ZyON: Enabling Spike Sorting on APSoC-Based Signal Processors for High-Density Microelectrode Arrays

Multi-Electrode Arrays and High-Density Multi-Electrode Arrays of sensors are a key instrument in neuroscience research. Such devices are evolving to provide ever-increasing temporal and spatial resolution, paving the way to unprecedented results when it comes to understanding the behaviour of neuronal networks and interacting with them. However, in some experimental cases, in-place low-latency processing of the sensor data acquired by the arrays is required. This poses the need for high-performance embedded computing platforms capable of processing in real-time the stream of samples produced by the acquisition front-end to extract higher-level information. Previous work has demonstrated that Field-Programmable Gate Array and All-Programmable System-On-Chip devices are suitable target technology for the implementation of real-time processors of High-Density Multi-Electrode Arrays data. However, approaches available in literature can process a limited number of channels or are designed to execute only the first steps of the neural signal processing chain. In this work, we propose an All-Programmable System-On-Chip based implementation capable of sorting neural spikes acquired by the sensors, to associate the shape of each spike to a specific firing neuron. Our system, implemented on a Xilinx Z7020 All-Programmable System-On-Chip is capable of executing on-line spike sorting up to 5500 acquisition channels, 43x more than state-of-the-art alternatives, supporting 18KHz acquisition frequency. We present an experimental study on a commonly used reference dataset, using on-line refinement of the sorting clusters to improve accuracy up to 82%, with only 4% degradation with respect to off-line analysis

Multi-electrode array recording and data analysis methods for molluscan central nervous systems

In this work the use of the central nervous system (CNS) of the aquatic snail Lymnaea stagnalis on planar multi-electrode arrays (MEAs) was developed and analysis methods for the data generated were created. A variety of different combinations of configurations of tissue from the Lymnaea CNS were explored to determine the signal characteristics that could be recorded by sixty channel MEAs. In particular, the suitability of the semi-intact system consisting of the lips, oesophagus, CNS, and associated nerve connectives was developed for use on the planar MEA. The recording target area of the dorsal surface of the buccal ganglia was selected as being the most promising for study and recordings of its component cells during fictive feeding behaviour stimulated by sucrose were made. The data produced by this type of experimentation is very high volume and so its analysis required the development of a custom set of software tools. The goal of this tool set is to find the signal from individual neurons in the data streams of the electrodes of a planar MEA, to estimate their position, and then to predict their causal connectivity. To produce such an analysis techniques for noise filtration, neural spike detection, and group detection of bursts of spikes were created to pre-process electrode data streams. The Kohonen self-organising map (SOM) algorithm was adapted for the purpose of separating detected spikes into data streams representing the spike output of individual cells found in the target system. A significant addition to SOM algorithm was developed by the concurrent use of triangulation methods based on current source density analysis to predict the position of individual cells based on their spike output on more than one electrode. The likely functional connectivity of individual neurons identified by the SOM technique were analysed through the use of a statistical causality method known as Granger causality/causal connectivity. This technique was used to produce a map of the likely connectivity between neural sources

Investigating information processing within the brain using multi-electrode array (MEA) electrophysiology data

How a stimulus, such as an odour, is represented in the brain is one of the main questions in neuroscience. It is becoming clearer that information is encoded by a population of neurons, but, how the spiking activity of a population of neurons conveys this information is unknown. Several population coding hypotheses have formulated over the years, and therefore, to obtain a more definitive answer as to how a population of neurons represents stimulus information we need to test, i.e. support or falsify, each of the hypotheses. One way of addressing these hypotheses is to record and analyse the activity of multiple individual neurons from the brain of a test subject when a stimulus is, and is not, presented. With the advent of multi electrode arrays (MEA) we can now record such activity. However, before we can investigate/test the population coding hypotheses using such recordings, we need to determine the number of neurons recorded by the MEA and their spiking activity, after spike detection, using an automatic spike sorting algorithm (we refer to the spiking activity of the neurons extracted from the MEA recordings as MEA sorted data). While there are many automatic spike sorting methods available, they have limitations. In addition, we are lacking methods to test/investigate the population coding hypotheses in detail using the MEA sorted data. That is, methods that show whether neurons respond in a hypothesised way and, if they do, shows how the stimulus is represented within the recorded area. Thus, in this thesis, we were motivated to, firstly, develop a new automatic spike sorting method, which avoids the limitations of other methods. We validated our method using simulated and biological data. In addition, we found our method can perform better than other standard methods. We next focused on the population rate coding hypothesis (i.e. the hypothesis that information is conveyed in the number of spikes fired by a pop- ulation of neurons within a relevant time period). More specifically, we developed a method for testing/investigating the population rate coding hypothesis using the MEA sorted data. That is, a method that uses the multi variate analysis of variance (MANOVA) test, where we modified its output, to show the most responsive subar- eas within the recorded area. We validated this using simulated and biological data. Finally, we investigated whether noise correlation between neurons (i.e. correlations in the trial to trial variability of the response of neurons to the same stimulus) in a rat's olfactory bulb can affect the amount of information a population rate code conveys about a set of stimuli. We found that noise correlation between neurons was predominately positive, which, ultimately, reduced the amount of information a population containing >45 neurons could convey about the stimuli by ~30%

A Neural Signal Processor for Low-Latency Spike Inference

This thesis describes the development of a system that can assign identities to a population of single-units, in multi-electrode recordings, at single-spike resolution with low-latency. The system has two parts. The first is a Field-Programmable Gate Array (FPGA)-based Neural Signal Processor (NSP) that receives raw input and generates labelled spikes as output, a process referred to as real-time spike inference. The second is a piece of software (Spiketag) that runs on a PC, communicates with the NSP, and generates a spike-sorted model to guide the real-time spike inference. The NSP provides clocks and control signals to five 32-channel INTAN RHD2132 chips to manage the acquisition of 160 channels of raw neural data. In parallel, the NSP further filters, detects and extracts extracellular spike waveforms from the raw neural data recorded by tetrodes or silicon probes and assigns single-unit identity to each detected spike. A set of Python application programming interfaces (APIs) was developed in Spiketag to enable the communication between the NSP and the PC. These APIs allow the NSP to obtain a model from the PC, which holds parameters such as reference channels, spike detection thresholds, spike feature transformation matrix and vector quantized clusters generated by spike sorting a short recording session. Using the spike-sorted model, the NSP performs data acquisition and real-time spike inference simultaneously. Algorithmic modules were implemented in the FPGA and pipelined to compute during 40 ms acquisition intervals. At the output end of the FPGA NSP, the real-time assigned single-unit identity (spike-id) is packaged with the timestamp, the electrode group, and the spike features as a spike-id packet. Spike-id packets are asynchronously transmitted through a low-latency Peripheral Component Interconnect Express (PCIe) interface to the PC, producing the real-time spike trains. The real-time spike trains can be used for further processing, such as real-time decoding. Several types of ground-truth data, including intracellular/extracellular paired recordings, synthesized tetrode extracellular waveforms with ground-truth spike timing and high-channel-count silicon probe recordings with ground-truth animal positions during navigation were used to validate the low-latency (1 ms) and high-accuracy (as high as state-of-the-art offline sorting and decoding algorithms) of the NSP’s real-time spike inference and the NSP-based real-time population decoding performance

Automatic Detection and Classification of Neural Signals in Epilepsy

The success of an epilepsy treatment, such as resective surgery, relies heavily on the accurate identification and localization of the brain regions involved in epilepsy for which patients undergo continuous intracranial electroencephalogram (EEG) monitoring. The prolonged EEG recordings are screened for two main biomarkers of epilepsy: seizures and interictal spikes. Visual screening and quantitation of these two biomarkers in voluminous EEG recordings is highly subjective, labor-intensive, tiresome and expensive. This thesis focuses on developing new techniques to detect and classify these events in the EEG to aid the review of prolonged intracranial EEG recordings. It has been observed in the literature that reliable seizure detection can be made by quantifying the evolution of seizure EEG waveforms. This thesis presents three new computationally simple non-patient-specific (NPS) seizure detection systems that quantify the temporal evolution of seizure EEG. The first method is based on the frequency-weighted-energy, the second method on quantifying the EEG waveform sharpness, while the third method mimics EEG experts. The performance of these new methods is compared with that of three state-of-the-art NPS seizure detection systems. The results show that the proposed systems outperform these state-of-the-art systems. Epilepsy therapies are individualized for numerous reasons, and patient-specific (PS) seizure detection techniques are needed not only in the pre-surgical evaluation of prolonged EEG recordings, but also in the emerging neuro-responsive therapies. This thesis proposes a new model-based PS seizure detection system that requires only the knowledge of a template seizure pattern to derive the seizure model consisting of a set of basis functions necessary to utilize the statistically optimal null filters (SONF) for the detection of the subsequent seizures. The results of the performance evaluation show that the proposed system provides improved results compared to the clinically-used PS system. Quantitative analysis of the second biomarker, interictal spikes, may help in the understanding of epileptogenesis, and to identify new epileptic biomarkers and new therapies. However, such an analysis is still done manually in most of the epilepsy centers. This thesis presents an unsupervised spike sorting system that does not require a priori knowledge of the complete spike data

How does the brain extract acoustic patterns? A behavioural and neural study

In complex auditory scenes the brain exploits statistical regularities to group sound elements into streams. Previous studies using tones that transition from being randomly drawn to regularly repeating, have highlighted a network of brain regions involved during this process of regularity detection, including auditory cortex (AC) and hippocampus (HPC; Barascud et al., 2016). In this thesis, I seek to understand how the neurons within AC and HPC detect and maintain a representation of deterministic acoustic regularity. I trained ferrets (n = 6) on a GO/NO-GO task to detect the transition from a random sequence of tones to a repeating pattern of tones, with increasing pattern lengths (3, 5 and 7). All animals performed significantly above chance, with longer reaction times and declining performance as the pattern length increased. During performance of the behavioural task, or passive listening, I recorded from primary and secondary fields of AC with multi-electrode arrays (behaving: n = 3), or AC and HPC using Neuropixels probes (behaving: n = 1; passive: n = 1). In the local field potential, I identified no differences in the evoked response between presentations of random or regular sequences. Instead, I observed significant increases in oscillatory power at the rate of the repeating pattern, and decreases at the tone presentation rate, during regularity. Neurons in AC, across the population, showed higher firing with more repetitions of the pattern and for shorter pattern lengths. Single-units within AC showed higher precision in their firing when responding to their best frequency during regularity. Neurons in AC and HPC both entrained to the pattern rate during presentation of the regular sequence when compared to the random sequence. Lastly, development of an optogenetic approach to inactivate AC in the ferret paves the way for future work to probe the causal involvement of these brain regions

Do not waste your electrodes - Principles of optimal electrode geometry for spike sorting

Objective: This study examines how the geometrical arrangement of electrodes influences spike sorting efficiency, and attempts to formalise principles for the design of electrode systems enabling optimal spike sorting performance. Approach: The clustering performance of KlustaKwik, a popular toolbox, was evaluated using semi-artificial multi-channel data, generated from a library of real spike waveforms recorded in the CA1 region of mouse Hippocampus in vivo. Main results: Based on spike sorting results under various channel configurations and signal levels, a simple model was established to describe the efficiency of different electrode geometries. Model parameters can be inferred from existing spike recordings, which allowed quantifying both the cooperative effect between channels and the noise dependence of clustering performance. Significance: Based on the model, analytical and numerical results can be derived for the optimal spacing and arrangement of electrodes for one- and two-dimensional probe systems, targeting specific brain areas