method is introduced by performing an optimization. A stochastic gradient descent algorithm and a Gauss-Newton algorithm are developed and compared for their ability to recover the phase masks for previously reported point spread functions. The new Gauss-Newton algorithm converges to a minimum at much higher speeds. This algorithm is used to design a novel stretching-lobe phase mask to encode temporal and 3D spatial information simultaneously. The stretching-lobe phase mask and other masks are fabricated in-house for proof-of-concept using multi-level light lithography and an optimized commercially sourced stretching-lobe phase mask (PM) is validated experimentally to encode 3D spatial and temporal information. The algorithms’ generalizability is further demonstrated by generating a phase mask that comprises four different letters at different depths.
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    Hydra vulgaris shows stable responses to thermal stimulation despite large changes in the number of neurons
    (Cell Press, 2021) Tzouanas, Constantine N.; Kim, Soonyoung; Badhiwala, Krishna N.; Avants, Benjamin W.; Robinson, Jacob T.
    Many animals that lose neural tissue to injury or disease can maintain behavioral repertoires by regenerating new neurons or reorganizing existing neural circuits. However, most neuroscience small model organisms lack this high degree of neural plasticity. We show that Hydra vulgaris can maintain stable sensory-motor behaviors despite 2-fold changes in neuron count, due to naturally occurring size variation or surgical resection. Specifically, we find that both behavioral and neural responses to rapid temperature changes are maintained following these perturbations. We further describe possible mechanisms for the observed neural activity and argue that Hydra's radial symmetry may allow it to maintain stable behaviors when changes in the numbers of neurons do not selectively eliminate any specific neuronal cell type. These results suggest that Hydra provides a powerful model for studying how animals maintain stable sensory-motor responses within dynamic neural circuits and may lead to the development of general principles for injury-tolerant neural architectures.
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    Impedance scaling for gold and platinum microelectrodes
    (IOP Publishing, 2021) Fan, Bo; Wolfrum, Bernhard; Robinson, Jacob T.
    Objective. Electrical measurement of the activity of individual neurons is a primary goal for many invasive neural electrodes. Making these ‘single unit’ measurements requires that we fabricate electrodes small enough so that only a few neurons contribute to the signal, but not so small that the impedance of the electrode creates overwhelming noise or signal attenuation. Thus, neuroelectrode design often must strike a balance between electrode size and electrode impedance, where the impedance is often assumed to scale linearly with electrode area. Approach and main results. Here we study how impedance scales with neural electrode area and find that the 1 kHz impedance of Pt electrodes (but not Au electrodes) transitions from scaling with area (r −2) to scaling with perimeter (r −1) when the electrode radius falls below 10 µm. This effect can be explained by the transition from planar to spherical diffusion behavior previously reported for electrochemical microelectrodes. Significance. These results provide important intuition for designing small, single unit recording electrodes. Specifically, for materials where the impedance is dominated by a pseudo-capacitance that is associated with a diffusion limited process, the total impedance will scale with perimeter rather than area when the electrode size becomes comparable with the diffusion layer thickness. For Pt electrodes this transition occurs around 10 µm radius electrodes. At even lower frequencies (1 Hz) impedance approaches a constant. This transition to r −1 scaling implies that electrodes with a pseudo-capacitance can be made smaller than one might expect before thermal noise or voltage division limits the ability to acquire high-quality single-unit recordings.
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    Integrated light-sheet illumination using metallic slit microlenses
    (Optical Society of America, 2018) Ye, Fan; Avants, Benjamin W.; Veeraraghavan, Ashok; Robinson, Jacob T.
    Light sheet microscopy (LSM) - also known as selective plane illumination microscopy (SPIM) - enables high-speed, volumetric imaging by illuminating a two-dimensional cross-section of a specimen. Typically, this light sheet is created by table-top optics, which limits the ability to miniaturize the overall SPIM system. Replacing this table-top illumination system with miniature, integrated devices would reduce the cost and footprint of SPIM systems. One important element for a miniature SPIM system is a flat, easily manufactured lens that can form a light sheet. Here we investigate planar metallic lenses as the beam shaping element of an integrated SPIM illuminator. Based on finite difference time domain (FDTD) simulations, we find that diffraction from a single slit can create planar illumination with a higher light throughput than zone plate or plasmonic lenses. Metallic slit microlenses also show broadband operation across the entire visible range and are nearly polarization insensitive. Furthermore, compared to meta-lenses based on sub-wavelength-scale diffractive elements, metallic slit lenses have micron-scale features compatible with low-cost photolithographic manufacturing. These features allow us to create inexpensive integrated devices that generate light-sheet illumination comparable to tabletop microscopy systems. Further miniaturization of this type of integrated SPIM illuminators will open new avenues for flat, implantable photonic devices for in vivo biological imaging.
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    Interrogating sensorimotor information processing in the highly regenerative and diffuse nerve net of Hydra
    (2021-04-29) Badhiwala, Krishna; Robinson, Jacob T.
    Hydra vulgaris is an emerging model organism for neuroscience due to its small size, transparency, genetic tractability and regenerative nervous system. While this freshwater cnidarian has been studied for centuries by developmental biologists, fundamental properties of many sensorimotor behaviors remain unknown. Here, we use microfluidic devices combined with calcium imaging and resectioning to study how the nervous system coordinates the animal’s mechanosensory response. Our findings point to a model of information processing where the oral and aboral nerve rings work together to coordinate sensory motor behaviors. Specifically, we found that animals contract in response to mechanical stimuli, and this response relies on neurons in both the oral and aboral nerve rings, with the oral nerve ring being the most important for mediating this sensory motor behavior. In addition to being the primary mediator of the mechanosensory response, the oral nerve ring also plays a dominant role in regulating basal contraction rates. We also find that the oral nerve ring works in concert with the aboral nerve ring to coordinate muscle activity. This model for sensory information processing where the oral nerve ring is the primary integrator of sensory input is a step toward understanding how Hydra’s regenerative and diffuse nervous system supports sensorimotor behaviors, which is needed to make Hydra a richer model organism for neuroscience.
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    Magnetoelectrics for Implantable Bioelectronics: Progress to Date
    (American Chemical Society, 2024) Alrashdan, Fatima; Yang, Kaiyuan; Robinson, Jacob T.; Applied Physics Program
    ConspectusThe coupling of magnetic and electric properties manifested in magnetoelectric (ME) materials has unlocked numerous possibilities for advancing technologies like energy harvesting, memory devices, and medical technologies. Due to this unique coupling, the magnetic properties of these materials can be tuned by an electric field; conversely, their electric polarization can be manipulated through a magnetic field.Over the past seven years, our lab work has focused on leveraging these materials to engineer implantable bioelectronics for various neuromodulation applications. One of the main challenges for bioelectronics is to design miniaturized solutions that can be delivered with minimally invasive procedures and yet can receive sufficient power to directly stimulate tissue or power electronics to perform functions like communication and sensing.Magnetoelectric coupling in ME materials is strongest when the driving field matches a mechanical resonant mode. However, miniaturized ME transducers typically have resonance frequencies >100 kHz, which is too high for direct neuromodulation as neurons only respond to low frequencies (typically <1 kHz). We discuss two approaches that have been proposed to overcome this frequency mismatch: operating off-resonance and rectification. The off-resonance approach is most common for magnetoelectric nanoparticles (MENPs) that typically have resonance frequencies in the gigahertz range. In vivo experiments on rat models have shown that MENPs could induce changes in neural activity upon excitation with <200 Hz magnetic fields. However, the neural response has latencies of several seconds due to the weak coupling in the off-resonance regime.To stimulate neural responses with millisecond precision, we developed methods to rectify the ME response so that we could drive the materials at their resonant frequency but still produce the slowly varying voltages needed for direct neural stimulation. The first version of the stimulator combined a ME transducer and analog electronics for rectification. To create even smaller solutions, we introduced the first magnetoelectric metamaterial (MNM) that exhibits self-rectification. Both designs have effectively induced neural modulation in rat models with less than 5 ms latency.Based on our experience with in vivo testing of the rectified ME stimulators, we found it challenging to deliver the precisely controlled therapy required for clinical applications, given the ME transducer’s sensitivity to the external transmitter alignment. To overcome this challenge, we developed the ME-BIT (MagnetoElectric BioImplanT), a digitally programmable stimulator that receives wireless power and data through the ME link.We further expanded the utility of this technology to neuromodulation applications that require high stimulation thresholds by introducing the DOT (Digitally programmable Overbrain Therapeutic). The DOT has voltage compliance up to 14.5 V. We have demonstrated the efficacy of these designs through various in vivo studies for applications like peripheral nerve stimulation and epidural cortical stimulation.To further improve these systems to be adaptive and enable a network of coordinated devices, we developed a bidirectional communication system to transmit data to and from the implant. To enable even greater miniaturization, we developed a way to use the same ME transducer for wireless power and data communication by developing the first ME backscatter communication protocol.
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    Millimeter-sized battery-free epidural cortical stimulators
    (2023-10-04) Woods, Joshua; Robinson, Jacob T.
    Refractory neurological and psychiatric disorders are increasingly treated with brain stimulation therapies using implanted neuromodulation devices. Current commercially available stimulation systems, however, are limited by the need for implantable pulse generators and wired power; the complexity of this architecture creates multiple failure points including lead fractures, migration, and infection. Enabling less invasive approaches could increase access to these therapies. Here we demonstrate the first millimeter-sized leadless brain stimulator in large animal and human subjects. This Digitally programmable Over-brain Therapeutic (or DOT) is approximately 1 cm in width yet can produce sufficient energy to stimulate cortical activity on-demand through the dura. This extreme miniaturization is possible using recently developed magnetoelectric wireless power transfer that allows us to reach power levels required to stimulate the surface of the brain without direct contact to the cortical surface. This externally powered cortical stimulation (XCS) opens the possibility of simple minimally invasive surgical procedures to enable precise, long-lasting, and at-home neuromodulation with tiny implants that never contact the surface of the brain.
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    Mini-FlatScope: A Miniaturized Lensless Microscope for Neural Recording in Freely-Behaving Mice
    (2022-10-18) Yan, Dong; Robinson, Jacob T.
    Optical neural recording is recognized among all neural recording methods for its high resolution, large field of view (FOV) and low invasiveness. An ideal neural recording device would enable a resolution sufficiently high to identify the activity of each individual neuron, a FOV sufficiently large to cover all neurons within the cortex region of interest for a certain study, and a form factor sufficiently small to allow the studied animal to freely behave. Realizing that the trade-off between size and weight, resolution, and FOV of lens-based microscopes prevents the possibility to simultaneously achieve cellular resolution and large FOV with a small and lightweight lens-based microscope, our lab developed a lens-less microscope, “Bio-FlatScope”. By replacing lenses with a phase-shifting mask and image reconstruction algorithms, we demonstrated large FOV, cellular-resolution fluorescence imaging of fixed biological samples, as well as in vivo imaging of stimulus-evoked calcium activity from neuron clusters in the cortex of head-fixed mice. In this thesis, we show an upgraded version of Bio-FlatScope, termed “MiniFlatScope”, with an integrated illumination module, further decreased form factor, and a finer reconstruction algorithm. We demonstrate near-cellular resolution and large FOV in a resolution test target and fixed biological samples, and show the ability of this prototype to be carried by a mouse, enabling the future in vivo behavioral study in freely-behaving mice.
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    Miniature battery-free epidural cortical stimulators
    (AAAS, 2024) Woods, Joshua E.; Singer, Amanda L.; Alrashdan, Fatima; Tan, Wendy; Tan, Chunfeng; Sheth, Sunil A.; Sheth, Sameer A.; Robinson, Jacob T.; Applied Physics Program
    Miniaturized neuromodulation systems could improve the safety and reduce the invasiveness of bioelectronic neuromodulation. However, as implantable bioelectronic devices are made smaller, it becomes difficult to store enough power for long-term operation in batteries. Here, we present a battery-free epidural cortical stimulator that is only 9 millimeters in width yet can safely receive enough wireless power using magnetoelectric antennas to deliver 14.5-volt stimulation bursts, which enables it to stimulate cortical activity on-demand through the dura. The device has digitally programmable stimulation output and centimeter-scale alignment tolerances when powered by an external transmitter. We demonstrate that this device has enough power and reliability for real-world operation by showing acute motor cortex activation in human patients and reliable chronic motor cortex activation for 30 days in a porcine model. This platform opens the possibility of simple surgical procedures for precise neuromodulation.