This work was supported by NSERC Discovery grants to AL and AG.

All procedures described here were performed under an Animal Research Protocol approved by the University of Lethbridge Animal Welfare Committee.
1. Surgery
NOTE: The surgery procedures used to implant probes for neurophysiological recordings have been presented in other publications24,25,26. The exact details of the surgery for closed-loop stimulation depend on the type of r...

<ol>
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Authors do not have any conflict of interests related to this work.

The protocol described here, shows how to use a standard neurophysiological recording system to perform closed-loop stimulation. This protocol allows neuroscientists with limited expertise in computer science to rapidly implement a variety of closed-loop experiments with little cost. Such experiments are often necessary to study causal interactions in the brain.
After preparing an animal and installing the software (Steps 1 &amp; 2), the closed-loop experiment consists of two separate stages. ...

The goal of this protocol is to demonstrate how to implement closed-loop stimulation in neurophysiological experiments. The typical setup for closed-loop experiments in neuroscience involves triggering stimuli based on the online readout of neuronal activity. This, in turn, causes modifications in the brain activity, thus closing the feedback loop1,2. Such closed-loop experiments provide multiple benefits over standard open-loop setups, especially when combined with optogenetics, which allows researchers to target a specific subset of neurons. For example, Siegle and Wilson used closed-loop manipulations to study the role of theta oscillations in information processing3. They demonstrated that stimulating hippocampal neurons on the falling phase of theta oscillations had different effects on behavior than applying the same stimulation on the rising phase. Closed-loop experiments are also becoming increasingly important in preclinical studies. For instance, multiple epilepsy studies have shown that neuronal stimulation triggered on seizure onset is an effective approach to reduce the severity of seizures4,5,6. Moreover, systems for automated seizure detection and the contingent delivery of therapy7,8 showed significant benefits in epilepsy patients9,10,11,12. Another application area with rapid advancement of closed-loop methodologies is the control of neuroprosthetics with cortical brain&#8211;machine interfaces. This is because providing instantaneous feedback to users of prosthetic devices significantly improves accuracy and capability13.
In recent years, several labs have developed custom systems for the simultaneous electrical recording of neuronal activity and delivery of stimuli in a closed-loop system14,15,16,17,18. Although many of those setups have impressive characteristics, it is not always easy to implement them in other labs. This is because the systems often demand experienced technicians to assemble the required electronics and other necessary hardware and software components.
Therefore, in order to facilitate the adoption of closed-loop experiments in neuroscience research, this paper provides a protocol and Matlab code to convert an open-loop electrophysiological recording setup19,20,21,22 into a closed-loop system2,6,23. This protocol is designed to work with the Digital Lynx recording hardware, a popular laboratory system for neuronal population recordings. A typical experiment consists of the following: 1) Recording 5-20 minutes of spiking data; 2) Spike sorting to create neuronal templates; 3) Using these templates to perform online detection of neural activity patterns; and 4) Triggering stimulation or experimental events when user-specified patterns are detected.

<table>
	<tbody>
		<tr>
			<td>Baytril</td>
			<td>Bayer, Mississauga, CA</td>
			<td>DIN 02169428</td>
			<td>antibiotic; 50 mg/mL</td>
		</tr>
		<tr>
			<td>Cheetah 6.4</td>
			<td>NeuraLynx, Tucson, AZ</td>
			<td>6.4.0.beta</td>
			<td>Software interfaces for data acquisition&#160;</td>
		</tr>
		<tr>
			<td>Digital Lynx 4SX</td>
			<td>NeuraLynx, Tucson, AZ</td>
			<td>4SX</td>
			<td>recording equipment</td>
		</tr>
		<tr>
			<td>Headstage transmitter</td>
			<td>TBSI</td>
			<td>B10-3163-GK</td>
			<td>transmits the neural signal to the receiver</td>
		</tr>
		<tr>
			<td>Isoflurane</td>
			<td>Fresenius Kabi, Toronto, CA</td>
			<td>DIN 02237518</td>
			<td>inhalation anesthetic</td>
		</tr>
		<tr>
			<td>Jet Denture Powder &#38; Liqud</td>
			<td>Lang Dental, Wheeling, US</td>
			<td>1230</td>
			<td>dental acrylic</td>
		</tr>
		<tr>
			<td>Lacri-Lube</td>
			<td>Allergan, Markham, CA</td>
			<td>DIN 00210889</td>
			<td>eye ointment</td>
		</tr>
		<tr>
			<td>Lido-2</td>
			<td>Rafter 8, Calgary</td>
			<td>DIN 00654639</td>
			<td>local anesthetic; 20 mg/mL</td>
		</tr>
		<tr>
			<td>Matlab</td>
			<td>Mathworks</td>
			<td>R2018b</td>
			<td>software for signal processing and triggering external events</td>
		</tr>
		<tr>
			<td>Metacam</td>
			<td>Boehringer, Ingelheim, DE</td>
			<td>DIN 02240463</td>
			<td>analgesic; 5 mg/mL</td>
		</tr>
		<tr>
			<td>Netcom</td>
			<td>NeuraLynx</td>
			<td>v1</td>
			<td>Application Programming Interface (API) that communicates with Cheetah</td>
		</tr>
		<tr>
			<td>Silicone probe</td>
			<td>Cambridge Neurotech</td>
			<td>ASSY-156-DBC2</td>
			<td>implanted device</td>
		</tr>
		<tr>
			<td>SpikeSort 3D&#160;</td>
			<td>NeuraLynx, Tucson, AZ</td>
			<td>SS3D</td>
			<td>spike waveform-to-cell classification tools</td>
		</tr>
		<tr>
			<td>Wireless Radio Receiver</td>
			<td>TBSI</td>
			<td>911-1062-00</td>
			<td>transmits the neural signal to the Digital Lynx</td>
		</tr>
	</tbody>
</table>

using neuron spiking activity to trigger closed-loop stimuli in neurophysiological experiments

Closed-loop neurophysiological systems use patterns of neuronal activity to trigger stimuli, which in turn affect brain activity. Such closed-loop systems are already found in clinical applications, and are important tools for basic brain research. A particularly interesting recent development is the integration of closed-loop approaches with optogenetics, such that specific patterns of neuronal activity can trigger optical stimulation of selected neuronal groups. However, setting up an electrophysiological system for closed-loop experiments can be difficult. Here, a ready-to-apply Matlab code is provided for triggering stimuli based on the activity of single or multiple neurons. This sample code can be easily modified based on individual needs. For instance, it shows how to trigger sound stimuli and how to change it to trigger an external device connected to a PC serial port. The presented protocol is designed to work with a popular neuronal recording system for animal studies (Neuralynx). The implementation of closed-loop stimulation is demonstrated in an awake rat.

Fisher-Brown Norway rats born and raised on-site were habituated to handling for two weeks prior to the experiment. A recording drive was surgically implanted, similar to methods described previously28,29,30,31,32,33,34. The neuronal signals were recorded at 32 kHz with a digital acquisition...

Watch this Scientific Journal Video about Using Neuron Spiking Activity to Trigger Closed-Loop Stimuli in Neurophysiological Experiments at JoVE.com

Using Neuron Spiking Activity to Trigger Closed-Loop Stimuli in Neurophysiological Experiments

This protocol demonstrates how to use an electrophysiological system for closed-loop stimulation triggered by neuronal activity patterns. Sample Matlab code that can be easily modified for different stimulation devices is also provided.

Closed-loop neurophysiological systems use patterns of neuronal activity to trigger stimuli, which in turn affect brain activity. Such closed-loop systems ...

This standard neurophysiological recording system can be used to perform a closed-loop stimulation which is useful for studying causal interactions in the brain. This protocol allows neuroscientists with only limited expertise in computer science to rapidly implement a variety of closed-loop experiments with little cost. Closed-loop experiments have becaming increasingly important for basic science and research.For instance, multiple epilepsy studies have shown that neuron stimulation trigger on seizure onset is an an effective approach to reduce the severity of seizures. To facilitate the adoption of closed-loop experiments in neuroscience research, this protocol provides MATLAB code to convert an open-loop electrophysiological recording system into a closed-loop system. This implementation of closed-loop stimulation is demonstrated in an awake rat.To install the Cheetah 6.4 Data Acquisition System, open the webpage for the software which includes libraries to interact with the Cheetah acquisitions system, and install SpikeSort-3D. Install the NetCom Development Package. Login to a MATLAB account to select the correct license, version, and operating system.Then, download the library for online event triggering as indicated and extract the files to the documents MATLAB folder. For data acquisition, open the Cheetah software and record spiking data to populate the template waveforms. After a few minutes, stop the data acquisition and perform a SpikeSort on the recorded data.Next, open SpikeSort3-D and click file menu and load spike file To select a spike file from the folder with the recorded data. Then, click cluster menu, autocluster using KlustaKwik, and run. To perform a closed-loop experiment, resume the data acquisition in Cheetah, and open MATLAB.Open ClosedLoop. M and click run. Alternatively, execute closed-loop in the command window.Browse to the recording folder and select one of the spiking data files to load the spike information defined in the initial recording. Click the appropriate check boxes under the plotted waveforms to select one or multiple neurons that will trigger stimulation. Define the minimum number of neurons that will trigger stimulation by entering an integer in the min matches text box and define the time window in which the spikes matching the different waveforms are considered coactive by entering a number into the window text box.Then, click send to begin the online triggering of events based on the spiking activity of the selected neurons. In this representative experiment, the rat was rested on a flower pot which was a familiar resting place during breaks in the behavioral experiments. Here, a representative simultaneous running of the recording software and the MATLAB program which displays spike waveforms acquired in real time can be observed.When spikes from predefined triggering clusters are detected, the waveforms are displayed with a bold dash line in the MATLAB figure window triggering a tone and providing a closed-loop system. In this figure, a representative histogram illustrating the delays between the time of generating an artificial spike and the time of inducing a triggered signal are shown. After preparing an animal, and installing the software, the closed-loop experiment consists of two main stages, the initial data acquisition and the closed-loop stimulation during which spikes trigger external stimuli.This protocol also allows the treating of a stimuli based on the activity of multiple neurons which is important for addressing questions about information processing in the brain. The advantages of this MATLAB solution are its low cost and flexibility in defining the activity patterns to trigger stimuli which can help in investigating a variety of neuroscientific questions.

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JoVE Journal

Neuroscience

6.9K 조회수.  University of Lethbridge. 이 표준 신경 생리적 기록 시스템은 뇌의 인과 상호 작용을 연구하는 데 유용한 폐쇄 루프 자극을 수행하는 데 사용할 수 있습니다. 이 프로토콜을 통해 컴퓨터 과학에 대한 전문 지식이 부족한 신경 과학자들은 약간의 비용으로 다양한 폐쇄 루프 실험을 신속하게 구현할 수 있습니다. 폐쇄 루프 실험은 기초 과학 및 연구에 점점 더 중요해지고 있습니다.예를 들면, 다중...