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In recent years, our group and others have reported multiple cases of consistent neurological recovery in people with spinal cord injury (SCI) following a protocol that integrates locomotion training with brain machine interfaces (BMI). The primary objective of this pilot study was to compare the neurological outcomes (motor, tactile, nociception, proprioception, and vibration) in both an intensive assisted locomotion training (LOC) and a neurorehabilitation protocol integrating assisted locomotion with a noninvasive brain-machine interface (L + BMI), virtual reality, and tactile feedback. We also investigated whether individuals with chronic-complete SCI could learn to perform leg motor imagery. We ran a parallel two-arm randomized pilot study; the experiments took place in São Paulo, Brazil. Eight adults sensorimotor-complete (AIS A) (all male) with chronic (> 6 months) traumatic spinal SCI participated in the protocol that was organized in two blocks of 14 weeks of training and an 8-week follow-up. The participants were allocated to either the LOC group (n = 4) or L + BMI group (n = 4) using block randomization (blinded outcome assessment). We show three important results: (i) locomotion training alone can induce some level of neurological recovery in sensorimotor-complete SCI, and (ii) the recovery rate is enhanced when such locomotion training is associated with BMI and tactile feedback (∆Mean Lower Extremity Motor score improvement for LOC = + 2.5, L + B = + 3.5; ∆Pinprick score: LOC = + 3.75, L + B = + 4.75 and ∆Tactile score LOC = + 4.75, L + B = + 9.5). (iii) Furthermore, we report that the BMI classifier accuracy was significantly above the chance level for all participants in L + B group. Our study shows potential for sensory and motor improvement in individuals with chronic complete SCI following a protocol with BMIs and locomotion therapy. We report no dropouts nor adverse events in both subgroups participating in the study, opening the possibility for a more definitive clinical trial with a larger cohort of people with SCI.Trial registration: http://www.ensaiosclinicos.gov.br/ identifier RBR-2pb8gq.

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Although international airports served as main entry points for SARS-CoV-2, the factors driving the uneven geographic spread of COVID-19 cases and deaths in Brazil remain mostly unknown. Here we show that three major factors influenced the early macro-geographical dynamics of COVID-19 in Brazil. Mathematical modeling revealed that the "super-spreading city" of São Paulo initially accounted for more than 85% of the case spread in the entire country. By adding only 16 other spreading cities, we accounted for 98-99% of the cases reported during the first 3 months of the pandemic in Brazil. Moreover, 26 federal highways accounted for about 30% of SARS-CoV-2's case spread. As cases increased in the Brazilian interior, the distribution of COVID-19 deaths began to correlate with the allocation of the country's intensive care units (ICUs), which is heavily weighted towards state capitals. Thus, severely ill patients living in the countryside had to be transported to state capitals to access ICU beds, creating a "boomerang effect" that contributed to skew the distribution of COVID-19 deaths. Therefore, if (i) a lockdown had been imposed earlier on in spreader-capitals, (ii) mandatory road traffic restrictions had been enforced, and (iii) a more equitable geographic distribution of ICU beds existed, the impact of COVID-19 in Brazil would be significantly lower.

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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Spinal cord injury (SCI) impairs the flow of sensory and motor signals between the brain and the areas of the body located below the lesion level. Here, we describe a neurorehabilitation setup combining several approaches that were shown to have a positive effect in patients with SCI: gait training by means of non-invasive, surface functional electrical stimulation (sFES) of the lower-limbs, proprioceptive and tactile feedback, balance control through overground walking and cue-based decoding of cortical motor commands using a brain-machine interface (BMI). The central component of this new approach was the development of a novel muscle stimulation paradigm for step generation using 16 sFES channels taking all sub-phases of physiological gait into account. We also developed a new BMI protocol to identify left and right leg motor imagery that was used to trigger an sFES-generated step movement. Our system was tested and validated with two patients with chronic paraplegia. These patients were able to walk safely with 65-70% body weight support, accumulating a total of 4,580 steps with this setup. We observed cardiovascular improvements and less dependency on walking assistance, but also partial neurological recovery in both patients, with substantial rates of motor improvement for one of them.

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Spinal cord injury (SCI) induces severe deficiencies in sensory-motor and autonomic functions and has a significant negative impact on patients' quality of life. There is currently no systematic rehabilitation technique assuring recovery of the neurological impairments caused by a complete SCI. Here, we report significant clinical improvement in a group of seven chronic SCI patients (six AIS A, one AIS B) following a 28-month, multi-step protocol that combined training with non-invasive brain-machine interfaces, visuo-tactile feedback and assisted locomotion. All patients recovered significant levels of nociceptive sensation below their original SCI (up to 16 dermatomes, average 11 dermatomes), voluntary motor functions (lower-limbs muscle contractions plus multi-joint movements) and partial sensory function for several modalities (proprioception, tactile, pressure, vibration). Patients also recovered partial intestinal, urinary and sexual functions. By the end of the protocol, all patients had their AIS classification upgraded (six from AIS A to C, one from B to C). These improvements translated into significant changes in the patients' quality of life as measured by standardized psychological instruments. Reexamination of one patient that discontinued the protocol after 12 months of training showed that the 16-month break resulted in neurological stagnation and no reclassification. We suggest that our neurorehabilitation protocol, based uniquely on non-invasive technology (therefore necessitating no surgical operation), can become a promising therapy for patients diagnosed with severe paraplegia (AIS A, B), even at the chronic phase of their lesion.

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Spinal cord injuries disrupt bidirectional communication between the patient's brain and body. Here, we demonstrate a new approach for reproducing lower limb somatosensory feedback in paraplegics by remapping missing leg/foot tactile sensations onto the skin of patients' forearms. A portable haptic display was tested in eight patients in a setup where the lower limbs were simulated using immersive virtual reality (VR). For six out of eight patients, the haptic display induced the realistic illusion of walking on three different types of floor surfaces: beach sand, a paved street or grass. Additionally, patients experienced the movements of the virtual legs during the swing phase or the sensation of the foot rolling on the floor while walking. Relying solely on this tactile feedback, patients reported the position of the avatar leg during virtual walking. Crossmodal interference between vision of the virtual legs and tactile feedback revealed that patients assimilated the virtual lower limbs as if they were their own legs. We propose that the addition of tactile feedback to neuroprosthetic devices is essential to restore a full lower limb perceptual experience in spinal cord injury (SCI) patients, and will ultimately, lead to a higher rate of prosthetic acceptance/use and a better level of motor proficiency.

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Brain-machine interfaces (BMIs) provide a new assistive strategy aimed at restoring mobility in severely paralyzed patients. Yet, no study in animals or in human subjects has indicated that long-term BMI training could induce any type of clinical recovery. Eight chronic (3-13 years) spinal cord injury (SCI) paraplegics were subjected to long-term training (12 months) with a multi-stage BMI-based gait neurorehabilitation paradigm aimed at restoring locomotion. This paradigm combined intense immersive virtual reality training, enriched visual-tactile feedback, and walking with two EEG-controlled robotic actuators, including a custom-designed lower limb exoskeleton capable of delivering tactile feedback to subjects. Following 12 months of training with this paradigm, all eight patients experienced neurological improvements in somatic sensation (pain localization, fine/crude touch, and proprioceptive sensing) in multiple dermatomes. Patients also regained voluntary motor control in key muscles below the SCI level, as measured by EMGs, resulting in marked improvement in their walking index. As a result, 50% of these patients were upgraded to an incomplete paraplegia classification. Neurological recovery was paralleled by the reemergence of lower limb motor imagery at cortical level. We hypothesize that this unprecedented neurological recovery results from both cortical and spinal cord plasticity triggered by long-term BMI usage.

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Although deep brain electrical stimulation can alleviate the motor symptoms of Parkinson disease (PD), just a small fraction of patients with PD can take advantage of this procedure due to its invasive nature. A significantly less invasive method--epidural spinal cord stimulation (SCS)--has been suggested as an alternative approach for symptomatic treatment of PD. However, the mechanisms underlying motor improvements through SCS are unknown. Here, we show that SCS reproducibly alleviates motor deficits in a primate model of PD. Simultaneous neuronal recordings from multiple structures of the cortico-basal ganglia-thalamic loop in parkinsonian monkeys revealed abnormal highly synchronized neuronal activity within each of these structures and excessive functional coupling among them. SCS disrupted this pathological circuit behavior in a manner that mimics the effects caused by pharmacological dopamine replacement therapy or deep brain stimulation. These results suggest that SCS should be considered as an additional treatment option for patients with PD.

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Multielectrodes have been used with great success to simultaneously record the activity of neuronal populations in awake, behaving animals. In particular, there is great promise in the use of this technique to allow the control of neuroprosthetic devices by human patients. However, it is crucial to fully characterize the tissue response to the chronic implants in animal models ahead of the initiation of human clinical trials. Here we evaluated the effects of unilateral multielectrode implants on the motor cortex of rats weekly recorded for 1-6 months using several histological methods to assess metabolic markers, inflammatory response, immediate-early gene (IEG) expression, cytoskeletal integrity and apoptotic profiles. We also investigated the correlations between each of these features and firing rates, to estimate the impact of post-implant time on neuronal recordings. Overall, limited neuronal loss and glial activation were observed on the implanted sites. Reactivity to enzymatic metabolic markers and IEG expression were not significantly different between implanted and non-implanted hemispheres. Multielectrode recordings remained viable for up to 6 months after implantation, and firing rates correlated well to the histochemical and immunohistochemical markers. Altogether, our results indicate that chronic tungsten multielectrode implants do not substantially alter the histological and functional integrity of target sites in the cerebral cortex.

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Neuroprosthetic devices based on brain-machine interface technology hold promise for the restoration of body mobility in patients suffering from devastating motor deficits caused by brain injury, neurologic diseases and limb loss. During the last decade, considerable progress has been achieved in this multidisciplinary research, mainly in the brain-machine interface that enacts upper-limb functionality. However, a considerable number of problems need to be resolved before fully functional limb neuroprostheses can be built. To move towards developing neuroprosthetic devices for humans, brain-machine interface research has to address a number of issues related to improving the quality of neuronal recordings, achieving stable, long-term performance, and extending the brain-machine interface approach to a broad range of motor and sensory functions. Here, we review the future steps that are part of the strategic plan of the Duke University Center for Neuroengineering, and its partners, the Brazilian National Institute of Brain-Machine Interfaces and the École Polytechnique Fédérale de Lausanne (EPFL) Center for Neuroprosthetics, to bring this new technology to clinical fruition.

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In 1949, Donald Hebb postulated that assemblies of synchronously activated neurons are the elementary units of information processing in the brain. Despite being one of the most influential theories in neuroscience, Hebb's cell assembly hypothesis only started to become testable in the past two decades due to technological advances. However, while the technology for the simultaneous recording of large neuronal populations undergoes fast development, there is still a paucity of analytical methods that can properly detect and track the activity of cell assemblies. Here we describe a principal component-based method that is able to (1) identify all cell assemblies present in the neuronal population investigated, (2) determine the number of neurons involved in ensemble activity, (3) specify the precise identity of the neurons pertaining to each cell assembly, and (4) unravel the time course of the individual activity of multiple assemblies. Application of the method to multielectrode recordings of awake and behaving rats revealed that assemblies detected in the cerebral cortex and hippocampus typically contain overlapping neurons. The results indicate that the PCA method presented here is able to properly detect, track and specify neuronal assemblies, irrespective of overlapping membership.

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Neuroprosthetic devices based on brain-machine interface technology hold promise for the restoration of body mobility in patients suffering from devastating motor deficits caused by brain injury, neurologic diseases and limb loss. During the last decade, considerable progress has been achieved in this multidisciplinary research, mainly in the brain-machine interface that enacts upper-limb functionality. However, a considerable number of problems need to be resolved before fully functional limb neuroprostheses can be built. To move towards developing neuroprosthetic devices for humans, brain-machine interface research has to address a number of issues related to improving the quality of neuronal recordings, achieving stable, long-term performance, and extending the brain-machine interface approach to a broad range of motor and sensory functions. Here, we review the future steps that are part of the strategic plan of the Duke University Center for Neuroengineering, and its partners, the Brazilian National Institute of Brain-Machine Interfaces and the École Polytechnique Fédérale de Lausanne (EPFL) Center for Neuroprosthetics, to bring this new technology to clinical fruition.

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BACKGROUND: Scale-invariant neuronal avalanches have been observed in cell cultures and slices as well as anesthetized and awake brains, suggesting that the brain operates near criticality, i.e. within a narrow margin between avalanche propagation and extinction. In theory, criticality provides many desirable features for the behaving brain, optimizing computational capabilities, information transmission, sensitivity to sensory stimuli and size of memory repertoires. However, a thorough characterization of neuronal avalanches in freely-behaving (FB) animals is still missing, thus raising doubts about their relevance for brain function. METHODOLOGY/PRINCIPAL FINDINGS: To address this issue, we employed chronically implanted multielectrode arrays (MEA) to record avalanches of action potentials (spikes) from the cerebral cortex and hippocampus of 14 rats, as they spontaneously traversed the wake-sleep cycle, explored novel objects or were subjected to anesthesia (AN). We then modeled spike avalanches to evaluate the impact of sparse MEA sampling on their statistics. We found that the size distribution of spike avalanches are well fit by lognormal distributions in FB animals, and by truncated power laws in the AN group. FB data surrogation markedly decreases the tail of the distribution, i.e. spike shuffling destroys the largest avalanches. The FB data are also characterized by multiple key features compatible with criticality in the temporal domain, such as 1/f spectra and long-term correlations as measured by detrended fluctuation analysis. These signatures are very stable across waking, slow-wave sleep and rapid-eye-movement sleep, but collapse during anesthesia. Likewise, waiting time distributions obey a single scaling function during all natural behavioral states, but not during anesthesia. Results are equivalent for neuronal ensembles recorded from visual and tactile areas of the cerebral cortex, as well as the hippocampus. CONCLUSIONS/SIGNIFICANCE: Altogether, the data provide a comprehensive link between behavior and brain criticality, revealing a unique scale-invariant regime of spike avalanches across all major behaviors.

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Primates often rely on vocal communication to mediate social interactions. Although much is known about the acoustic structure of primate vocalizations and the social context in which they are usually uttered, our knowledge about the neocortical control of audio-vocal interactions in primates is still incipient, being mostly derived from lesion studies in squirrel monkeys and macaques. To map the neocortical areas related to vocal control in a New World primate species, the common marmoset, we employed a method previously used with success in other vertebrate species: Analysis of the expression of the immediate early gene Egr-1 in freely behaving animals. The neocortical distribution of Egr-1 immunoreactive cells in three marmosets that were exposed to the playback of conspecific vocalizations and vocalized spontaneously (H/V group) was compared to data from three other marmosets that also heard the playback but did not vocalize (H/n group). The anterior cingulate cortex, the dorsomedial prefrontal cortex and the ventrolateral prefrontal cortex presented a higher number of Egr-1 immunoreactive cells in the H/V group than in H/n animals. Our results provide direct evidence that the ventrolateral prefrontal cortex, the region that comprises Broca's area in humans and has been associated with auditory processing of species-specific vocalizations and orofacial control in macaques, is engaged during vocal output in marmosets. Altogether, our results support the notion that the network of neocortical areas related to vocal communication in marmosets is quite similar to that of Old world primates. The vocal production role played by these areas and their importance for the evolution of speech in primates are discussed.

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The ability to detect unusual events occurring in the environment is essential for survival. Several studies have pointed to the hippocampus as a key brain structure in novelty detection, a claim substantiated by its wide access to sensory information through the entorhinal cortex and also distinct aspects of its intrinsic circuitry. Novelty detection is implemented by an associative match-mismatch algorithm involving the CA1 and CA3 hippocampal subfields that compares the stream of sensory inputs received by CA1 to the stored representation of spatiotemporal sequences in CA3. In some rodents, including the rat, the highly sensitive facial whiskers are responsible for providing accurate tactile information about nearby objects. Surprisingly, however, not much is known about how inputs from the whiskers reach CA1 and how they are processed therein. Using concurrent multielectrode neuronal recordings and chemical inactivation in behaving rats, we show that trigeminal inputs from the whiskers reach the CA1 region through thalamic and cortical relays associated with discriminative touch. Ensembles of hippocampal neurons also carry precise information about stimulus identity when recorded during performance in an aperture-discrimination task using the whiskers. We also found broad similarities between tactile responses of trigeminal stations and the hippocampus during different vigilance states (wake and sleep). Taken together, our results show that tactile information associated with fine whisker discrimination is readily available to the hippocampus for dynamic updating of spatial maps.

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Episodic and spatial memories engage the hippocampus during acquisition but migrate to the cerebral cortex over time. We have recently proposed that the interplay between slow-wave (SWS) and rapid eye movement (REM) sleep propagates recent synaptic changes from the hippocampus to the cortex. To test this theory, we jointly assessed extracellular neuronal activity, local field potentials (LFP), and expression levels of plasticity-related immediate-early genes (IEG) arc and zif-268 in rats exposed to novel spatio-tactile experience. Post-experience firing rate increases were strongest in SWS and lasted much longer in the cortex (hours) than in the hippocampus (minutes). During REM sleep, firing rates showed strong temporal dependence across brain areas: cortical activation during experience predicted hippocampal activity in the first post-experience hour, while hippocampal activation during experience predicted cortical activity in the third post-experience hour. Four hours after experience, IEG expression was specifically upregulated during REM sleep in the cortex, but not in the hippocampus. Arc gene expression in the cortex was proportional to LFP amplitude in the spindle-range (10-14 Hz) but not to firing rates, as expected from signals more related to dendritic input than to somatic output. The results indicate that hippocampo-cortical activation during waking is followed by multiple waves of cortical plasticity as full sleep cycles recur. The absence of equivalent changes in the hippocampus may explain its mnemonic disengagement over time.

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O crescente desenvolvimento de cepas bacterianas multirresistentes em ambientes hospitalares tem originado sérios problemas terapêuticos. O uso de computadores para analisar informaçöes relativas a estas infecçöes tem se mostrado útil para auxiliar no estabelecimento de condutas. Foram estudados dados referentes a 2.144 culturas positivas de pacientes internados no Serviço de Cirurgia de Emergência do Hospital das Clínicas da Faculdade de Medicina da Universidade de Säo Paulo, no período de janeiro de 1982 a dezembro de 1984. Com o auxílio de um microcomputador compatível com a linha Apple II plus foram elaborados gráficos dos padröes de incidência das 7 principais espécies bacterianas, responsáveis por 84% das infecçöes bacterianas nesta unidade, bem como suas respectivas curvas de sensibilidade antimicrobiana. Foram estudadas in vitro as incidências destas espécies bacterianas nos 6 principais locais de isolamento (cavidade abdominal, parede abdominal e perineal, cateteres, sangue, urina, secreçäo traqueobrônquica). Analisada em conjunto, a distribuiçäo de incidência evidencia a grande contribuiçäo da E. coli (20%) e da K. pneumoniae (20%), seguidas pelo S. aureus (15,1%). Demonstra-se nesta unidade o desenvolvimento de espécies bacterianas multirresistentes, em especial a K. pneumoniae e o S. aureus

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O crescente desenvolvimento de cepas bacterianas multirresistentes em ambientes hospitalares tem originado sérios problemas terapêuticos. O uso de computadores para analisar informaçöes relativas a estas infecçöes tem se mostrado útil para auxiliar no estabelecimento de condutas. Foram estudados dados referentes a 2.144 culturas positivas de pacientes internados no Serviço de Cirurgia de Emergência do Hospital das Clínicas da Faculdade de Medicina da Universidade de Säo Paulo, no período de janeiro de 1982 a dezembro de 1984. Com o auxilio de um microcomputador compatível com o sistema Apple II plus foram elaborados gráficos dos padröes de incidência das 7 principais espécies bacterianas, responsáveis por 84% das infecçöes bacterianas nesta unidade, bem como suas respectivas curvas de sensibilidade antimicrobiana. Foram estudadas as incidências destas espécies bacterianas "in vitro" nos 6 principais locais de isolamento (cavidade abdominal, parede abdominal e perineal, catéteres, sangue, urina e secreçäo tráqueo-brônquica). Analisada em conjunto, a distribuiçäo de incidência evidencia a grande contribuiçäo da E. coli (20%) e da K. pneumoniae (20%), seguidas pelo S. aureus (15,1%). Demonstra-se nesta unidade o desenvolvimento de espécies bacterianas multirresistentes, em especial a K. pneumoniae e o S. aureus

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