The human brain is a remarkable computing machine, i.e. vastly parallel, self-organizing, robust, and energy efficient. To gain a better understanding into how the brain works, a cyborg (cybernetic organism, a combination of machine and living tissue) is currently being made in an interdisciplinary effort, known as the Cyborg project. In this paper we describe how living cultures of neurons (biological neural networks) are successfully grown in-vitro over Micro-Electrode Arrays (MEAs), which allow them to be interfaced to a robotic body through electrical stimulation and neural recordings. Furthermore, we describe the bio-and nano-technological procedures utilized for the culture of such dissociated neural networks and the interface software and hardware framework used for creating a closed-loop hybrid neuro-system. A Reservoir Computing (RC) approach is used to harness the computational power of the neuronal culture.
A patterned spread of proteinopathy represents a common characteristic of many neurodegenerative diseases. In Parkinson's disease (PD), misfolded forms of alpha-synuclein proteins accumulate in hallmark pathological inclusions termed Lewy bodies and Lewy neurites. Such protein aggregates seem to affect selectively vulnerable neuronal populations in the substantia nigra and to propagate within interconnected neuronal networks. Research findings suggest that these proteinopathic inclusions are present at very early timepoints in disease development, even before clear behavioural symptoms of dysfunction arise. In this study we investigate the early pathophysiology developing after induced formation of such PD-related alpha-synuclein inclusions, in a physiologically relevant in vitro setup using engineered human neural networks. We monitor the neural network activity using multielectrode arrays (MEAs) for a period of three weeks following proteinopathy induction to identify associated changes in network function, with a special emphasis on the measure of network criticality. Self-organised criticality represents the critical point between resilience against perturbation and adaptational flexibility, which appears to be a functional trait in self-organising neural networks, both in vitro and in vivo. We show that although developing pathology at early onset is not clearly manifest in standard measurements of network function, it may be discerned by investigating differences in network criticality states.
In vitro electrophysiological investigation of neural activity at a network level holds tremendous potential for elucidating underlying features of brain function (and dysfunction). In standard neural network modelling systems, however, the fundamental three-dimensional (3D) character of the brain is a largely disregarded feature. This widely applied neuroscientific strategy affects several aspects of the structure–function relationships of the resulting networks, altering network connectivity and topology, ultimately reducing the translatability of the results obtained. As these model systems increase in popularity, it becomes imperative that they capture, as accurately as possible, fundamental features of neural networks in the brain, such as small-worldness. In this report, we combine in vitro neural cell culture with a biologically compatible scaffolding substrate, surface-grafted polymer particles (PPs), to develop neural networks with 3D topology. Furthermore, we investigate their electrophysiological network activity through the use of 3D multielectrode arrays. The resulting neural network activity shows emergent behaviour consistent with maturing neural networks capable of performing computations, i.e. activity patterns suggestive of both information segregation (desynchronized single spikes and local bursts) and information integration (network spikes). Importantly, we demonstrate that the resulting PP-structured neural networks show both structural and functional features consistent with small-world network topology.
Objective. Extraction of temporal features of neuronal activity from electrophysiological data can be used for accurate classification of neural networks in healthy and pathologically perturbed conditions. In this study, we provide an extensive approach for the classification of human in vitro neural networks with and without an underlying pathology, from electrophysiological recordings obtained using a microelectrode array (MEA) platform. Approach. We developed a Dirichlet mixture (DM) Point Process statistical model able to extract temporal features related to neurons. We then applied a machine learning algorithm to discriminate between healthy control and pathologically perturbed in vitro neural networks. Main Results. We found a high degree of separability between the classes using DM point process features (p-value <0.001 for all the features, paired t-test), which reaches 93.10 of accuracy (92.37 of ROC AUC) with the Random Forest classifier. In particular, results show a higher latency in firing for pathologically perturbed neurons (43±16 ms versus 67±31 ms, m IG feature distribution). Significance. Our approach has been successful in extracting temporal features related to the neurons' behaviour, as well as distinguishing healthy from pathologically perturbed networks, including classification of responses to a transient induced perturbation.
Running titleStructure and function in engineered human LRRK2 networks Total number of pages: 40 Total number of words: (i) whole manuscript: 8062; (ii) abstract: 235 AbstractMutations in the LRRK2 gene have been widely linked to Parkinson ś disease. The G2019S variant has been shown to contribute uniquely to both familial and sporadic forms of the disease. LRRK2-related mutations have been extensively studied, yet the wide variety of cellular and network events directly or indirectly related to these mutations remain poorly understood. In this study, we structured multi-nodal human neural networks carrying the G2019S mutation using custom-designed microfluidic chips coupled to microelectrode-arrays. By applying live imaging approaches, immunocytochemistry and computational modelling, we have revealed alterations in both the structure and function of the resulting neural networks when compared to controls. We provide first evidence of increased neuritic density associated with the G2019S LRRK2 mutation, while previous studies have found either a strong decrease, or no change, compared to controls. Additionally, we corroborate previous findings regarding increased baseline network activity compared to control neural networks. Furthermore, we can reveal additional network alterations attributable to the specific mutation by selectively inducing transient overexcitation to confined parts of the structured multi-nodal networks. These alterations, which we were able to capture both at the micro-and mesoscale manifested as differences in relative network activity and correlation, as well as in mitochondria activation, neuritic remodelling, and synaptic alterations. Our study thus provides important new insights into early signs of neural network pathology significantly expanding upon the current knowledge relating to the G2019S Parkinson's disease mutation.
In the brain, the structure of a network of neurons defines how these neurons implement the computations that underlie the mind and the behavior of animals and humans. Provided that we can describe the network of neurons as a graph, we can employ methods from graph theory to investigate its structure or use cellular automata to mathematically assess its function. Additionally, these graphs can provide biologically plausible designs for networks, which can be integrated as reservoirs to support computing. Although, software for the analysis of graphs and cellular automata are widely available. Graph extraction from the image of networks of brain cells remains difficult. Nervous tissue is heterogeneous, and differences in anatomy may reflect relevant differences in function. Here we introduce a deep learning based toolbox to extracts graphs from images of brain tissue. This toolbox provides an easyto-use framework allowing system neuroscientists to generate graphs based on images of brain tissue by combining methods from image processing, deep learning, and graph theory. The goals are to simplify the training and usage of deep learning methods for computer vision and facilitate its integration into graph extraction pipelines. In this way, the toolbox provides an alternative to the required laborious manual process of tracing, sorting and classifying. We expect to democratize the machine learning methods to a wider community of users beyond the computer vision experts and improve the time-efficiency of graph extraction from large brain image datasets, which may lead to further understanding of the human mind.
The human brain is a remarkable computing machine, i.e. vastly parallel, self-organizing, robust, and energy efficient. To gain a better understanding into how the brain works, a cyborg (cybernetic organism, a combination of machine and living tissue) is currently being made in an interdisciplinary effort, known as the Cyborg project. In this paper we describe how living cultures of neurons (biological neural networks) are successfully grown in-vitro over Micro-Electrode Arrays (MEAs), which allow them to be interfaced to a robotic body through electrical stimulation and neural recordings. Furthermore, we describe the bio-and nano-technological procedures utilized for the culture of such dissociated neural networks and the interface software and hardware framework used for creating a closed-loop hybrid neuro-system. A Reservoir Computing (RC) approach is used to harness the computational power of the neuronal culture.
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