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The field of connectomics aims to reconstruct the wiring diagram of Neurons and synapses to enable new insights into the workings of the brain. Reconstructing and analyzing the Neuronal connectivity, however, relies on many individual steps, starting from high‐resolution data acquisition to automated segmentation, proofreading, interactive data exploration, and circuit analysis. All of these steps have to handle large and complex datasets and rely on or benefit from integrated visualization methods. In this state‐of‐the‐art report, we describe visualization methods that can be applied throughout the connectomics pipeline, from data acquisition to circuit analysis. We first define the different steps of the pipeline and focus on how visualization is currently integrated into these steps. We also survey open science initiatives in connectomics, including usable open‐source tools and publicly available datasets. Finally, we discuss open challenges and possible future directions of this exciting research field.

 

Three-dimensional (3D) reconstruction of living brain tissue down to an individual synapse level would create opportunities for decoding the dynamics and structure–function relationships of the brain’s complex and dense information processing network; however, this has been hindered by insufficient 3D resolution, inadequate signal-to-noise ratio and prohibitive light burden in optical imaging, whereas electron microscopy is inherently static. Here we solved these challenges by developing an integrated optical/machine-learning technology, LIONESS (live information-optimized nanoscopy enabling saturated segmentation). This leverages optical modifications to stimulated emission depletion microscopy in comprehensively, extracellularly labeled tissue and previous information on sample structure via machine learning to simultaneously achieve isotropic super-resolution, high signal-to-noise ratio and compatibility with living tissue. This allows dense deep-learning-based instance segmentation and 3D reconstruction at a synapse level, incorporating molecular, activity and morphodynamic information. LIONESS opens up avenues for studying the dynamic functional (nano-)architecture of living brain tissue. 

3D instance segmentation for unlabeled imaging modalities is a challenging but essential task as collecting expert annotation can be expensive and time-consuming. Existing works segment a new modality by either deploying pre-trained models optimized on diverse training data or sequentially conducting image translation and segmentation with two relatively independent networks. In this work, we propose a novel Cyclic Segmentation Generative Adversarial Network (CySGAN) that conducts image translation and instance segmentation simultaneously using a unified network with weight sharing. Since the image translation layer can be removed at inference time, our proposed model does not introduce additional computational cost upon a standard segmentation model. For optimizing CySGAN, besides the CycleGAN losses for image translation and supervised losses for the annotated source domain, we also utilize self-supervised and segmentation-based adversarial objectives to enhance the model performance by leveraging unlabeled target domain images. We benchmark our approach on the task of 3D neuronal nuclei segmentation with annotated electron microscopy (EM) images and unlabeled expansion microscopy (ExM) data. The proposed CySGAN outperforms pre-trained generalist models, feature-level domain adaptation models, and the baselines that conduct image translation and segmentation sequentially. Our implementation and the newly collected, densely annotated ExM zebrafish brain nuclei dataset, named NucExM, are publicly available at https://connectomics-bazaar.github.io/proj/CySGAN/index.html. 

Recent advances in high-resolution connectomics provide researchers access to accurate reconstructions of vast neuronal circuits and brain networks for the first time. Neuroscientists anticipate analyzing these networks to gain a better understanding of information processing in the brain. In particular, scientists are interested in identifying specific network motifs, i.e., repeating subgraphs of the larger brain network that are believed to be neuronal building blocks. To analyze these motifs, it is crucial to review instances of a motif in the brain network and then map the graph structure to the detailed 3D reconstructions of the involved neurons and synapses. We present Vimo, an interactive visual approach to analyze neuronal motifs and motif chains in large brain networks. Experts can sketch network motifs intuitively in a visual interface and specify structural properties of the involved neurons and synapses to query large connectomics datasets. Motif instances (MIs) can be explored in high-resolution 3D renderings of the involved neurons and synapses. To reduce visual clutter and simplify the analysis of MIs, we designed a continuous focus&context metaphor inspired by continuous visual abstractions [MAAB∗18] that allows the user to transition from the highly-detailed rendering of the anatomical structure to views that emphasize the underlying motif structure and synaptic connectivity. Furthermore, Vimo supports the identification of motif chains where a motif is used repeatedly to form a longer synaptic chain. We evaluate Vimo in a user study with seven domain experts and an in-depth case study on motifs in the central complex (CX) of the fruit fly brain. 

Abstract Following significant advances in image acquisition, synapse detection, and neuronal segmentation in connectomics, researchers have extracted an increasingly diverse set of wiring diagrams from brain tissue. Neuroscientists frequently represent these wiring diagrams as graphs with nodes corresponding to a single neuron and edges indicating synaptic connectivity. The edges can contain “colors” or “labels”, indicating excitatory versus inhibitory connections, among other things. By representing the wiring diagram as a graph, we can begin to identify motifs, the frequently occurring subgraphs that correspond to specific biological functions. Most analyses on these wiring diagrams have focused on hypothesized motifs—those we expect to find. However, one of the goals of connectomics is to identify biologically-significant motifs that we did not previously hypothesize. To identify these structures, we need large-scale subgraph enumeration to find the frequencies of all unique motifs. Exact subgraph enumeration is a computationally expensive task, particularly in the edge-dense wiring diagrams. Furthermore, most existing methods do not differentiate between types of edges which can significantly affect the function of a motif. We propose a parallel, general-purpose subgraph enumeration strategy to count motifs in the connectome. Next, we introduce a divide-and-conquer community-based subgraph enumeration strategy that allows for enumeration per brain region. Lastly, we allow for differentiation of edges by types to better reflect the underlying biological properties of the graph. We demonstrate our results on eleven connectomes and publish for future analyses extensive overviews for the 26 trillion subgraphs enumerated that required approximately 9.25 years of computation time.