A 16-Channel Neural Recording System-on-Chip With CHT Feature Extraction Processor in 65-nm CMOS

Next-generation invasive neural interfaces require fully implantable wireless systems that can record from a large number of channels simultaneously. However, transferring the recorded data from the implant to an external receiver emerges as a significant challenge due to the high throughput. To address this challenge, this article presents a neural recording system-on-chip that achieves high resource and wireless bandwidth efficiency by employing on-chip feature extraction. Energy-area-efficient 10-bit 20-kS/s front end amplifies and digitizes the neural signals within the local field potential (LFP) and action potential (AP) bands. The raw data from each channel are decomposed into spectral features using a compressed Hadamard transform (CHT) processor. The selection of the features to be computed is tailored through a machine learning algorithm such that the overall data rate is reduced by 80% without compromising classification performance. Moreover, the CHT feature extractor allows waveform reconstruction on the receiver side for monitoring or additional post-processing. The proposed approach was validated through in vivo and off-line experiments. The prototype fabricated in 65-nm CMOS also includes wireless power and data receiver blocks to demonstrate the energy and area efficiency of the complete system. The overall signal chain consumes 2.6 μW and occupies 0.021 mm² per channel, pointing toward its feasibility for 1000-channel single-die neural recording systems

Dégénérescence des photorécepteurs de types cônes dans des modèles animaux du syndrome HANAC et du syndrome d'Usher.

Les photorécepteurs sont des neurones très spécifiques dédiés à la phototransduction et reposant sur une machinerie cellulaire très complexe. La dépolarisation permanente dans le noir des photorécepteurs déclenche une transmission synaptique constante et extrêmement spécifique qui requièrent une quantité d'énergie considérable. Les photorécepteurs peuvent dégénérer lorsque la phototransduction ou l'apport énergétique sont altérés. Le syndrome d'Usher conduit à une surdité et une cécité. La recherche du rôle des protéines usher dans les photorécepteurs a été freinée par l'absence de phénotype rétinien dans les modèles. De la même façon, la compréhension des mécanismes moléculaires conduisant à l'atteinte des cônes dans la rétinopathie diabétique a été entravée par l'absence de symptômes vasculaires et neuronaux dans les modèles. Durant ma thèse, j'ai caractérisé deux modèles animaux des syndromes Usher et HANAC. Des atteintes neuronales ont été démontrées par électrorétinogramme et par l'observation de changements morphologiques des cellules. Dans les modèles Usher, j'ai également montré une neuroprotection des photorécepteurs par plusieurs stratégies. Dans le modèle HANAC, les atteintes neuronales étaient associées à une tortuosité vasculaire anormale une augmentation de la perméabilité vasculaire et l'expression accrue de VEGF. Les évaluations phénotypiques de ces trois modèles fournissent un nouvel aperçu de la physiopathologie des dégénérescences des cônes dans le syndrome d'Usher et dans les maladies vasculaires complexes. Ce travail ouvre surtout la voie au développement et à l'évaluation de nouvelles stratégies thérapeutiques pour ces maladies menant à la cécité.Photoreceptors are very specific neurons dedicated to phototransduction, which relies on very complex machinery. The maintained depolarization in darkness triggers a constant and thus very specific type of synaptic transmission. These require high energy need. As a consequence, photoreceptors can degenerate in various hereditary retinal diseases when phototransduction or energy consumption are altered. The Usher syndrome is such a hereditary disease leading to both deafness and blindness. If Usher proteins are involved in the mechanotransduction in hair cells, investigating their role in photoreceptors has been hamperedby the lack of a retinal phenotype in murine models. Similarly, understanding themolecular mechanisms of cone dysfunction in diabetic retinopathy has beenhampered by the lack of vascular and neuronal symptoms and neuronal models. During my PhD, I have developed animal models of Usher and HANAC syndromes both leading to cone photoreceptor dysfunction and damage. Cone dysfunction was demonstrated by electroretinogram recording and by morphological changes, retinal gliosis and microglial activation. In the Usher models, I also demonstrated photoreceptor neuroprotection by different strategies. In the HANAC model, neuronal dysfunction was associated as in diabetic retinopathy to blood vessel tortuosity, blood vessel permeability and incresead VEGF expression levels. These phenotypic evaluations of mouse models provide new insights into the physiopathology of cone photoreceptor degeneration in Usher syndrome and in complex vascular diseases. It also open the way for the development and assessment of new therapeutic strategies for these diseases leading to blindness

Dégénérescence des photorécepteurs de types cônes dans des modèles animaux du syndrome HANAC et du syndrome d'Usher.

Les photorécepteurs sont des neurones très spécifiques dédiés à la phototransduction et reposant sur une machinerie cellulaire très complexe. La dépolarisation permanente dans le noir des photorécepteurs déclenche une transmission synaptique constante et extrêmement spécifique qui requièrent une quantité d'énergie considérable. Les photorécepteurs peuvent dégénérer lorsque la phototransduction ou l'apport énergétique sont altérés. Le syndrome d'Usher conduit à une surdité et une cécité. La recherche du rôle des protéines usher dans les photorécepteurs a été freinée par l'absence de phénotype rétinien dans les modèles. De la même façon, la compréhension des mécanismes moléculaires conduisant à l'atteinte des cônes dans la rétinopathie diabétique a été entravée par l'absence de symptômes vasculaires et neuronaux dans les modèles. Durant ma thèse, j'ai caractérisé deux modèles animaux des syndromes Usher et HANAC. Des atteintes neuronales ont été démontrées par électrorétinogramme et par l'observation de changements morphologiques des cellules. Dans les modèles Usher, j'ai également montré une neuroprotection des photorécepteurs par plusieurs stratégies. Dans le modèle HANAC, les atteintes neuronales étaient associées à une tortuosité vasculaire anormale une augmentation de la perméabilité vasculaire et l'expression accrue de VEGF. Les évaluations phénotypiques de ces trois modèles fournissent un nouvel aperçu de la physiopathologie des dégénérescences des cônes dans le syndrome d'Usher et dans les maladies vasculaires complexes. Ce travail ouvre surtout la voie au développement et à l'évaluation de nouvelles stratégies thérapeutiques pour ces maladies menant à la cécité.Photoreceptors are very specific neurons dedicated to phototransduction, which relies on very complex machinery. The maintained depolarization in darkness triggers a constant and thus very specific type of synaptic transmission. These require high energy need. As a consequence, photoreceptors can degenerate in various hereditary retinal diseases when phototransduction or energy consumption are altered. The Usher syndrome is such a hereditary disease leading to both deafness and blindness. If Usher proteins are involved in the mechanotransduction in hair cells, investigating their role in photoreceptors has been hamperedby the lack of a retinal phenotype in murine models. Similarly, understanding themolecular mechanisms of cone dysfunction in diabetic retinopathy has beenhampered by the lack of vascular and neuronal symptoms and neuronal models. During my PhD, I have developed animal models of Usher and HANAC syndromes both leading to cone photoreceptor dysfunction and damage. Cone dysfunction was demonstrated by electroretinogram recording and by morphological changes, retinal gliosis and microglial activation. In the Usher models, I also demonstrated photoreceptor neuroprotection by different strategies. In the HANAC model, neuronal dysfunction was associated as in diabetic retinopathy to blood vessel tortuosity, blood vessel permeability and incresead VEGF expression levels. These phenotypic evaluations of mouse models provide new insights into the physiopathology of cone photoreceptor degeneration in Usher syndrome and in complex vascular diseases. It also open the way for the development and assessment of new therapeutic strategies for these diseases leading to blindness

A low-profile electromechanical packaging system for soft-to-flexible bioelectronic interfaces

Interfacing the human body with the next generation of electronics requires technological advancement in designing and producing bioelectronic circuits. These circuits must integrate electrical functionality while simultaneously addressing limitations in mechanical compliance and dynamics, biocompatibility, and consistent, scalable manufacturing. The combination of mechanically disparate materials ranging from elastomers to inorganic crystalline semiconductors calls for modular designs with reliable and scalable electromechanical connectors. Here, we report on a novel interconnection solution for soft-to-flexible bioelectronic interfaces using a patterned and machined flexible printed circuit board, which we term FlexComb, interfaced with soft transducing systems. Using a simple assembly process, arrays of protruding “fingers” bearing individual electrical terminals are laser-machined on a standard flexible printed circuit board to create a comb-like structure, namely, the FlexComb. A matching pattern is also machined in the soft system to host and interlock electromechanically the FlexComb connections via a soft electrically conducting composite. We examine the electrical and electromechanical properties of the interconnection and demonstrate the versatility and scalability of the method through various customized submillimetric designs. In a pilot in vivo study, we validate the stability and compatibility of the FlexComb technology in a subdural electrocorticography system implanted for 6 months on the auditory cortex of a minipig. The FlexComb provides a reliable and simple technique to bond and connect soft transducing systems with flexible or rigid electronic boards, which should find many implementations in soft robotics and wearable and implantable bioelectronics

NeuralTree: A 256-Channel 0.227uJ/class Versatile Neural Activity Classification and Closed-Loop Neuromodulation SoC

Closed-loop neural interfaces with on-chip machine learning can detect and suppress disease symptoms in neurological disorders or restore lost functions in paralyzed patients. While high-density neural recording can provide rich neural activity information for accurate disease-state detection, existing systems have low channel count and poor scalability, which could limit their therapeutic efficacy. This work presents a highly scalable and versatile closed-loop neural interface SoC that can overcome these limitations. A 256-channel time-division multiplexed (TDM) front-end with a two-step fast-settling mixed-signal DC servo loop (DSL) is proposed to record high-spatial-resolution neural activity and perform channel-selective brain-state inference. A tree-structured neural network (NeuralTree) classification processor extracts a rich set of neural biomarkers in a patient- and disease-specific manner. Trained with an energy-aware learning algorithm, the NeuralTree classifier detects the symptoms of underlying disorders (e.g., epilepsy and movement disorders) at an optimal energy-accuracy trade-off. A 16-channel high-voltage (HV) compliant neurostimulator closes the therapeutic loop by delivering charge-balanced biphasic current pulses to the brain. The proposed SoC was fabricated in 65nm CMOS and achieved a 0.227uJ/class energy efficiency in a compact area of 0.014mm^2/channel. The SoC was extensively verified on human electroencephalography (EEG) and intracranial EEG (iEEG) epilepsy datasets, obtaining 95.6%/94% sensitivity and 96.8%/96.9% specificity, respectively. In-vivo neural recordings using soft uECoG arrays and multi-domain biomarker extraction were further performed on a rat model of epilepsy. In addition, for the first time in literature, on-chip classification of rest-state tremor in Parkinson's disease from human local field potentials (LFPs) was demonstrated

NeuralTree: A 256-Channel 0.227-mu J/Class Versatile Neural Activity Classification and Closed-Loop Neuromodulation SoC

Closed-loop neural interfaces with on-chip machine learning can detect and suppress disease symptoms in neurological disorders or restore lost functions in paralyzed patients. While high-density neural recording can provide rich neural activity information for accurate disease-state detection, existing systems have low channel counts and poor scalability, which could limit their therapeutic efficacy. This work presents a highly scalable and versatile closed-loop neural interface SoC that can overcome these limitations. A 256-channel time-division multiplexed (TDM) front end with a two-step fast-settling mixed-signal DC servo loop (DSL) is proposed to record high-spatial-resolution neural activity and perform channel-selective brain-state inference. A tree-structured neural network (NeuralTree) classification processor extracts a rich set of neural biomarkers in a patient-and disease-specific manner. Trained with an energy-aware learning algorithm, the NeuralTree classifier detects the symptoms of underlying disorders (e.g., epilepsy and movement disorders) at an optimal energy-accuracy tradeoff. A 16-channel high-voltage (HV) compliant neurostimulator closes the therapeutic loop by delivering charge-balanced biphasic current pulses to the brain. The proposed SoC was fabricated in 65-nm CMOS and achieved a 0.227-mu J/class energy efficiency in a compact area of 0.014 mm(2)/channel. The SoC was extensively verified on human electroencephalography (EEG) and intracranial EEG (iEEG) epilepsy datasets, obtaining 95.6%/94% sensitivity and 96.8%/96.9% specificity, respectively. In vivo neural recordings using soft mu ECoG arrays and multi-domain biomarker extraction were further performed on a rat model of epilepsy. In addition, for the first time in literature, on-chip classification of rest-state tremor in Parkinson's disease (PD) from human local field potentials (LFPs) was demonstrated

Viscoelastic surface electrode arrays to interface with viscoelastic tissues

Bioelectronic interfacing with living tissues should match the biomechanical properties of biological materials to reduce damage to the tissues. Here, the authors present a fully viscoelastic microelectrode array composed of an alginate matrix and carbon-based nanomaterials encapsulated in a viscoelastic hydrogel for electrical stimulation and signal recording of heart and brain activities in vivo.Living tissues are non-linearly elastic materials that exhibit viscoelasticity and plasticity. Man-made, implantable bioelectronic arrays mainly rely on rigid or elastic encapsulation materials and stiff films of ductile metals that can be manipulated with microscopic precision to offer reliable electrical properties. In this study, we have engineered a surface microelectrode array that replaces the traditional encapsulation and conductive components with viscoelastic materials. Our array overcomes previous limitations in matching the stiffness and relaxation behaviour of soft biological tissues by using hydrogels as the outer layers. We have introduced a hydrogel-based conductor made from an ionically conductive alginate matrix enhanced with carbon nanomaterials, which provide electrical percolation even at low loading fractions. Our combination of conducting and insulating viscoelastic materials, with top-down manufacturing, allows for the fabrication of electrode arrays compatible with standard electrophysiology platforms. Our arrays intimately conform to the convoluted surface of the heart or brain cortex and offer promising bioengineering applications for recording and stimulation

Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndrome

International audienceThe HANAC syndrome is caused by mutations in the gene coding for collagen4a1, a major component of blood vessel basement membranes. Ocular symptoms include an increase in blood vessel tortuosity and occasional hemorrhages. To examine how vascular defects can affect neuronal function, we analyzed the retinal phenotype of a HANAC mouse model. Heterozygous mutant mice displayed both a thinning of the basement membrane in retinal blood vessels and in Bruch's membrane resulting in vascular leakage. Homozygous mice had additional vascular changes, including greater vessel coverage and tortuosity. This greater tortuosity was associated to higher expression levels of vascular endothelial growth factor (VEGF). These major changes to the blood vessels were correlated with photoreceptor dysfunction and degeneration. The neuronal damage was associated with reactive gliosis in astrocytes and Müller glial cells, and by the migration of microglial cells into the outer retina. This study illustrates how vascular changes can trigger neuronal degeneration in a new model of HANAC syndrome that can be used to further study dysfunctions of neurovascular coupling

Cone degeneration is triggered by the absence of USH1 proteins but prevented by antioxidant treatments

International audienceUsher syndrome type 1 (USH1) is a major cause of inherited deafness and blindness in humans. The eye disorder is often referred to as retinitis pigmentosa, which is characterized by a secondary cone degeneration following the rod loss. The development of treatments to prevent retinal degeneration has been hampered by the lack of clear evidence for retinal degeneration in mutant mice deficient for the Ush1 genes, which instead faithfully mimic the hearing deficit. We show that, under normal housing conditions, Ush1g−/− and Ush1c−/− albino mice have dysfunctional cone photoreceptors whereas pigmented knockout animals have normal photoreceptors. The key involvement of oxidative stress in photoreceptor apoptosis and the ensued retinal gliosis were further confirmed by their prevention when the mutant mice are reared under darkness and/or supplemented with antioxidants. The primary degeneration of cone photoreceptors contrasts with the typical forms of retinitis pigmentosa. Altogether, we propose that oxidative stress probably accounts for the high clinical heterogeneity among USH1 siblings, which also unveils potential targets for blindness prevention

Effects of azithromycin and doxycycline on the vaginal microbiota of women with urogenital Chlamydia trachomatis infection: a substudy of the Chlazidoxy randomized controlled trial

Objectives: Dysbiotic bacterial communities within the vagina are associated with Chlamydia trachomatis infection. We compared the effect of treatment with azithromycin and doxycycline on the vaginal microbiota in a cohort of women with a urogenital C. trachomatis infection randomly assigned to one of these treatments (Chlazidoxy trial). Methods: We analysed vaginal samples from 284 women (135 in the azithromycin group and 149 in the doxycycline group) collected at baseline and 6 weeks after treatment initiation. The vaginal microbiota was characterized using 16S rRNA gene sequencing and classified into community state types (CSTs). Results: At baseline, 75% (212/284) of the women had a high-risk microbiota (CST-III or CST-IV). A crosssectional comparison 6 weeks after treatment showed that 15 phylotypes were differentially abundant, but this difference was not reflected at the CST (p 0.772) or diversity level (p 0.339). Between baseline and the 6-week visit, a-diversity (p 0.140) and transition probabilities between CSTs were not significantly different between the groups, and no phylotype was differentially abundant. Discussion: In women with urogenital C. trachomatis infection, the vaginal microbiota does not seem to be affected by azithromycin or doxycycline 6 weeks after treatment. Because the vaginal microbiota remains susceptible to C. trachomatis infection (with CST-III or CST-IV) after antibiotic treatment, women remain at risk of reinfection, which could originate from unprotected sexual intercourse or untreated anorectal C. trachomatis infection. This last consideration advocates for the use of doxycycline instead of azithromycin because of its higher anorectal microbiological cure rate. Jeanne Tamarelle, Clin Microbiol Infect 2023;29:1056 & COPY; 2023 European Society of Clinical Microbiology and Infectious Diseases.Plateforme d'Innovation " Forêt-Bois-Fibre-Biomasse du Futur