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Background: Stroke is one of the most frequent diseases, and half of the stroke survivors are left with permanent impairment. Prediction of individual outcome is still difficult. Many but not all patients with stroke improve by approximately 1.7 times the initial impairment, that has been termed proportional recovery rule. The present study aims at identifying factors predicting motor outcome after stroke more accurately than before, and observe associations of rehabilitation treatment with outcome. Methods: The study is designed as a multi-centre prospective clinical observational trial. An extensive primary data set of clinical, neuroimaging, electrophysiological, and laboratory data will be collected within 96 h of stroke onset from patients with relevant upper extremity deficit, as indexed by a Fugl-Meyer-Upper Extremity (FM-UE) score ≤ 50. At least 200 patients will be recruited. Clinical scores will include the FM-UE score (range 0-66, unimpaired function is indicated by a score of 66), Action Research Arm Test, modified Rankin Scale, Barthel Index and Stroke-Specific Quality of Life Scale. Follow-up clinical scores and applied types and amount of rehabilitation treatment will be documented in the rehabilitation hospitals. Final follow-up clinical scoring will be performed 90 days after the stroke event. The primary endpoint is the change in FM-UE defined as 90 days FM-UE minus initial FM-UE, divided by initial FM-UE impairment. Changes in the other clinical scores serve as secondary endpoints. Machine learning methods will be employed to analyze the data and predict primary and secondary endpoints based on the primary data set and the different rehabilitation treatments. Discussion: If successful, outcome and relation to rehabilitation treatment in patients with acute motor stroke will be predictable more reliably than currently possible, leading to personalized neurorehabilitation. An important regulatory aspect of this trial is the first-time implementation of systematic patient data transfer between emergency and rehabilitation hospitals, which are divided institutions in Germany.

Developmental programs that guide neurons and their neurites into specific subvolumes of the mammalian neocortex give rise to lifelong constraints for the formation of synaptic connections. To what degree do these constraints affect cortical wiring diagrams? Here we introduce an inverse modeling approach to show how cortical networks would appear if they were solely due to the spatial distributions of neurons and neurites. We find that neurite packing density and morphological diversity will inevitably translate into non-random pairwise and higher-order connectivity statistics. More importantly, we show that these non-random wiring properties are not arbitrary, but instead reflect the specific structural organization of the underlying neuropil. Our predictions are consistent with the empirically observed wiring specificity from subcellular to network scales. Thus, independent from learning and genetically encoded wiring rules, many of the properties that define the neocortex’ characteristic network architecture may emerge as a result of neuron and neurite development.

Objective: To evaluate the spatial and temporal resolution obtained upon electrical sinusoidal stimulation of retinal circuits in photoreceptor-degenerated mouse retina. Materials and methods: We interfaced ex vivo retina from photoreceptor-degenerated retina in epiretinal configuration to CMOS-based[for full text, please go to the a.m. URL], Artificial Vision 2019

Single-molecule localization microscopy constructs super-resolution images by the sequential imaging and computational localization of sparsely activated fluorophores. Accurate and efficient fluorophore localization algorithms are key to the success of this computational microscopy method. We present a novel localization algorithm based on deep learning which significantly improves upon the state of the art. Our contributions are a novel network architecture for simultaneous detection and localization, and a new training algorithm which enables this deep network to solve the Bayesian inverse problem of detecting and localizing single molecules. Our network architecture uses temporal context from multiple sequentially imaged frames to detect and localize molecules. Our training algorithm combines simulation-based supervised learning with autoencoder-based unsupervised learning to make it more robust against mismatch in the generative model. We demonstrate the performance of our method on datasets imaged using a variety of point spread functions and fluorophore densities. While existing localization algorithms can achieve optimal localization accuracy in data with low fluorophore density, they are confounded by high densities. Our method significantly outperforms the state of the art at high densities and thus, enables faster imaging than previous approaches. Our work also more generally shows how to train deep networks to solve challenging Bayesian inverse problems in biology and physics.

Mechanistic models of single-neuron dynamics have been extensively studied in computational neuroscience. However, identifying which models can quantitatively reproduce empirically measured data has been challenging. We propose to overcome this limitation by using likelihood-free inference approaches (also known as Approximate Bayesian Computation, ABC) to perform full Bayesian inference on single-neuron models. Our approach builds on recent advances in ABC by learning a neural network which maps features of the observed data to the posterior distribution over parameters. We learn a Bayesian mixture-density network approximating the posterior over multiple rounds of adaptively chosen simulations. Furthermore, we propose an efficient approach for handling missing features and parameter settings for which the simulator fails, as well as a strategy for automatically learning relevant features using recurrent neural networks. On synthetic data, our approach efficiently estimates posterior distributions and recovers ground-truth parameters. On in-vitro recordings of membrane voltages, we recover multivariate posteriors over biophysical parameters, which yield model-predicted voltage traces that accurately match empirical data. Our approach will enable neuroscientists to perform Bayesian inference on complex neuron models without having to design model-specific algorithms, closing the gap between mechanistic and statistical approaches to single-neuron modelling., Comment: NIPS 2017. The first two authors contributed equally

Neural population activity often exhibits rich variability. This variability is thought to arise from single-neuron stochasticity, neural dynamics on short time-scales, as well as from modulations of neural firing properties on long time-scales, often referred to as non-stationarity. To better understand the nature of co-variability in neural circuits and their impact on cortical information processing, we introduce a hierarchical dynamics model that is able to capture inter-trial modulations in firing rates, as well as neural population dynamics. We derive an algorithm for Bayesian Laplace propagation for fast posterior inference, and demonstrate that our model provides a better account of the structure of neural firing than existing stationary dynamics models, when applied to neural population recordings from primary visual cortex.

Neural responses in visual cortex are influenced by visual stimuli and by ongoing spiking activity in local circuits. An important challenge in computational neuroscience is to develop models that can account for both of these features in large multi-neuron recordings and to reveal how stimulus representations interact with and depend on cortical dynamics. Here we introduce a statistical model of neural population activity that integrates a nonlinear receptive field model with a latent dynamical model of ongoing cortical activity. This model captures the temporal dynamics, effective network connectivity in large population recordings, and correlations due to shared stimulus drive as well as common noise. Moreover, because the nonlinear stimulus inputs are mixed by the ongoing dynamics, the model can account for a relatively large number of idiosyncratic receptive field shapes with a small number of nonlinear inputs to a low-dimensional latent dynamical model. We introduce a fast estimation method using online expectation maximization with Laplace approximations. Inference scales linearly in both population size and recording duration. We apply this model to multi-channel recordings from primary visual cortex and show that it accounts for a large number of individual neural receptive fields using a small number of nonlinear inputs and a low-dimensional dynamical model.

Neural population activity in cortical circuits is not solely driven by external inputs, but is also modulated by endogenous states. These cortical states vary on multiple time-scales and also across areas and layers of the neocortex. To understand information processing in cortical circuits, we need to understand the statistical structure of internal states and their interaction with sensory inputs. Here, we present a statistical model for extracting hierarchically organized neural population states from multi-channel recordings of neural spiking activity. We model population states using a hidden Markov decision tree with state-dependent tuning parameters and a generalized linear observation model. Using variational Bayesian inference, we estimate the posterior distribution over parameters from population recordings of neural spike trains. On simulated data, we show that we can identify the underlying sequence of population states over time and reconstruct the ground truth parameters. Using extracellular population recordings from visual cortex, we find that a model with two levels of population states outperforms a generalized linear model which does not include state-dependence, as well as models which only including a binary state. Finally, modelling of state-dependence via our model also improves the accuracy with which sensory stimuli can be decoded from the population response.

Neural population activity often exhibits rich variability and temporal structure. This variability is thought to arise from single-neuron stochasticity, neural dynam- ics on short time-scales, as well as from modulations of neural firing properties on long time-scales, often referred to as “non-stationarity”. To better understand the nature of co-variability in neural circuits and their impact on cortical information processing, we need statistical models that are able to capture multiple sources of variability on different time-scales. Here, we introduce a hierarchical statistical model of neural population activity which models both neural population dynamics as well as inter-trial modulations in firing rates. In addition, we extend the model to allow us to capture non-stationarities in the population dynamics itself (i.e., correlations across neurons). We develop variational inference methods for learning model parameters, and demonstrate that the method can recover non-stationarities in both average firing rates and correlation structure. Applied to neural population recordings from anesthetized macaque primary visual cortex, our models provide a better account of the structure of neural firing than stationary dynamics models.

Simultaneous recordings of the activity of large neural populations are extremely valuable as they can be used to infer the dynamics and interactions of neurons in a local circuit, shedding light on the computations performed. It is now possible to measure the activity of hundreds of neurons using 2-photon calcium imaging. However, many computations are thought to involve circuits consisting of thousands of neurons, such as cortical barrels in rodent somatosensory cortex. Here we contribute a statistical method for stitching'' together sequentially imaged sets of neurons into one model by phrasing the problem as fitting a latent dynamical system with missing observations. This method allows us to substantially expand the population-sizes for which population dynamics can be characterized---beyond the number of simultaneously imaged neurons. In particular, we demonstrate using recordings in mouse somatosensory cortex that this method makes it possible to predict noise correlations between non-simultaneously recorded neuron pairs.

Latent linear dynamical systems with generalised-linear observation models arise in a variety of applications, for example when modelling the spiking activity of populations of neurons. Here, we show how spectral learning methods for linear systems with Gaussian observations (usually called subspace identification in this context) can be extended to estimate the parameters of dynamical system models observed through non-Gaussian noise models. We use this approach to obtain estimates of parameters for a dynamical model of neural population data, where the observed spike-counts are Poisson-distributed with log-rates determined by the latent dynamical process, possibly driven by external inputs. We show that the extended system identification algorithm is consistent and accurately recovers the correct parameters on large simulated data sets with much smaller computational cost than approximate expectation-maximisation (EM) due to the non-iterative nature of subspace identification. Even on smaller data sets, it provides an effective initialization for EM, leading to more robust performance and faster convergence. These benefits are shown to extend to real neural data.

Neurons in the neocortex code and compute as part of a locally interconnected population. Large-scale multi-electrode recording makes it possible to access these population processes empirically by fitting statistical models to unaveraged data. What statistical structure best describes the concurrent spiking of cells within a local network? We argue that in the cortex, where firing exhibits extensive correlations in both time and space and where a typical sample of neurons still reflects only a very small fraction of the local population, the most appropriate model captures shared variability by a low-dimensional latent process evolving with smooth dynamics, rather than by putative direct coupling. We test this claim by comparing a latent dynamical model with realistic spiking observations to coupled generalised linear spike-response models (GLMs) using cortical recordings. We find that the latent dynamical approach outperforms the GLM in terms of goodness-offit, and reproduces the temporal correlations in the data more accurately. We also compare models whose observations models are either derived from a Gaussian or point-process models, finding that the non-Gaussian model provides slightly better goodness-of-fit and more realistic population spike counts.

Maximum entropy models have become popular statistical models in neuroscience and other areas in biology, and can be useful tools for obtaining estimates of mutual information in biological systems. However, maximum entropy models fit to small data sets can be subject to sampling bias; i.e. the true entropy of the data can be severely underestimated. Here we study the sampling properties of estimates of the entropy obtained from maximum entropy models. We show that if the data is generated by a distribution that lies in the model class, the bias is equal to the number of parameters divided by twice the number of observations. However, in practice, the true distribution is usually outside the model class, and we show here that this misspecification can lead to much larger bias. We provide a perturbative approximation of the maximally expected bias when the true model is out of model class, and we illustrate our results using numerical simulations of an Ising model; i.e. the second-order maximum entropy distribution on binary data.

Imaging techniques such as optical imaging of intrinsic signals, 2-photon calcium imaging and voltage sensitive dye imaging can be used to measure the functional organization of visual cortex across different spatial and temporal scales. Here, we present Bayesian methods based on Gaussian processes for extracting topographic maps from functional imaging data. In particular, we focus on the estimation of orientation preference maps (OPMs) from intrinsic signal imaging data. We model the underlying map as a bivariate Gaussian process, with a prior covariance function that reflects known properties of OPMs, and a noise covariance adjusted to the data. The posterior mean can be interpreted as an optimally smoothed estimate of the map, and can be used for model based interpolations of the map from sparse measurements. By sampling from the posterior distribution, we can get error bars on statistical properties such as preferred orientations, pinwheel locations or pinwheel counts. Finally, the use of an explicit probabilistic model facilitates interpretation of parameters and quantitative model comparisons. We demonstrate our model both on simulated data and on intrinsic signaling data from ferret visual cortex.

Simultaneously recorded neurons often exhibit correlations in their spiking activity. These correlations shape the statistical structure of the population activity, and can lead to substantial redundancy across neurons. Here, we study the effect of pairwise correlations on the population spike count statistics and redundancy in populations of threshold-neurons in which response-correlations arise from correlated Gaussian inputs. We investigate the scaling of the redundancy as the population size is increased, and compare the asymptotic redundancy in our models to the corresponding maximum- and minimum entropy models.

Stimulus selectivity of sensory neurons is often characterized by estimating their receptive field properties such as orientation selectivity. Receptive fields are usually derived from the mean (or covariance) of the spike-triggered stimulus ensemble. This approach treats each spike as an independent message but does not take into account that information might be conveyed through patterns of neural activity that are distributed across space or time. Can we find a concise description for the processing of a whole population of neurons analogous to the receptive field for single neurons? Here, we present a generalization of the linear receptive field which is not bound to be triggered on individual spikes but can be meaningfully linked to distributed response patterns. More precisely, we seek to identify those stimulus features and the corresponding patterns of neural activity that are most reliably coupled. We use an extension of reverse-correlation methods based on canonical correlation analysis. The resulting population receptive fields span the subspace of stimuli that is most informative about the population response. We evaluate our approach using both neuronal models and multi-electrode recordings from rabbit retinal ganglion cells. We show how the model can be extended to capture nonlinear stimulus-response relationships using kernel canonical correlation analysis, which makes it possible to test different coding mechanisms. Our technique can also be used to calculate receptive fields from multi-dimensional neural measurements such as those obtained from dynamic imaging methods.

Attempting to model human categorization and similarity judgements is both a very interesting but also an exceedingly difficult challenge. Some of the difficulty arises because of conflicting evidence whether human categorization and similarity judgements should or should not be modelled as to operate on a mental representation that is essentially metric. Intuitively, this has a strong appeal as it would allow (dis)similarity to be represented geometrically as distance in some internal space. Here we show how a single stimulus, carefully constructed in a psychophysical experiment, introduces l2 violations in what used to be an internal similarity space that could be adequately modelled as Euclidean. We term this one influential data point a conflictual judgement. We present an algorithm of how to analyse such data and how to identify the crucial point. Thus there may not be a strict dichotomy between either a metric or a non-metric internal space but rather degrees to which potentially large subsets of stimuli are represented metrically with a small subset causing a global violation of metricity.

To test the hypothesis that DNA sequence variation in the androgen receptor gene plays a causal role in the development of male sexual orientation, we have (1) measured the degree of concordance of androgen receptor alleles in 36 pairs of homosexual brothers, (2) compared the lengths of polyglutamine and polyglycine tracts in the amino-terminal domain of the androgen receptor in a sample of 197 homosexual males and 213 unselected subjects, and (3) screened the the entire androgen receptor coding region for sequence variation by PCR and denaturing gradient-gel electrophoresis (DGGE) and/or single-strand conformation polymorphism analysis in 20 homosexual males with homosexual or bisexual brothers and one homosexual male with no homosexual brothers, and screened the amino-terminal domain of the receptor for sequence variation in an additional 44 homosexual males, 37 of whom had one or more first- or second-degree male relatives who were either homosexual or bisexual. These analyses show that (1) homosexual brothers are as likely to be discordant as concordant for androgen receptor alleles; (2) there are no large-scale differences between the distributions of polyglycine or polyglutamine tract lengths in the homosexual and control groups; and (3) coding region sequence variation is not commonly found within the androgen receptor gene of homosexual men. The DGGE screen identified two rare amino acid substitutions, ser205-to-arg and glu793-to-asp, the biological significance of which is unknown.

Generalized linear models are the most commonly used tools to describe the stimulus selectivity of sensory neurons. Here we present a Bayesian treatment of such models. Using the expectation propagation algorithm, we are able to approximate the full posterior distribution over all weights. In addition, we use a Laplacian prior to favor sparse solutions. Therefore, stimulus features that do not critically influence neural activity will be assigned zero weights and thus be effectively excluded by the model. This feature selection mechanism facilitates both the interpretation of the neuron model as well as its predictive abilities. The posterior distribution can be used to obtain confidence intervals which makes it possible to assess the statistical significance of the solution. In neural data analysis, the available amount of experimental measurements is often limited whereas the parameter space is large. In such a situation, both regularization by a sparsity prior and uncertainty estimates for the model parameters are essential. We apply our method to multi-electrode recordings of retinal ganglion cells and use our uncertainty estimate to test the statistical significance of functional couplings between neurons. Furthermore we used the sparsity of the Laplace prior to select those filters from a spike-triggered covariance analysis that are most informative about the neural response.