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

As we may think and be: Brain-computer interfaces to expand the substrate of mind

Over a half-century ago, the scientist Vannevar Bush explored the conundrum of how to tap the exponentially rising sea of human knowledge for the betterment of humanity. In his description of a hypothetical electronic library he dubbed the memex, he anticipated internet search and online encyclopedias (Bush, 1945). By blurring the boundary between brain and computer, brain-computer interfaces (BCI) could lead to more efficient use of electronic resources (Schalk, 2008). We could expand the substrate of the mind itself rather than merely interfacing it to external computers. Components of brain-computer interfaces could be re-arranged to create brain-brain interfaces, or tightly interconnected links between a person’s brain and ectopic neural modules. Such modules – whether sitting in a bubbling Petri dish, rendered in reciprocally linked integrated circuits, or implanted in our belly – would mark the first step on to a path of breaking out of the limitations imposed by our phylogenetic past Novel BCI architectures could generate novel abilities to navigate and access information that might speed translational science efforts and push the boundaries of human knowledge in an unprecedented manner

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

Tolerability of Switching Cholinesterase Inhibitors to Memantine Monotherapy Versus Adding Memantine as Combination Therapy for All-Cause Neurodegenerative Disorders

Background: Prior studies have focused on the clinical efficacy of combination therapy, Donepezil and Memantine, for patient’s diagnosed with Alzheimer’s disease. However, the potential adverse drug reactions while described as mild can have serious sequelae in older adults who are already managing the side effects of polypharmacy. Objective: This study looks to explore the tolerability of switching cholinesterase inhibitors to memantine monotherapy versus adding memantine as combination therapy for all-cause neurodegenerative disorders. Methods: The study is a retrospective chart review that includes 175 patients aged 50 and older diagnosed with neurocognitive disorders (ICD 10 F00-F03.91 and ICD10 G30-G31.84) managed on combination therapy, memantine monotherapy and CI monotherapy from 2016-2019. Results: The odds of a patient reporting side effects on combination therapy in comparison with those patients on memantine monotherapy reporting side effects were significantly greater (OR = 4.33, CI 95% (1.62, 11.52), p=0.003). There was marginal significance in variables such as polypharmacy (p=0.057) and dosing of cholinesterase inhibitors (p = 0.087) in a binary logistic regression model (Table 1). Of the patient population who qualified as excessive polypharmacy (\u3e10), more than half 60% reported side effects. Discussion: The likelihood of reporting side effects is significantly increased for patients on combination therapy when compared to those on monotherapy(p=0.003). Sample size was a limiting factor in determining significant predictors for those reporting side effects on combination therapy; however, there was marginal significance for patients on \u3e 4 other medications while on combination therapy (p=0.057) in predicting outcomes. In our patient sample, more than 80% of the patients reporting side effects qualified as polypharmacy or excessive polypharmacy

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

The role of electrical stimulation for rehabilitation and regeneration after spinal cord injury

Electrical stimulation is used to elicit muscle contraction and can be utilized for neurorehabilitation following spinal cord injury when paired with voluntary motor training. This technology is now an important therapeutic intervention that results in improvement in motor function in patients with spinal cord injuries. The purpose of this review is to summarize the various forms of electrical stimulation technology that exist and their applications. Furthermore, this paper addresses the potential future of the technology

Meeting the Critical Need for Ventilators in Treatment of COVID-19 Patients

We have designed and built a microprocessor-controlled valve manifold having a single air input supplied from a standard ventilator, three air outlets (one per patient), and a digital control panel for setting the pressure supplied to each patient as well as the desired respiration rate. The manifold features multiple pressure sensors for system monitoring. Each inspiration limb of the manifold will be fitted with a viral filter. Each expiration limb will have a passive HME in line with a viral filter to prevent patient cross-contamination and spread of virions. Each patient will receive one epoch of inspiration pressure followed by expiration as set by the operator. The electronic system ensures that the respiratory cycles are repeated for each patient at a set respiratory rate. In a later version of the device, the pressure waveform may be variable and different for each patient. In operation, the device will display the realtime pressure and respiration rate for each outlet. Because the device will merely multiplex an existing FDAapproved critical care ventilator now in use at Jefferson, it will not exceed the safety and therapy parameters set for the patients, merely delivering those parameters to three patients instead of one, thereby multiplying surge capacity

The Nurosleeve, a User-Centered 3D Printed Hybrid Orthosis for Individuals With Upper Extremity Impairment

BACKGROUND: Active upper extremity (UE) assistive devices have the potential to restore independent functional movement in individuals with UE impairment due to neuromuscular diseases or injury-induced chronic weakness. Academically fabricated UE assistive devices are not usually optimized for activities of daily living (ADLs), whereas commercially available alternatives tend to lack flexibility in control and activation methods. Both options are typically difficult to don and doff and may be uncomfortable for extensive daily use due to their lack of personalization. To overcome these limitations, we have designed, developed, and clinically evaluated the NuroSleeve, an innovative user-centered UE hybrid orthosis. METHODS: This study introduces the design, implementation, and clinical evaluation of the NuroSleeve, a user-centered hybrid device that incorporates a lightweight, easy to don and doff 3D-printed motorized UE orthosis and a functional electrical stimulation (FES) component. Our primary goals are to develop a customized hybrid device that individuals with UE neuromuscular impairment can use to perform ADLs and to evaluate the benefits of incorporating the device into occupational therapy sessions. The trial is designed as a prospective, open-label, single-cohort feasibility study of eight-week sessions combined with at-home use of the device and implements an iterative device design process where feedback from participants and therapists informs design improvement cycles. RESULTS: All participants learned how to independently don, doff, and use the NuroSleeve in ADLs, both in clinical therapy and in their home environments. All participants showed improvements in their Canadian Occupational Performance Measure (COPM), which was the primary clinical trial outcome measure. Furthermore, participants and therapists provided valuable feedback to guide further development. CONCLUSIONS: Our results from non-clinical testing and clinical evaluation demonstrate that the NuroSleeve has met feasibility and safety goals and effectively improved independent voluntary function during ADLs. The study\u27s encouraging preliminary findings indicate that the NuroSleeve has met its technical and clinical objectives while improving upon the limitations of the existing UE orthoses owing to its personalized and flexible approach to hardware and firmware design. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04798378, https://clinicaltrials.gov/ct2/show/NCT04798378 , date of registration: March 15, 2021

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