New paper: simulating electrode recordings in the brain

I was at the Organization for Computational Neuroscience annual meeting (CNS 2014) in Quebec City all last week, which I aim to blog about in the near future (if you’re keen you can see my posters on figshare), but before that, I should write about our paper. It’s been available online since the end of May (open access) but I’ve been tidying up bits and pieces of the code so haven’t got round to advertising it much.

The basic motivation behind the paper is the current lack of knowledge about the relationship between the voltage measurements made using extracellular electrodes (local field potentials – LFPs) and the activity of the neurons that underlies those measurements. It is very difficult to infer how currents are flowing in groups of neurons given a set of extracellular voltage measurements, as an infinite number of arrangements of current sources can give rise to the same LFP. Our approach instead was to take a particular pattern of activity in a neural network that was already well characterised experimentally, and to predict given this pattern what the extracellular voltage measurements would be given the physics of current flow in biological tissue. This is the “forward modelling” approach used previously in various studies (see here for a recent review and description of this approach). Our paper describes a simulation tool for performing these simulations (the Virtual Electrode Recording Tool for EXtracellular potentials: VERTEX), as well as some results from a large network model that we compared directly with experimental data.

The simulation tool is written in Matlab (sorry Python aficionados…) and can run in parallel if you have the Parallel Computing Toolbox installed. Matlab is often thought of as being slow, but if you’re cunning you can get things to run surprisingly speedily, which we have managed to do to a reasonable extent with VERTEX I think. You can download it from www.vertexsimulator.org – the download also includes files to run the model described in the paper, as well as some tutorials for setting up simulations. We’ve also made the experimental data available on figshare.

So now you know a little bit about what I was doing all those years up in the City of Dreams…

Reference:

Tomsett RJ, Ainsworth M, Thiele A, Sanayei M et al. Virtual Electrode Recording Tool for EXtracellular potentials (VERTEX): comparing multi-electrode recordings from simulated and biological mammalian cortical tissue. Brain Structure and Function (2014) doi:10.1007/s00429-014-0793-x

Wrong studies: is this how science progresses?

An article by Sylvia McLain in the Guardian’s Science Blogs section yesterday argued against John Ioannidis’ provocative view that “most scientific studies are wrong, and they are wrong because scientists are interested in funding and careers rather than truth.” The comments on the Guardian article are good; I thought I might add a little example of why I think Sylvia is wrong in saying that prevailing trends in published research (that most studies turn out to be wrong) just reflect scientific progress as usual.

There is a debate in the neuroscience literature at the moment regarding the electrical properties of brain tissue. When analysing the frequencies of electrical potential recordings from the brain, it is apparent that higher frequencies are attenuated more than lower frequencies – slower events show up with more power than faster events. The electrical properties of brain tissue affect the measured potentials, so it is important to know what these properties are so that the recordings can be properly interpreted. Currently, two theories can explain the observed data: the high-frequency reduction is a result of the properties of the space around neurons (made up mostly of glial cells), which result in a varying impedance that attenuates higher frequencies; or it is a result of passive neuronal membrane properties and the physics of current flow through neurons’ dendrites, and the space around neurons doesn’t have an effect. Both of these explanations are plausible, both are supported by theoretical models, and both have some experimental data supporting them. This is a good case of scientific disagreement, which will be resolved by further more refined models and experiments (I’ll put some links below). It could be that aspects of both theory become accepted, or that one is rejected outright. In that case, the studies will have been shown to be “wrong”, but that is besides the point. They will have advanced scientific knowledge by providing alternative plausible and testable theories to explore.

The kind of “wrong” study that Ioannidis describes is quite different. His hypothesis is that many positive findings are results of publication bias. High profile journals want to publish exciting results, and exciting results are usually positive findings (“we found no effect” is rarely exciting). Scientists are under pressure to publish in high profile journals in order to progress in their careers (in some cases even just to graduate), so are incentivised to fudge statistics, fish for p-values, or just not publish their negative results (not to mention the problems inherent in null hypothesis testing, which are often ignored or not known about by many study designers). Pharmaceutical companies have further obvious incentives only to publish positive results from trials (visit www.alltrials.net !). This doesn’t lead to a healthy environment for scientific debate between theories; it distorts the literature and hinders scientific progress by allowing scientists and doctors to become distracted by spurious results. It is not – or should not be – “business as usual”, but is a result of the incentive structure scientists currently face.

Hopefully it’s clear why the second kind of wrong is much more damaging than the first kind (the first is healthy), and that’s why I think Sylvia’s Guardian piece is a bit wrong. Changing the incentives is a tricky matter that I won’t go into now, but as an early career researcher it’s something I don’t feel I have a lot of power over.

REFERENCES
Note: this is far from comprehensive and mostly focuses on the work of two groups

References in support of the variable impedance of brain tissue causing the low-pass filtering of brain recordings:
Modeling Extracellular Field Potentials and the Frequency-Filtering Properties of Extracellular Space
Model of low-pass filtering of local field potentials in brain tissue
Evidence for frequency-dependent extracellular impedance from the transfer function between extracellular and intracellular potentials
Comparative power spectral analysis of simultaneous elecroencephalographic and magnetoencephalographic recordings in humans suggests non-resistive extracellular media

References in support of intrinsic dendritic filtering properties causing the low-pass filtering of brain recordings:
Amplitude Variability and Extracellular Low-Pass Filtering of Neuronal Spikes
Intrinsic dendritic filtering gives low-pass power spectra of local field potentials
Frequency Dependence of Signal Power and Spatial Reach of the Local Field Potential
In Vivo Measurement of Cortical Impedance Spectrum in Monkeys: Implications for Signal Propagation (this is, as far as I know, the most recent direct experimental study measuring the impedance of brain tissue, finding that the impedance is frequency-independent)