Computational neuroscience is not only about making theories. A large part of the field is also about simulations of neural models on a computer. In fact, there is little theoretical work in neuroscience that does not involve simulations at some stage. The epistemological status of simulations is quite interesting, and studies about it in philosophy of knowledge are quite recent. There is for example the work of Eric Winsberg, but I believe it mostly addresses questions related to physics. In particular, he starts one of his most cited papers (“Simulations, models and theories”, 2001) by stating: “I will be talking about the use of computers for modeling very complex physical phenomena for which there already exist good, well-understood theories of the processes underlying the phenomena in question”. This is an important distinction, and I will come back to it.

What is interesting about simulations from an epistemological viewpoint is that from a strictly Popperian viewpoint, simulation is useless. Indeed it looks like a sort of experiment, but there is no interaction with the world. It starts from a theory and a set of factual statements, and derives another set of factual statements. It is neither the making of a theory (no universal statement is produced), nor the test of a theory. So why is it that simulation is used so broadly?

In fact there are different types of simulation work. Broadly speaking, we may think of two categories: theory-driven simulations, and data-driven simulations.

I will start with theory-driven simulations. There are in fact two different motivations to use simulations in theoretical work. One is exploratory: simulations are used in the process of making theories, because the models are so complex so that it may be difficult to predict their behavior. This is a general problem with so-called complex systems. Simulations are then used for example to explore the effect of various parameters on the behavior of the model, or to see whether some property can appear given a set of rules, etc. Another motivation is to test a theory. Now this may seem odd since we are not speaking of an empirical test. First of all, this apparent oddity perhaps stems from the myth that theoretical work is essentially about making logical deductions from initial statements. But in reality, especially in biology where models can be very complex, theoretical work almost invariably involves some guess work, approximations, and sometimes vaguely justified intuitions. Therefore, it makes sense to check the validity of these approximations in a number of scenarios. For example, in my paper with Jonathan Platkiewicz about the spike threshold, we derived an equation for the spike threshold from the Hodgkin-Huxley equations. It involved approximations of the sodium current, and we also developed the theory in an isopotential neuron. Therefore in that paper, we checked the theory against the numerical simulation of a complex multicompartmental neuron model, and it was not obvious that it would work.

There is another motivation, which is more specific to computational neuroscience. Theories in this field are about how the interaction of neurons produces behavior, or in other words, about linking physiology, at the neuron level, and function, at the systems or organism level. But to speak of function, one needs an environment. This external element is not part of the neural model, yet it is critical to the relevance of the model. Theories generally do not include explicit models of the environment, or only simplistic versions. For example, in my paper about sound localization with Dan Goodman, we proposed a mechanism by which selective synchrony occurs when a sound is presented at specific locations, leading to a simple spiking model that can accurately estimation the location of a sound source in the presence of realistic diffraction properties. In principle it works perfectly, but of course in a real environment the acoustical signals are unknown, but not arbitrary, they may have a limited spectrum, there may be noise, diffraction properties are also unknown but not arbitrary, there may be ambiguities (e.g. the cones of confusion), etc. For this reason, the model needed to be implemented and its performance tested, which we did with recorded sounds, measured acoustical filters and acoustical noise. Thus it appears that even for theory-driven work, simulation is unavoidable because the theory applies to the interaction with an unknown, complex environment. In fact, ideally, models should be simulated, embodied (in a robot) and allowed to interact with a real (non simulated) environment. Since theories in computational neuroscience claim to link physiology and function, this would be the kind of empirical work required to substantiate such claims.

The other type of simulation work is data-driven. I believe this is usually what is meant by “simulation-based science”. In this kind work, there is little specific theory – that is, only established theories are used, such as cable equation theory. Instead, models are built based on measurements. The simulations are then truly used as a kind of experiment, to observe what might emerge from the complex interaction of neuron models. It is sometimes said that simulations are used to do “virtual experiments” when the actual experiments would be impractical. Another typical use is to test the behavior of a complex model when parameters are varied in a range that is considered plausible.

In physics, such computer simulations are also used, for example to simulate the explosion of a nuclear bomb. But as Winsberg noted, there is a very important epistemological distinction between simulations in physics and in biology: in the former, there is an extremely detailed knowledge of both the laws that govern the underlying processes and of the arrangement of the individual elements in the simulations. Note that even in this case, the value of such simulations is controversial. But in the case of biology and especially neuroscience, the situation is quite different. It is in fact acknowledged by the typical use cases mentioned above.

Consider the statement that a simulation is used to perform a “virtual experiment” when actual experiments are impractical. This seems similar to the simulation of a nuclear explosion. In that case, one is interested in the large scale behavior of the system, and at such a large scale the experiment is difficult to do. But in neuroscience, the situation is exactly the opposite. The experiment with a full organism is actually what is easy to do (or at least feasible), it is a behavioral experiment. So simulations are not used to observe how an animal behaves. They are used to observe the microstructure of the system. But then this means that this microstructure was not known at the time when the model was built, and so these properties that are to be observed are considered as sufficiently constrained by the initial set of measurements to be derived from them.

The second, and generally complementary, use case is to simulate the model while varying a number of parameters so as to find the viable region in which the model produces results consistent with some higher-order measurements (for example, local field potentials). If the parameters are varied, then this means they are actually not known with great certainty. Thus it is clear that biophysical models based on measurements are in fact much less reliable than physical models such as those of nuclear explosions.

One source of uncertainty is the values of parameters in the models, for example channel densities. This is already one great problem. Probably the biggest issue here is not so much the uncertainty about parameters, which is an issue in models of all fields, but the fact the parameters are most likely not independent, i.e., they covary in a given cell or between cells. This lack of independence comes from the fact that the model is of a living thing, and in a living thing all components and processes contribute to the function of the organism, which implies tight relations between them. The study of these relations is a defining part of biology as a field, but if a model does not explicitly include these relations, then it would seem extraordinary that proper function can arise without them, given that they are hidden under the uncertainty in the parameters. For example, consider action potential generation. Sodium channels are responsible for initiation, potassium channels for repolarization. There are a number of recent studies showing that their properties and densities are precisely tuned with respect to each other so that energy consumption is minimized: indeed energy is lost if they are simultaneously open because they have opposite effects. If this functional relation were unknown and only channel densities were known within some range, then the coordination would go unnoticed and a naive model simply using independent values from these distributions would display inefficient action potential generation, unlike real neurons.

I will try to summarize the above point. Such simulations are based on the assumption that the laws that govern the underlying processes are very well understood. This may well be true for the laws of neural electricity (cable equations, Hodgkin-Huxley equations). However, in biology in general and in neuroscience in particular, the relevant laws are also those that describe the relations between the different elements of the model. This is a completely different set of laws. For the example of action potential generation, the laws are related to the co-expression of channels, which is more related to the molecular machinery of the cell than to its electrical properties.

Now these laws, which relate to the molecular and genetic machinery, are certainly not so well known. And yet, they are more relevant to what defines a living thing than those describing the propagation of electrical activity, since indeed these are the laws that maintain the structure that maintain the cells alive. Thus, models based on measurements attempt to reproduce biological function without capturing the logics of the living, and this seems rather hopeful. There are also many examples in recent research that show that the knowledge we have of neural function is rather poor, compared to what is to be found. For example, glial cells (which make most of the cells in the brain) are now thought to play a much more important role in brain function than before, and these are generally ignored in models. Another example is in action potential initiation. Detailed biophysical models are based on morphological reconstructions of the axon, but in fact in the axon initial segment, there is also a scaffold that presumably alters the electrical properties along the axon (for example the axial resistivity should be higher).

All these remarks are meant to point out that in fact, it is illusory to think that there are, or will be in the near future, realistic models of neural networks based on measurements. What is worse, such models seem to miss a critical point in the study of living systems: these are not defined only by their structure (values of parameters, shape of cells) but by processes to maintain that structure and produce function. To quote Maturana (1974), there is a difference between the structure (channel densities etc) and the organization, which is the set of processes that set up that structure, and it is the organization, not the structure, that defines a living thing. Epistemologically speaking, the idea that things not accessible to experiment can be simulated based on measurements that constrain a model is induction. But the predictive power of induction is rather limited when there is such uncertainty.

I do not want to sound as if I were entirely dismissing data-driven simulations. Such simulations can still be useful, as an exploratory tool. For example, one may simulate a neuron using measured channel densities and test whether the results are consistent with what the actual cell does. If they are not, then we know we are missing some important property. But it is wrong to claim that such models are more realistic because they are based on measurements. On one hand, they are based on empirical measurements, on the other hand, they are dismissing mechanisms (or “principles”), which is another empirical aspect to be accounted for in living things. I will come back in a later post to the notion of “realistic model”.