State dependence of stimulus-induced variability tuning in macaque MT.

Behavioral states marked by varying levels of arousal and attention modulate some properties of cortical responses (e.g. average firing rates or pairwise correlations), yet it is not fully understood what drives these response changes and how they might affect downstream stimulus decoding. Here we show that changes in state modulate the tuning of response variance-to-mean ratios (Fano factors) in a fashion that is neither predicted by a Poisson spiking model nor changes in the mean firing rate, with a substantial effect on stimulus discriminability. We recorded motion-sensitive neurons in middle temporal cortex (MT) in two states: alert fixation and light, opioid anesthesia. Anesthesia tended to lower average spike counts, without decreasing trial-to-trial variability compared to the alert state. Under anesthesia, within-trial fluctuations in excitability were correlated over longer time scales compared to the alert state, creating supra-Poisson Fano factors. In contrast, alert-state MT neurons have higher mean firing rates and largely sub-Poisson variability that is stimulus-dependent and cannot be explained by firing rate differences alone. The absence of such stimulus-induced variability tuning in the anesthetized state suggests different sources of variability between states. A simple model explains state-dependent shifts in the distribution of observed Fano factors via a suppression in the variance of gain fluctuations in the alert state. A population model with stimulus-induced variability tuning and behaviorally constrained information-limiting correlations explores the potential enhancement in stimulus discriminability by the cortical population in the alert state.

Findings from an Assessment and Inventory of a Regional, Decentralized Stockpile.

Stockpiles can aid with healthcare surge that occurs after a disaster, and experts recommend that these caches be assessed at least annually to ensure supply integrity. The purpose of this study was to assess a regional stockpile to determine its viability and readiness. An assessment was performed in the summer and fall of 2016 on a regionally funded stockpile that was decentralized through a regional network of 15 local hospitals. Each supply was assessed to determine whether the correct amount was present, if it was in a safe and usable condition (ie, deployable), and whether it had expired. Stockpiled materials were categorized by the type of supply or equipment for analysis. The percent of deployable materials was calculated for each item, each category of supplies, and for the entire cache. Almost all sites (93.3%, n = 14) reported that they inventory their cache at least once a year. On average, 60.1% of each site's cache materials were present and deployable (range: 22.1%-87.5%). The best-maintained supplies included personal protective equipment (79.4% deployable) and general medical supplies (73.5% deployable). Decontamination equipment and pediatric supplies had the lowest percentages of deployability (29.0% and 37.7%, respectively). Although almost all sites claimed to assess the stockpile annually, results from this study indicate that almost half of the supplies are either missing or in an unusable condition. This not only represents wasted resources, but it could also hinder disaster response, leading to increased morbidity and mortality. Facilities may need to invest in infrastructure to maintain stockpiled materials after purchase to ensure viability.

Emergent coordination underlying learning to reach to grasp with a brain-machine interface.

The development of coordinated reach-to-grasp movement has been well studied in infants and children. However, the role of motor cortex during this development is unclear because it is difficult to study in humans. We took the approach of using a brain-machine interface (BMI) paradigm in rhesus macaques with prior therapeutic amputations to examine the emergence of novel, coordinated reach to grasp. Previous research has shown that after amputation, the cortical area previously involved in the control of the lost limb undergoes reorganization, but prior BMI work has largely relied on finding neurons that already encode specific movement-related information. In this study, we taught macaques to cortically control a robotic arm and hand through operant conditioning, using neurons that were not explicitly reach or grasp related. Over the course of training, stereotypical patterns emerged and stabilized in the cross-covariance between the reaching and grasping velocity profiles, between pairs of neurons involved in controlling reach and grasp, and to a comparable, but lesser, extent between other stable neurons in the network. In fact, we found evidence of this structured coordination between pairs composed of all combinations of neurons decoding reach or grasp and other stable neurons in the network. The degree of and participation in coordination was highly correlated across all pair types. Our approach provides a unique model for studying the development of novel, coordinated reach-to-grasp movement at the behavioral and cortical levels. NEW & NOTEWORTHY Given that motor cortex undergoes reorganization after amputation, our work focuses on training nonhuman primates with chronic amputations to use neurons that are not reach or grasp related to control a robotic arm to reach to grasp through the use of operant conditioning, mimicking early development. We studied the development of a novel, coordinated behavior at the behavioral and cortical level, and the neural plasticity in M1 associated with learning to use a brain-machine interface.

Best Practices for Healthcare Facility and Regional Stockpile Maintenance and Sustainment: A Literature Review.

Preparing for mass casualty incidents is essential to maximizing community resilience. Many US-based organizations and regions have developed stockpiles of medications, supplies, and equipment for mass casualty incident preparedness. The Centers for Disease Control and Prevention (CDC) assess and manage federally stockpiled materials, but hospitals, healthcare systems, and regional organizations are responsible for maintaining locally owned caches. The CDC has protocols for assessing and managing the Strategic National Stockpile, but no such guidance exists for local or geographical/regional stockpiles. This article outlines best practices and recommendations identified in the literature related to maintaining and sustaining a local or regional stockpile. Recommendations are provided on the timing and procedures for assessing, inventorying, storing, managing, tracking, and deploying materials stockpiled on site, in a trailer, or in a warehouse. In addition, alternative approaches for maintaining a local or regional cache, such as vendor- or user-managed inventory methods, are addressed. Management of local or regional caches requires an investment in infrastructure and training but is necessary to ensure the integrity of stockpiled medication and supplies and to enable rapid and appropriate activation during a mass casualty incident. Hospitals, healthcare systems, businesses, academic institutions, public health agencies, organizations, and regions can use the recommendations here to develop protocols or policies to properly manage their existing stockpiles, which should minimize costs related to damaged supplies.

Spatiotemporal Filter for Visual Motion Integration from Pursuit Eye Movements in Humans and Monkeys.

Despite the enduring interest in motion integration, a direct measure of the space-time filter that the brain imposes on a visual scene has been elusive. This is perhaps because of the challenge of estimating a 3D function from perceptual reports in psychophysical tasks. We take a different approach. We exploit the close connection between visual motion estimates and smooth pursuit eye movements to measure stimulus-response correlations across space and time, computing the linear space-time filter for global motion direction in humans and monkeys. Although derived from eye movements, we find that the filter predicts perceptual motion estimates quite well. To distinguish visual from motor contributions to the temporal duration of the pursuit motion filter, we recorded single-unit responses in the monkey middle temporal cortical area (MT). We find that pursuit response delays are consistent with the distribution of cortical neuron latencies and that temporal motion integration for pursuit is consistent with a short integration MT subpopulation. Remarkably, the visual system appears to preferentially weight motion signals across a narrow range of foveal eccentricities rather than uniformly over the whole visual field, with a transiently enhanced contribution from locations along the direction of motion. We find that the visual system is most sensitive to motion falling at approximately one-third the radius of the stimulus aperture. Hypothesizing that the visual drive for pursuit is related to the filtered motion energy in a motion stimulus, we compare measured and predicted eye acceleration across several other target forms.SIGNIFICANCE STATEMENT A compact model of the spatial and temporal processing underlying global motion perception has been elusive. We used visually driven smooth eye movements to find the 3D space-time function that best predicts both eye movements and perception of translating dot patterns. We found that the visual system does not appear to use all available motion signals uniformly, but rather weights motion preferentially in a narrow band at approximately one-third the radius of the stimulus. Although not universal, the filter predicts responses to other types of stimuli, demonstrating a remarkable degree of generalization that may lead to a deeper understanding of visual motion processing.

Efficient sensory cortical coding optimizes pursuit eye movements.

In the natural world, the statistics of sensory stimuli fluctuate across a wide range. In theory, the brain could maximize information recovery if sensory neurons adaptively rescale their sensitivity to the current range of inputs. Such adaptive coding has been observed in a variety of systems, but the premise that adaptation optimizes behaviour has not been tested. Here we show that adaptation in cortical sensory neurons maximizes information about visual motion in pursuit eye movements guided by that cortical activity. We find that gain adaptation drives a rapid (<100 ms) recovery of information after shifts in motion variance, because the neurons and behaviour rescale their sensitivity to motion fluctuations. Both neurons and pursuit rapidly adopt a response gain that maximizes motion information and minimizes tracking errors. Thus, efficient sensory coding is not simply an ideal standard but a description of real sensory computation that manifests in improved behavioural performance.

Shared sensory estimates for human motion perception and pursuit eye movements.

Are sensory estimates formed centrally in the brain and then shared between perceptual and motor pathways or is centrally represented sensory activity decoded independently to drive awareness and action? Questions about the brain's information flow pose a challenge because systems-level estimates of environmental signals are only accessible indirectly as behavior. Assessing whether sensory estimates are shared between perceptual and motor circuits requires comparing perceptual reports with motor behavior arising from the same sensory activity. Extrastriate visual cortex both mediates the perception of visual motion and provides the visual inputs for behaviors such as smooth pursuit eye movements. Pursuit has been a valuable testing ground for theories of sensory information processing because the neural circuits and physiological response properties of motion-responsive cortical areas are well studied, sensory estimates of visual motion signals are formed quickly, and the initiation of pursuit is closely coupled to sensory estimates of target motion. Here, we analyzed variability in visually driven smooth pursuit and perceptual reports of target direction and speed in human subjects while we manipulated the signal-to-noise level of motion estimates. Comparable levels of variability throughout viewing time and across conditions provide evidence for shared noise sources in the perception and action pathways arising from a common sensory estimate. We found that conditions that create poor, low-gain pursuit create a discrepancy between the precision of perception and that of pursuit. Differences in pursuit gain arising from differences in optic flow strength in the stimulus reconcile much of the controversy on this topic.

Concurrent imaging of synaptic vesicle recycling and calcium dynamics.

Synaptic transmission involves the calcium dependent release of neurotransmitter from synaptic vesicles. Genetically encoded optical probes emitting different wavelengths of fluorescent light in response to neuronal activity offer a powerful approach to understand the spatial and temporal relationship of calcium dynamics to the release of neurotransmitter in defined neuronal populations. To simultaneously image synaptic vesicle recycling and changes in cytosolic calcium, we developed a red-shifted reporter of vesicle recycling based on a vesicular glutamate transporter, VGLUT1-mOrange2 (VGLUT1-mOr2), and a presynaptically localized green calcium indicator, synaptophysin-GCaMP3 (SyGCaMP3) with a large dynamic range. The fluorescence of VGLUT1-mOr2 is quenched by the low pH of synaptic vesicles. Exocytosis upon electrical stimulation exposes the luminal mOr2 to the neutral extracellular pH and relieves fluorescence quenching. Reacidification of the vesicle upon endocytosis again reduces fluorescence intensity. Changes in fluorescence intensity thus monitor synaptic vesicle exo- and endocytosis, as demonstrated previously for the green VGLUT1-pHluorin. To monitor changes in calcium, we fused the synaptic vesicle protein synaptophysin to the recently improved calcium indicator GCaMP3. SyGCaMP3 is targeted to presynaptic varicosities, and exhibits changes in fluorescence in response to electrical stimulation consistent with changes in calcium concentration. Using real time imaging of both reporters expressed in the same synapses, we determine the time course of changes in VGLUT1 recycling in relation to changes in presynaptic calcium concentration. Inhibition of P/Q- and N-type calcium channels reduces calcium levels, as well as the rate of synaptic vesicle exocytosis and the fraction of vesicles released.

Computation and physiology of sensory-motor processing in eye movements.

Performance in sensory-motor behaviors guides our understanding of many of the key computational functions of the brain: the representation of sensory information, the translation of sensory signals to commands for movement, and the production of behavior. Eye movement behaviors have become a valuable testing ground for theories of neural computation because the neural circuitry has been well characterized and the mechanical control of the eye is comparatively simple. Here I review recent studies of eye movement behaviors that provide insight into sensory-motor computation at the single neuron and systems levels. They show that errors in sensory estimation dominate eye movement variability and that the motor system functions to reduce the behavioral impact of its own intrinsic noise sources.

Searching for simplicity in the analysis of neurons and behavior.

What fascinates us about animal behavior is its richness and complexity, but understanding behavior and its neural basis requires a simpler description. Traditionally, simplification has been imposed by training animals to engage in a limited set of behaviors, by hand scoring behaviors into discrete classes, or by limiting the sensory experience of the organism. An alternative is to ask whether we can search through the dynamics of natural behaviors to find explicit evidence that these behaviors are simpler than they might have been. We review two mathematical approaches to simplification, dimensionality reduction and the maximum entropy method, and we draw on examples from different levels of biological organization, from the crawling behavior of Caenorhabditis elegans to the control of smooth pursuit eye movements in primates, and from the coding of natural scenes by networks of neurons in the retina to the rules of English spelling. In each case, we argue that the explicit search for simplicity uncovers new and unexpected features of the biological system and that the evidence for simplification gives us a language with which to phrase new questions for the next generation of experiments. The fact that similar mathematical structures succeed in taming the complexity of very different biological systems hints that there is something more general to be discovered.

Spatial and temporal integration of visual motion signals for smooth pursuit eye movements in monkeys.

To probe how the brain integrates visual motion signals to guide behavior, we analyzed the smooth pursuit eye movements evoked by target motion with a stochastic component. When each dot of a texture executed an independent random walk such that speed or direction varied across the spatial extent of the target, pursuit variance increased as a function of the variance of visual pattern motion. Noise in either target direction or speed increased the variance of both eye speed and direction, implying a common neural noise source for estimating target speed and direction. Spatial averaging was inefficient for targets with >20 dots. Together these data suggest that pursuit performance is limited by the properties of spatial averaging across a noisy population of sensory neurons rather than across the physical stimulus. When targets executed a spatially uniform random walk in time around a central direction of motion, an optimized linear filter that describes the transformation of target motion into eye motion accounted for approximately 50% of the variance in pursuit. Filters had widths of approximately 25 ms, much longer than the impulse response of the eye, and filter shape depended on both the range and correlation time of motion signals, suggesting that filters were products of sensory processing. By quantifying the effects of different levels of stimulus noise on pursuit, we have provided rigorous constraints for understanding sensory population decoding. We have shown how temporal and spatial integration of sensory signals converts noisy population responses into precise motor responses.

The neural basis for combinatorial coding in a cortical population response.

We have used a combination of theory and experiment to assess how information is represented in a realistic cortical population response, examining how motion direction and timing is encoded in groups of neurons in cortical area MT. Combining data from several single-unit experiments, we constructed model population responses in small time windows and represented the response in each window as a binary vector of 1s or 0s signifying spikes or no spikes from each cell. We found that patterns of spikes and silence across a population of nominally redundant neurons can carry up to twice as much information about visual motion than does population spike count, even when the neurons respond independently to their sensory inputs. This extra information arises by virtue of the broad diversity of firing rate dynamics found in even very similarly tuned groups of MT neurons. Additionally, specific patterns of spiking and silence can carry more information than the sum of their parts (synergy), opening up the possibility for combinatorial coding in cortex. These results also held for populations in which we imposed levels of nonindependence (correlation) comparable to those found in cortical recordings. Our findings suggest that combinatorial codes are advantageous for representing stimulus information on short time scales, even when neurons have no complicated, stimulus-dependent correlation structure.

Time course of precision in smooth-pursuit eye movements of monkeys.

To evaluate the nature and possible sources of variation in sensory-motor behavior, we measured the signal-to-noise ratio for the initiation of smooth-pursuit eye movements as a function of time and computed thresholds that indicate how well the pursuit system discriminates small differences in the direction, speed, or time of onset of target motion. Thresholds improved rapidly as a function of time and came close to their minima during the interval when smooth eye movement is driven only by visual motion inputs. Many features of the data argued that motor output and sensory discrimination are limited by the same noise source. Pursuit thresholds reached magnitudes similar to those for perception: <2-3 degrees of direction, approximately 11-15% of target speed, and 8 ms of change in the time of onset of target motion. Pursuit and perceptual thresholds had similar dependencies on the duration of the motion stimulus and showed similar effects of target speed. The evolution of information about direction of target motion followed the same time course in pursuit behavior and in a previously reported sample of neuronal responses from extrastriate area MT. Changing the form of the sensory input while keeping the motor response fixed had significant effects on the signal-to-noise ratio in pursuit for direction discrimination, whereas holding the sensory input constant while changing the combination of muscles used for the motor output did not. We conclude that noise in sensory processing of visual motion provides the major source of variation in the initiation of pursuit.

A sensory source for motor variation.

Suppose that the variability in our movements is caused not by noise in the motor system itself, nor by fluctuations in our intentions or plans, but rather by errors in our sensory estimates of the external parameters that define the appropriate action. For tasks in which precision is at a premium, performance would be optimal if no noise were added in movement planning and execution: motor output would be as accurate as possible given the quality of sensory inputs. Here we use visually guided smooth-pursuit eye movements in primates as a testing ground for this notion of optimality. In response to repeated presentations of identical target motions, nearly 92% of the variance in eye trajectory can be accounted for as a consequence of errors in sensory estimates of the speed, direction and timing of target motion, plus a small background noise that is observed both during eye movements and during fixations. The magnitudes of the inferred sensory errors agree with the observed thresholds for sensory discrimination by perceptual systems, suggesting that the very different neural processes of perception and action are limited by the same sources of noise.

Time course of information about motion direction in visual area MT of macaque monkeys.

We used the responses of neurons in extrastriate visual area MT to determine how well neural noise can be reduced by averaging the responses of neurons across time. For individual MT neurons, we calculated the time course of Shannon information about motion direction from sustained motion at constant velocities. Stimuli were random dot patterns moving at the preferred speed of the cell for 256 msec, in a direction chosen randomly with 15 degrees increments. Information about motion direction calculated from cumulative spike count rose rapidly from the onset of the neural response and then saturated, reaching 80% of maximum information in the first 100 msec. Most of the early saturation of information could be attributed to correlated fluctuations in the spike counts of individual neurons on time scales in excess of 100 msec. Thus, temporal correlations limit the benefits of averaging across time, much as correlations among the responses of different neurons limit the benefits of averaging across large populations. Although information about direction was available quickly from MT neurons, the direction discrimination by individual MT neurons was poor, with mean thresholds above 30 degrees in most neurons. We conclude that almost all available directional information could be extracted from the first few spikes of the response of the neuron, on a time scale comparable with the initiation of smooth pursuit eye movements. However, neural responses still must be pooled across the population in MT to account for the direction discrimination of the pursuit behavior.