Connecting the Brain to Itself through an Emulation.

Pilot clinical trials of human patients implanted with devices that can chronically record and stimulate ensembles of hundreds to thousands of individual neurons offer the possibility of expanding the substrate of cognition. Parallel trains of firing rate activity can be delivered in real-time to an array of intermediate external modules that in turn can trigger parallel trains of stimulation back into the brain. These modules may be built in software, VLSI firmware, or biological tissue as in vitro culture preparations or in vivo ectopic construct organoids. Arrays of modules can be constructed as early stage whole brain emulators, following canonical intra- and inter-regional circuits. By using machine learning algorithms and classic tasks known to activate quasi-orthogonal functional connectivity patterns, bedside testing can rapidly identify ensemble tuning properties and in turn cycle through a sequence of external module architectures to explore which can causatively alter perception and behavior. Whole brain emulation both (1) serves to augment human neural function, compensating for disease and injury as an auxiliary parallel system, and (2) has its independent operation bootstrapped by a human-in-the-loop to identify optimal micro- and macro-architectures, update synaptic weights, and entrain behaviors. In this manner, closed-loop brain-computer interface pilot clinical trials can advance strong artificial intelligence development and forge new therapies to restore independence in children and adults with neurological conditions

Outcomes of the NuroSleeve and Occupational Therapy on Upper Limb Function of an Individual with Chronic Hemiparesis Following a Stroke: A Case Report

Background: Upper limb neuromuscular impairments can adversely impact function. This case report investigates the process and outcomes of occupational therapy (OT) for training in the use of the NuroSleeve, a novel research-grade exoskeletal powered orthosis, with a participant with chronic right hemiparesis following a stroke. Method: The participant engaged in 24 OT sessions using the NuroSleeve over 10 weeks. Therapeutic interventions included neuromuscular reeducation, device management, and engagement in occupation-based activities with training to use the NuroSleeve. The Canadian Occupational Performance Measure (COPM), ABILHAND, Patient Reported Outcomes Measurement Information System Upper Extremity Short Form 7a (PROMIS UE SF), Action Research Arm Test (ARAT), and Manual Muscle Testing (MMT) were administered before and after the 24 sessions. Results: With the NuroSleeve, there were clinically important increases in COPM performance and satisfaction for 6/8 and 7/8 goals, respectively; ABILHAND showed a clinically important increase of 4.959 logits; and there was an 11-point increase on the ARAT, indicating a clinically important difference. T-score on the PROMIS UE SF was 33.7 (SD = 2) compared to 23 (SD = 2.8) without the device. MMT remain unchanged. Conclusion: The data suggest that the NuroSleeve was the primary source of increased function and that incorporating OT with the NuroSleeve has benefits

Neural Substrate Expansion for the Restoration of Brain Function

Restoring neurological and cognitive function in individuals who have suffered brain damage is one of the principal objectives of modern translational neuroscience. Electrical stimulation approaches, such as deep-brain stimulation, have achieved the most clinical success, but they ultimately may be limited by the computational capacity of the residual cerebral circuitry. An alternative strategy is brain substrate expansion, in which the computational capacity of the brain is augmented through the addition of new processing units and the reconstitution of network connectivity. This latter approach has been explored to some degree using both biological and electronic means but thus far has not demonstrated the ability to reestablish the function of large-scale neuronal networks. In this review, we contend that fulfilling the potential of brain substrate expansion will require a significant shift from current methods that emphasize direct manipulations of the brain (e.g., injections of cellular suspensions and the implantation of multi-electrode arrays) to the generation of more sophisticated neural tissues and neural-electric hybrids in vitro that are subsequently transplanted into the brain. Drawing from neural tissue engineering, stem cell biology, and neural interface technologies, this strategy makes greater use of the manifold techniques available in the laboratory to create biocompatible constructs that recapitulate brain architecture and thus are more easily recognized and utilized by brain networks

Innervation: The Missing Link for Biofabricated Tissues and Organs

Innervation plays a pivotal role as a driver of tissue and organ development as well as a means for their functional control and modulation. Therefore, innervation should be carefully considered throughout the process of biofabrication of engineered tissues and organs. Unfortunately, innervation has generally been overlooked in most non-neural tissue engineering applications, in part due to the intrinsic complexity of building organs containing heterogeneous native cell types and structures. To achieve proper innervation of engineered tissues and organs, specific host axon populations typically need to be precisely driven to appropriate location(s) within the construct, often over long distances. As such, neural tissue engineering and/or axon guidance strategies should be a necessary adjunct to most organogenesis endeavors across multiple tissue and organ systems. To address this challenge, our team is actively building axon-based living scaffolds that may physically wire in during organ development in bioreactors and/or serve as a substrate to effectively drive targeted long-distance growth and integration of host axons after implantation. This article reviews the neuroanatomy and the role of innervation in the functional regulation of cardiac, skeletal, and smooth muscle tissue and highlights potential strategies to promote innervation of biofabricated engineered muscles, as well as the use of living scaffolds in this endeavor for both in vitro and in vivo applications. We assert that innervation should be included as a necessary component for tissue and organ biofabrication, and that strategies to orchestrate host axonal integration are advantageous to ensure proper function, tolerance, assimilation, and bio-regulation with the recipient post-implant

Emerging regenerative medicine and tissue engineering strategies for Parkinson\u27s disease.

Parkinson\u27s disease (PD) is the second most common progressive neurodegenerative disease, affecting 1-2% of people over 65. The classic motor symptoms of PD result from selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in a loss of their long axonal projections to the striatum. Current treatment strategies such as dopamine replacement and deep brain stimulation (DBS) can only minimize the symptoms of nigrostriatal degeneration, not directly replace the lost pathway. Regenerative medicine-based solutions are being aggressively pursued with the goal of restoring dopamine levels in the striatum, with several emerging techniques attempting to reconstruct the entire nigrostriatal pathway-a key goal to recreate feedback pathways to ensure proper dopamine regulation. Although many pharmacological, genetic, and optogenetic treatments are being developed, this article focuses on the evolution of transplant therapies for the treatment of PD, including fetal grafts, cell-based implants, and more recent tissue-engineered constructs. Attention is given to cell/tissue sources, efficacy to date, and future challenges that must be overcome to enable robust translation into clinical use. Emerging regenerative medicine therapies are being developed using neurons derived from autologous stem cells, enabling the construction of patient-specific constructs tailored to their particular extent of degeneration. In the upcoming era of restorative neurosurgery, such constructs may directly replace SNpc neurons, restore axon-based dopaminergic inputs to the striatum, and ameliorate motor deficits. These solutions may provide a transformative and scalable solution to permanently replace lost neuroanatomy and improve the lives of millions of people afflicted by PD

Development of optically controlled living electrodes with long-projecting axon tracts for a synaptic brain-machine interface.

For implantable neural interfaces, functional/clinical outcomes are challenged by limitations in specificity and stability of inorganic microelectrodes. A biological intermediary between microelectrical devices and the brain may improve specificity and longevity through (i) natural synaptic integration with deep neural circuitry, (ii) accessibility on the brain surface, and (iii) optogenetic manipulation for targeted, light-based readout/control. Accordingly, we have developed implantable living electrodes, living cortical neurons, and axonal tracts protected within soft hydrogel cylinders, for optobiological monitoring/modulation of brain activity. Here, we demonstrate fabrication, rapid axonal outgrowth, reproducible cytoarchitecture, and simultaneous optical stimulation and recording of these tissue engineered constructs in vitro. We also present their transplantation, survival, integration, and optical recording in rat cortex as an in vivo proof of concept for this neural interface paradigm. The creation and characterization of these functional, optically controllable living electrodes are critical steps in developing a new class of optobiological tools for neural interfacing

Neuromotor prosthetic to treat stroke-related paresis: N-of-1 trial

Background: Functional recovery of arm movement typically plateaus following a stroke, leaving chronic motor deficits. Brain-computer interfaces (BCI) may be a potential treatment for post-stroke deficits Methods: In this n-of-1 trial (NCT03913286), a person with chronic subcortical stroke with upper-limb motor impairment used a powered elbow-wrist-hand orthosis that opened and closed the affected hand using cortical activity, recorded from a percutaneous BCI comprised of four microelectrode arrays implanted in the ipsilesional precentral gyrus, based on decoding of spiking patterns and high frequency field potentials generated by imagined hand movements. The system was evaluated in a home setting for 12 weeks Results: Robust single unit activity, modulating with attempted or imagined movement, was present throughout the precentral gyrus. The participant acquired voluntary control over a hand-orthosis, achieving 10 points on the Action Research Arm Test using the BCI, compared to 0 without any device, and 5 using myoelectric control. Strength, spasticity, the Fugl-Meyer scores improved. Conclusions: We demonstrate in a human being that ensembles of individual neurons in the cortex overlying a chronic supratentorial, subcortical stroke remain active and engaged in motor representation and planning and can be used to electrically bypass the stroke and promote limb function. The participant’s ability to rapidly acquire control over otherwise paralyzed hand opening, more than 18 months after a stroke, may justify development of a fully implanted movement restoration system to expand the utility of fully implantable BCI to a clinical population that numbers in the tens of millions worldwide