multiscale-investigations-cortical-processing-integrating-laminar

Multiscale Investigations of Cortical Processing by Integrating Laminar Polytrodes and Optogenetics with Micro Electrocorticography in Rodents

Electrocorticography (ECoG) is a methodological bridge between basic neuroscience and understanding human brain function in health and disease. ECoG ...

Lawrence Berkeley National Lab

UC Berkeley

Predicting future events is a critical computation for both perception and behavior. Despite the essential nature of this computation, there are few studies demonstrating neural activity that predicts specific events in learned, probabilistic sequences. Here, we test the hypotheses that the dynamics of internally generated neural activity are predictive of future events and are structured by the learned temporal-sequential statistics of those events. We recorded neural activity in Bengalese finch sensory-motor area HVC in response to playback of sequences from individuals' songs, and examined the neural activity that continued after stimulus offset. We found that the strength of response to a syllable in the sequence depended on the delay at which that syllable was played, with a maximal response when the delay matched the intersyllable gap normally present for that specific syllable during song production. Furthermore, poststimulus neural activity induced by sequence playback resembled the neural response to the next syllable in the sequence when that syllable was predictable, but not when the next syllable was uncertain. Our results demonstrate that the dynamics of internally generated HVC neural activity are predictive of the learned temporal-sequential structure of produced song and that the strength of this prediction is modulated by uncertainty.

Auditory-induced neural dynamics in sensory-motor circuitry predict learned temporal and sequential statistics of birdsong.

Opportunities offered by new neuro-technologies are threatened by lack of coherent plans to analyze, manage, and understand the data. High-performance computing will allow exploratory analysis of massive datasets stored in standardized formats, hosted in open repositories, and integrated with simulations.

High-Performance Computing in Neuroscience for Data-Driven Discovery, Integration, and Dissemination.

Understanding how neuronal signals propagate in local network is an important step in understanding information processing. As a result, spike trains recorded with multi-electrode arrays (MEAs) have been widely used to study the function of neural networks. Studying the dynamics of neuronal networks requires the identification of both excitatory and inhibitory connections. The detection of excitatory relationships can robustly be inferred by characterizing the statistical relationships of neural spike trains. However, the identification of inhibitory relationships is more difficult: distinguishing endogenous low firing rates from active inhibition is not obvious.

In vitro validation of in silico identified inhibitory interactions.

Despite the fact that the loss functions of deep neural networks are highly nonconvex, gradient-based optimization algorithms converge to approximately the same performance from many random initial points. One thread of work has focused on explaining this phenomenon by numerically characterizing the local curvature near critical points of the loss function, where the gradients are near zero. Such studies have reported that neural network losses enjoy a no-bad-local-minima property, in disagreement with more recent theoretical results. We report here that the methods used to find these putative critical points suffer from a bad local minima problem of their own: they often converge to or pass through regions where the gradient norm has a stationary point. We call these gradient-flat regions, since they arise when the gradient is approximately in the kernel of the Hessian, such that the loss is locally approximately linear, or flat, in the direction of the gradient. We describe how the presence of these regions necessitates care in both interpreting past results that claimed to find critical points of neural network losses and in designing second-order methods for optimizing neural networks.

Critical Point-Finding Methods Reveal Gradient-Flat Regions of Deep Network Losses.

The membrane potential of individual neurons depends on a large number of interacting biophysical processes operating on spatial-temporal scales spanning several orders of magnitude. The multi-scale nature of these processes dictates that accurate prediction of membrane potentials in specific neurons requires the utilization of detailed simulations. Unfortunately, constraining parameters within biologically detailed neuron models can be difficult, leading to poor model fits. This obstacle can be overcome partially by numerical optimization or detailed exploration of parameter space. However, these processes, which currently rely on central processing unit (CPU) computation, often incur orders of magnitude increases in computing time for marginal improvements in model behavior. As a result, model quality is often compromised to accommodate compute resources.

NeuroGPU: Accelerating multi-compartment, biophysically detailed neuron simulations on GPUs.

Electrocorticography (ECoG) methodologically bridges basic neuroscience and understanding of human brains in health and disease. However, the localization of ECoG signals across the surface of the brain and the spatial distribution of their generating neuronal sources are poorly understood. To address this gap, we recorded from rat auditory cortex using customized μECoG, and simulated cortical surface electrical potentials with a full-scale, biophysically detailed cortical column model. Experimentally, μECoG-derived auditory representations were tonotopically organized and signals were anisotropically localized to less than or equal to ±200 μm, that is, a single cortical column. Biophysical simulations reproduce experimental findings and indicate that neurons in cortical layers V and VI contribute ∼85% of evoked high-gamma signal recorded at the surface. Cell number and synchrony were the primary biophysical properties determining laminar contributions to evoked μECoG signals, whereas distance was only a minimal factor. Thus, evoked μECoG signals primarily originate from neurons in the infragranular layers of a single cortical column. ECoG methodologically bridges basic neuroscience and understanding of human brains in health and disease. However, the localization of ECoG signals across the surface of the brain and the spatial distribution of their generating neuronal sources are poorly understood. We investigated the localization and origins of sensory-evoked ECoG responses. We experimentally found that ECoG responses were anisotropically localized to a cortical column. Biophysically detailed simulations revealed that neurons in layers V and VI were the primary sources of evoked ECoG responses. These results indicate that evoked ECoG high-gamma responses are primarily generated by the population spike rate of pyramidal neurons in layers V and VI of single cortical columns and highlight the possibility of understanding how microscopic sources produce mesoscale signals.

Columnar Localization and Laminar Origin of Cortical Surface Electrical Potentials.

BigNeuron is an open community bench-testing platform with the goal of setting open standards for accurate and fast automatic neuron tracing. We gathered a diverse set of image volumes across several species that is representative of the data obtained in many neuroscience laboratories interested in neuron tracing. Here, we report generated gold standard manual annotations for a subset of the available imaging datasets and quantified tracing quality for 35 automatic tracing algorithms. The goal of generating such a hand-curated diverse dataset is to advance the development of tracing algorithms and enable generalizable benchmarking. Together with image quality features, we pooled the data in an interactive web application that enables users and developers to perform principal component analysis, t-distributed stochastic neighbor embedding, correlation and clustering, visualization of imaging and tracing data, and benchmarking of automatic tracing algorithms in user-defined data subsets. The image quality metrics explain most of the variance in the data, followed by neuromorphological features related to neuron size. We observed that diverse algorithms can provide complementary information to obtain accurate results and developed a method to iteratively combine methods and generate consensus reconstructions. The consensus trees obtained provide estimates of the neuron structure ground truth that typically outperform single algorithms in noisy datasets. However, specific algorithms may outperform the consensus tree strategy in specific imaging conditions. Finally, to aid users in predicting the most accurate automatic tracing results without manual annotations for comparison, we used support vector machine regression to predict reconstruction quality given an image volume and a set of automatic tracings.

BigNeuron: a resource to benchmark and predict performance of algorithms for automated tracing of neurons in light microscopy datasets.

In the brain, all neurons are driven by the activity of other neurons, some of which maybe simultaneously recorded, but most are not. As such, models of neuronal activity need to account for simultaneously recorded neurons and the influences of unmeasured neurons. This can be done through inclusion of model terms for observed external variables (e.g., tuning to stimuli) as well as terms for latent sources of variability. Determining the influence of groups of neurons on each other relative to other influences is important to understand brain functioning. The parameters of statistical models fit to data are commonly used to gain insight into the relative importance of those influences. Scientific interpretation of models hinge upon unbiased parameter estimates. However, evaluation of biased inference is rarely performed and sources of bias are poorly understood. Through extensive numerical study and analytic calculation, we show that common inference procedures and models are typically biased. We demonstrate that accurate parameter selection before estimation resolves model non-identifiability and mitigates bias. In diverse neurophysiology data sets, we found that contributions of coupling to other neurons are often overestimated while tuning to exogenous variables are underestimated in common methods. We explain heterogeneity in observed biases across data sets in terms of data statistics. Finally, counter to common intuition, we found that model non-identifiability contributes to bias, not variance, making it a particularly insidious form of statistical error. Together, our results identify the causes of statistical biases in common models of neural data, provide inference procedures to mitigate that bias, and reveal and explain the impact of those biases in diverse neural data sets.

Resolving Non-identifiability Mitigates Bias in Models of Neural Tuning and Functional Coupling.

Traumatic brain injury (TBI) affects how the brain functions in the short and long term. Resulting patient outcomes across physical, cognitive, and psychological domains are complex and often difficult to predict. Major challenges to developing personalized treatment for TBI include distilling large quantities of complex data and increasing the precision with which patient outcome prediction (prognoses) can be rendered. We developed and applied interpretable machine learning methods to TBI patient data. We show that complex data describing TBI patients' intake characteristics and outcome phenotypes can be distilled to smaller sets of clinically interpretable latent factors. We demonstrate that 19 clusters of TBI outcomes can be predicted from intake data, a ~ 6× improvement in precision over clinical standards. Finally, we show that 36% of the outcome variance across patients can be predicted. These results demonstrate the importance of interpretable machine learning applied to deeply characterized patients for data-driven distillation and precision prognosis.

Data-driven distillation and precision prognosis in traumatic brain injury with interpretable machine learning.

Author Correction: BigNeuron: a resource to benchmark and predict performance of algorithms for automated tracing of neurons in light microscopy datasets.

Article	Year
Auditory-induced neural dynamics in sensory-motor circuitry predict learned temporal and sequential statistics of birdsong. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 27506786	2016
High-Performance Computing in Neuroscience for Data-Driven Discovery, Integration, and Dissemination. Neuron\| PubMed ID: 27810006	2016
In vitro validation of in silico identified inhibitory interactions. Journal of neuroscience methods\| PubMed ID: 30965073	2019
Critical Point-Finding Methods Reveal Gradient-Flat Regions of Deep Network Losses. Neural computation\| PubMed ID: 34496389	2021
NeuroGPU: Accelerating multi-compartment, biophysically detailed neuron simulations on GPUs. Journal of neuroscience methods\| PubMed ID: 34728257	2022
Columnar Localization and Laminar Origin of Cortical Surface Electrical Potentials. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 35332084	2022
BigNeuron: a resource to benchmark and predict performance of algorithms for automated tracing of neurons in light microscopy datasets. Nature methods\| PubMed ID: 37069271	2023
Resolving Non-identifiability Mitigates Bias in Models of Neural Tuning and Functional Coupling. bioRxiv : the preprint server for biology\| PubMed ID: 37503030	2023
Data-driven distillation and precision prognosis in traumatic brain injury with interpretable machine learning. Scientific reports\| PubMed ID: 38040784	2023
Author Correction: BigNeuron: a resource to benchmark and predict performance of algorithms for automated tracing of neurons in light microscopy datasets. Nature methods\| PubMed ID: 39090383	2024

Kristofer E. Bouchard

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