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Across many brain areas, neural population activity appears to be constrained to a low-dimensional manifold within a neural state space of considerably higher dimension. Recent studies of the primary motor cortex (M1) suggest that the activity within the low-dimensional manifold, rather than the activity of individual neurons, underlies the computations required for planning and executing movements. To date, these studies have been limited to data obtained in constrained laboratory settings where monkeys executed repeated, stereotyped tasks. An open question is whether the observed low dimensionality of the neural manifolds is due to these constraints; the dimensionality of M1 activity during the execution of more natural and unconstrained movements, like walking and picking food, remains unknown. We have now found similarly low-dimensional manifolds associated with various unconstrained natural behaviors, with dimensionality only slightly higher than those associated with constrained laboratory behaviors. To quantify the extent to which these low-dimensional manifolds carry task-relevant information, we built task-specific linear decoders that predicted EMG activity from M1 manifold activity. In both settings, decoding performance based on activity within the estimated low-dimensional manifold was the same as decoding performance based on the activity of all recorded neurons. These results establish functional links between task-specific manifolds and motor behaviors, and highlight that both constrained and unconstrained behaviors are associated with low-dimensional M1 manifolds.

Intracortical brain-computer interfaces (iBCIs) enable paralyzed persons to generate movement, but current methods require large amounts of both neural and movement-related data to be collected from the iBCI user for supervised decoder training. We hypothesized that the low-dimensional latent neural representations of motor behavior, known to be preserved across time, might also be preserved across individuals, and allow us to circumvent this problem. We trained a decoder to predict the electromyographic (EMG) activity for a “source” monkey from the latent signals of motor cortex. We then used Canonical Correlation Analysis to align the latent signals of a “target” monkey to those of the source. These decoders were as accurate across monkeys as they were across sessions for a given monkey. Remarkably, the same process with latent signals from a human participant with tetraplegia was within 90% of the with-monkey decoding across session accuracy. Our findings suggest that consistent representations of motor activity exist across animals and even species. Discovering this common representation is a crucial first step in designing iBCI decoders that perform well without large amounts of data and supervised subject-specific tuning.

It is generally accepted that the number of neurons in a given brain area far exceeds the number of neurons needed to carry any specific function controlled by that area. For example, motor areas of the human brain contain tens of millions of neurons that control the activation of tens or at most hundreds of muscles. This massive redundancy implies the covariation of many neurons, which constrains the population activity to a low-dimensional manifold within the space of all possible patterns of neural activity. To gain a conceptual understanding of the complexity of the neural activity within a manifold, it is useful to estimate its dimensionality, which quantifies the number of degrees of freedom required to describe the observed population activity without significant information loss. While there are many algorithms for dimensionality estimation, we do not know which are well suited for analyzing neural activity. The objective of this study was to evaluate the efficacy of several representative algorithms for estimating the dimensionality of linearly and nonlinearly embedded data. We generated synthetic neural recordings with known intrinsic dimensionality and used them to test the algorithms’ accuracy and robustness. We emulated some of the important challenges associated with experimental data by adding noise, altering the nature of the embedding of the low-dimensional manifold within the high-dimensional recordings, varying the dimensionality of the manifold, and limiting the amount of available data. We demonstrated that linear algorithms overestimate the dimensionality of nonlinear, noise-free data. In cases of high noise, most algorithms overestimated the dimensionality. We thus developed a denoising algorithm based on deep learning, the “Joint Autoencoder”, which significantly improved subsequent dimensionality estimation. Critically, we found that all algorithms failed when the intrinsic dimensionality was high (above 20) or when the amount of data used for estimation was low. Based on the challenges we observed, we formulated a pipeline for estimating the dimensionality of experimental neural data., Author summary The number of neurons that we can simultaneously record from has increased exponentially for decades; today that number is in the thousands of neurons. However, the individual firing rates are highly redundant. One approach to identifying important features from redundant data is to estimate the dimensionality of the neural recordings, which represents the number of degrees of freedom required to describe the data without significant information loss. Better understanding of dimensionality may also uncover the mechanisms of computation within a neural circuit. Circuits carrying out complex computations might be higher-dimensional than those carrying out simpler computations. Typically, studies have quantified neural dimensionality using one of several available methods reflecting a lack of consensus on which method would be most appropriate for neural data. In this work, we used several methods to investigate the accuracy of simulated neural data with properties mimicking those of actual neural recordings. Based on these results, we devised an analysis pipeline to estimate the dimensionality of neural recordings. Our work will allow scientists to extract informative features from a large number of highly redundant neurons, as well as quantify the complexity of information encoded by these neurons.

Even simple sensory stimuli evoke neural responses that are dynamic and complex. Are the temporally patterned neural activities important for controlling the behavioral output? Here, we investigated this issue. Our results reveal that in the insect antennal lobe, due to circuit interactions, distinct neural ensembles are activated during and immediately following the termination of every odorant. Such non-overlapping response patterns are not observed even when the stimulus intensity or identities were changed. In addition, we find that ON and OFF ensemble neural activities differ in their ability to recruit recurrent inhibition, entrain field-potential oscillations and more importantly in their relevance to behaviour (initiate versus reset conditioned responses). Notably, we find that a strikingly similar strategy is also used for encoding sound onsets and offsets in the marmoset auditory cortex. In sum, our results suggest a general approach where recurrent inhibition is associated with stimulus ‘recognition' and ‘derecognition'., Sensory stimuli evoke temporally dynamic responses. Here the authors report that responses to odour onset and offset are orthogonally represented in the locust antennal lobe, differentially entrain oscillations, and propose a model in which they are necessary for initiation and termination of behaviour.

Cyborg insects provide a unique platform to implement autonomous robotics on a large scale. Compared to vertebrates, insect cyborgs can be deployed in swarms and at a significantly lower cost. In this paper, we propose a cyborg sensing platform that leverages the acute olfactory sensing capability of locusts (Schistocerca americana) for standoff detection of target chemicals. Contrary to cyborg sensing technologies that are based on implantable neural devices, the proposed platform relies on extraneous palp tracking which can be measured non-invasively for extended periods of time. In this work, locusts are conditioned (trained) to respond (move their palp) to a specific target odor and the palp movements are measured in real-time using a silver-enhanced infrared reflectance technique. The measured results correlate well with a gold-standard palp tracking method. The efficacy of our platform based on behavioral readout is demonstrated for non-invasive chemical sensing.

Proton pump inhibitors (PPIs) have considerably improved quality of life in patients with gastroesophageal reflux disease (GERD). However, many patients remain symptomatic despite standard PPI therapy.This review focuses on evolving therapeutic strategies related to the pathophysiological processes of GERD and insufficient response to PPIs. Several clinical trials evaluated new PPI formulations and newer types of acid-suppressive drugs. These studies have evaluated traditional end points in GERD, but have not shown clinical superiority to current PPIs. Novel therapeutic strategies targeting underlying mechanisms of GERD, such as transient lower esophageal sphincter relaxations (TLESRs) and esophageal hypersensitivity, are being developed for add-on therapy to PPIs. Prokinetic drugs may also have some potential in the add-on treatment of GERD with insufficient response to PPIs. Add-on studies are hampered by insufficient information on optimal patient selection and lack of established end points.Newer drugs for symptomatic control in GERD have largely focused on improved acid suppression, without evidence of clinical superiority. Drugs targeting esophageal motility and sensitivity to be used as add-onc therapy in PPI insufficient responders have not reached Phase III trials to date, due to difficulties with patient selection, tolerability and end points.

Functional dyspepsia (FD) is a highly prevalent condition with major socioeconomic and healthcare impact. To date, no pharmacological treatment for FD has been approved. The Rome consensus proposed to subdivide FD into postprandial distress syndrome (PDS), characterized by meal-related symptoms and epigastric pain syndrome, characterized by pain and burning. Acotiamide (Z-338 or YM443) is a new drug, developed for the treatment of FD. Acotiamide enhances acetylcholine release from enteric neurons through muscarinic receptor antagonism and acetycholinesterase inhibition, thereby enhancing gastric emptying and gastric accommodation. Acotiamide was evaluated in FD in clinical studies in Europe, Japan and the USA, beneficial effects were observed for the PDS symptoms of postprandial fullness and early satiation, with a dose of 100 mg three-times a day. A 4-week placebo-controlled Phase III study in PDS patients in Japan confirmed efficacy of acotiamide in relieving postprandial fullness, early satiation and upper abdominal bloating.

Background: Gastroesophageal reflux (GER) and microaspiration of gastric contents has been proposed as an important mechanism in the pathogenesis of ventilator associated pneumonia (VAP) but properties of GER in patients receiving acid suppresive therapy in intensive care unit (ICU) and its effect on VAP and respiratory function in these patients is not elucidated. Aim: This study aims to assess the association between GER and VAP by defining the differences between VAP and non-VAP patients in ICU in terms of proximal extension and chemical properties of GER assessed by 24 hour combined esophageal intraluminal electrical impedance/pH measurements. We also aimed to study the association of impedance/pH values with respiratory function (PaO2/FiO2 ratio) and gastropulmonary microaspiration assessed by pepsin measurements in deep tracheal aspirates(DTA). Methods: 20 intubated patients on acid suppressive medication for stress ulcer prophylaxis in a neurological and medical ICU were included in this study. Patients who had pneumonia at the time of intubation or who were diagnosed with pneumonia during the first 48 hours after intubation were excluded. Pepsinmeasurements weremade onDTA samples on the third day. Afterwards esophageal impedance/pHmetry catheters were placed and 24 hour recordings were analyzed. Patients were followed throughout their stay in ICU for VAP and daily PaO2/FiO2 ratios were recorded for one week. Impedance/pH values and pepsin levels were compared between VAP and nonVAP patients. Results: 8 patients were diagnosed with VAP. VAP patients had more proximal reflux compared to non-VAP patients (7(2-14) vs. 3,5(0-8))(p=0,003). Proximal weakly acidic reflux was again more common in VAP patients (4,5(2-9) vs 2(04)(p=0,006). Pepsin levels in DTA samples were correlated with the number of weakly acidic reflux episodes(r=0,615;p=0,004). Pepsin levels were also correlated with the number of proximal reflux episodes, especially with proximal weakly acidic reflux(r=0,489;p=0,029 ; r=0,651,p=0,002 ). PaO2/FiO2 ratios were negatively correlated with both pepsin levels and proximal weakly acidic reflux (r=-0,585,p=0,007 ; r=-0,620;p=0,004). Conclusion: Proximal extension of GER, especially proximal weakly acidic reflux is associated with microaspiration, VAP and worsening of respiratory function in intubated ICU patients on acid suppressive therapy.

participating 15 refused, 10 were deceased secondary to unrelated conditions, 5 were medically incapacitated for unrelated reasons, and 2 could not be reached. Of the 94 participants, 68% were female with a mean age of 53 years old. Manometric findings were normal in 63 (67%), weak peristalsis in 23 (25%), frequent failed peristalsis in 2 (2%), and hypertensive peristalsis in 6 (6%). No patients with normal studies or borderline manometric abnormalities had undergone myotomy or dilation. Further, PPI use and fundoplication rates were similar in patients with borderline manometric abnormalities when compared to those with normal esophageal manometry. Significant dysphagia at follow up (IDQ>8) was rare, seen in only 9 patients. The main indications for HRM were dysphagia (46%) and gastroesophageal reflux (35%), with no association between these indications and peristaltic abnormalities or persistence of dysphagia at follow up. (Table) Conclusion: Patients defined as normal or having borderline esophageal motor function using the Chicago classification appear to have minimal symptoms or medical interventions related to esophageal dysfunction during a 5 year follow-up.Only 14% of patients had significant dysphagia. Thus, identification of normal and borderline motor function is a good prognostic indicator as these patterns are associated with minimal long term consequences. Natural history of peristalsis patterns on HRM