It’s been about two weeks since I first set out my bucket, although I had to move it to a less obtrusive location. Still no signs of mosquito larvae, although judging from my bite frequency even with mosquito repellant, mosquito activity is still high in my garden. I see the occasional insect trapped (they are not really floating since at their size water is highly viscous) in the surface and there is a nice collection of plant debris at the bottom. The water level seems a little bit higher. It has rained at least once every two days since my first post although it has also been very hot so the input seems mostly balanced by the evaporative loss. I’m starting to believe that mosquitos have their prefered gestation grounds that they perpetually use and only exploit new locales when necessary.
Here is an audio recording synchronized to slides of my talk a week and a half ago in Pittsburgh. I noticed some places where I said the wrong thing such as conflating neuron with synapse. I also did not explain the learning part very well. I should point out that we are not applying a control to the network. We train a set of weights so that given some initial condition, the neuron firing rates follow a specified target pattern. I also made a joke that implied that the Recursive Least Squares algorithm dates to 1972. That is not correct. It goes back much further back than that. I also take a pot shot at physicists. It was meant as a joke of course and describes many of my own papers.
You should listen to this podcast from Quirks and Quarks about how University of Calgary scientist Judit Smits is trying to use selenium rich lentils from Saskatchewan, Canada to treat arsenic poisoning in Bangladesh. Well water in parts of rural Bangladesh have high levels of natural arsenic and this is a major health problem. Professor Smits, who is actually in the department of veterinary medicine, has done work using arsenic to treat selenium poisoning in animals. It turns out that arsenic and selenium, both of which can be toxic in high doses, effectively neutralize each other. They each seem to increase excretion of the other into the bile. So she hypothesized that selenium might counter arsenic poisoning but the interaction is nontrivial so it is not a certainty that it would work. Dr. Smits organized a study to transport ten tons of lentils from Canada to Bangladesh this past summer to test the hypothesis and you can hear about the trials and tribulations of getting the study done. The results are not yet in but I think this is a perfect example of how cleverness combined with determination can make a real difference. This study is funded entirely from Canadian sources but it sounds like something the Gates and Clinton foundations could be interested in.
2016-9-26. Corrected a typo, changed Saskatchewan to Bangladesh
I have read two essays in the past month on the brain and consciousness and I think both point to examples of why consciousness per se and the “problem of consciousness” are both so confusing and hard to understand. The first article is by philosopher Galen Strawson in The Stone series of the New York Times. Strawson takes issue with the supposed conventional wisdom that consciousness is extremely mysterious and cannot be easily reconciled with materialism. He argues that the problem isn’t about consciousness, which is certainly real, but rather matter, for which we have no “true” understanding. We know what consciousness is since that is all we experience but physics can only explain how matter behaves. We have no grasp whatsoever of the essence of matter. Hence, it is not clear that consciousness is at odds with matter since we don’t understand matter.
I think Strawson’s argument is mostly sound but he misses on the crucial open question of consciousness. It is true that we don’t have an understanding of the true essence of matter and we probably never will but that is not why consciousness is mysterious. The problem is that we do now know whether the rules that govern matter, be they classical mechanics, quantum mechanics, statistical mechanics, or general relativity, could give rise to a subjective conscious experience. Our understanding of the world is good enough for us to build bridges, cars, computers and launch a spacecraft 4 billion kilometers to Pluto, take photos, and send them back. We can predict the weather with great accuracy for up to a week. We can treat infectious diseases and repair the heart. We can breed super chickens and grow copious amounts of corn. However, we have no idea how these rules can explain consciousness and more importantly we do not know whether these rules are sufficient to understand consciousness or whether we need a different set of rules or reality or whatever. One of the biggest lessons of the twentieth century is that knowing the rules does not mean you can predict the outcome of the rules. Not even taking into the computability and decidability results of Turing and Gödel, it is still not clear how to go from the microscopic dynamics of molecules to the Navier-Stokes equation for macroscopic fluid flow and how to get from Navier-Stokes to the turbulent flow of a river. Likewise, it is hard to understand how the liver works, much less the brain, starting from molecules or even cells. Thus, it is possible that consciousness is an emergent phenomenon of the rules that we already know, like wetness or a hurricane. We simply do not know and are not even close to knowing. This is the hard problem of consciousness.
The second article is by psychologist Robert Epstein in the online magazine Aeon. In this article, Epstein rails against the use of computers and information processing as a metaphor for how the brain works. He argues that this type of restricted thinking is why we can’t seem to make any progress understanding the brain or consciousness. Unfortunately, Epstein seems to completely misunderstand what computers are and what information processing means.
Firstly, a computation does not necessarily imply a symbolic processing machine like a von Neumann computer with a central processor, memory, inputs and outputs. A computation in the Turing sense is simply about finding or constructing a desired function from one countable set to another. Now, the brain certainly performs computations; any time we identify an object in an image or have a conversation, the brain is performing a computation. You can couch it in whatever language you like but it is a computation. Additionally, the whole point of a universal computer is that it can perform any computation. Computations are not tied to implementations. I can always simulate whatever (computable) system you want on a computer. Neural networks and deep learning are not symbolic computations per se but they can be implemented on a von Neumann computer. We may not know what the brain is doing but it certainly involves computation of some sort. Any thing that can sense the environment and react is making a computation. Bacteria can compute. Molecules compute. However, that is not to say that everything a brain does can be encapsulated by Turing universal computation. For example, Penrose believes that the brain is not computable although as I argued in a previous post, his argument is not very convincing. It is possible that consciousness is beyond the realm of computation and thus would entail very different physics. However, we have yet to find an example of a real physical phenomenon that is not computable.
Secondly, the brain processes information by definition. Information in both the Shannon and Fisher senses is a measure of uncertainty reduction. For example, in order to meet someone for coffee you need at least two pieces of information, where and when. Before you received that information your uncertainty was huge since there were so many possible places and times the meeting could take place. After receiving the information your uncertainty was eliminated. Just knowing it will be on Thursday is already a big decrease in uncertainty and an increase in information. Much of the brain’s job at least for cognition is about uncertainly reduction. When you are searching for your friend in the crowded cafe, you are eliminating possibilities and reducing uncertainty. The big mistake that Epstein makes is conflating an example with the phenomenon. Your brain does not need to function like your smartphone to perform computations or information processing. Computation and information theory are two of the most important mathematical tools we have for analyzing cognition.
Shashaank Vattikuti , Phyllis Thangaraj, Hua W. Xie, Stephen J. Gotts, Alex Martin, Carson C. Chow. Canonical Cortical Circuit Model Explains Rivalry, Intermittent Rivalry, and Rivalry Memory. PLoS Computational Biology (2016).
It has been shown that the same canonical cortical circuit model with mutual inhibition and a fatigue process can explain perceptual rivalry and other neurophysiological responses to a range of static stimuli. However, it has been proposed that this model cannot explain responses to dynamic inputs such as found in intermittent rivalry and rivalry memory, where maintenance of a percept when the stimulus is absent is required. This challenges the universality of the basic canonical cortical circuit. Here, we show that by including an overlooked realistic small nonspecific background neural activity, the same basic model can reproduce intermittent rivalry and rivalry memory without compromising static rivalry and other cortical phenomena. The background activity induces a mutual-inhibition mechanism for short-term memory, which is robust to noise and where fine-tuning of recurrent excitation or inclusion of sub-threshold currents or synaptic facilitation is unnecessary. We prove existence conditions for the mechanism and show that it can explain experimental results from the quartet apparent motion illusion, which is a prototypical intermittent rivalry stimulus.
When the brain is presented with an ambiguous stimulus like the Necker cube or what is known as the quartet illusion, the perception will alternate or rival between the possible interpretations. There are neurons in the brain whose activity is correlated with the perception and not the stimulus. Hence, perceptual rivalry provides a unique probe of cortical function and could possibly serve as a diagnostic tool for cognitive disorders such as autism. A mathematical model based on the known biology of the brain has been developed to account for perceptual rivalry when the stimulus is static. The basic model also accounts for other neural responses to stimuli that do not elicit rivalry. However, these models cannot explain illusions where the stimulus is intermittently switched on and off and the same perception returns after an off period because there is no built-in mechanism to hold the memory. Here, we show that the inclusion of experimentally observed low-level background neural activity is sufficient to explain rivalry for static inputs, and rivalry for intermittent inputs. We validate the model with new experiments.
This paper is the latest of a continuing series of papers outlining how a canonical cortical circuit of excitatory and inhibitory cells can explain psychophysical and electrophysiological data of perceptual and cortical dynamics under a wide range of stimuli and conditions. I’ve summarized some of the work before (e.g. see here). In this particular paper, we show how the same circuit previously shown to explain winner-take-all behavior, normalization, and oscillations at various time scales, can also possess memory in the absence of input. Previous work has shown that if you have a circuit with effective mutual inhibition between two pools representing different percepts and include some type of fatigue process such as synaptic depression or spike frequency adaptation, then the circuit exhibits various dynamics depending on the parameters and input conditions. If the inhibition strength is relatively low and the two pools receive equal inputs then the model will have a symmetric fixed point where both pools are equally active. As the inhibition strength (or input strength) increases, then there can be a bifurcation to oscillations between the two pools with a frequency that is dependent on the strengths of inhibition, recurrent excitation, input, and the time constant of the fatigue process. A further increase in inhibition leads to a bifurcation to a winner-take-all (WTA) state where one of the pools dominates the others. However, the same circuit would be expected to not possess “rivalry memory”, where the same percept returns after the stimulus is completely removed for a duration that is long compared to the average oscillation period (dominance time). The reason is that during rivalry, the dominant pool is weakened while the suppressed pool is strengthened by the fatigue process. Thus when the stimulus is removed and returned, the suppressed pool would be expected to win the competition and become dominant. This reasoning had led people, including myself, to believe that rivalry memory could not be explained by this same model.
However, one thing Shashaank observed and that I hadn’t really noticed before was that the winner-take-all state can persist for arbitrarily low input strength. We prove a little theorem in the paper showing that if the gain function (or FI curve) is concave (i.e. does not bend up), then the winner-take-all will persist for arbitrarily low input if the inhibition is strong enough. Most importantly, the input does not need to be tuned and could be provided by the natural background activity known to exist in the brain. Even zero mean noise is sufficient to maintain the WTA state. This low-activity WTA state can then serve as a memory since whatever was active during a state with strong input can remain active when the input is turned off and the neurons just receive low level background activity. It is thus a purely mutual inhibition maintained memory. We dubbed this “topological memory” because it is like a kink in the carpet that never disappears and persists over a wide range of parameter values and input strengths. Although, we only consider rivalry memory in this paper, the mechanism could also apply in other contexts such as working memory. In this paper, we also focus on a specific rivalry illusion called the quartet illusion, which makes the model slightly more complicated but we show how it naturally reduces to a two pool model. We are currently finishing a paper quantifying precisely how excitatory and inhibitory strengths affect rivalry and other cortical phenomena so watch this space. We also have submitted an abstract to neuroscience demonstrating how you can get WTA and rivalry in a balanced-state network.
Update: link to paper is fixed.
Pradhan MA1, Blackford JA Jr1, Devaiah BN2, Thompson PS2, Chow CC3, Singer DS2, Simons SS Jr4. Kinetically Defined Mechanisms and Positions of Action of Two New Modulators of Glucocorticoid Receptor-regulated Gene Induction. J Biol Chem. 2016 Jan 1;291(1):342-54. doi: 10.1074/jbc.M115.683722. Epub 2015 Oct 26.
Abstract: Most of the steps in, and many of the factors contributing to, glucocorticoid receptor (GR)-regulated gene induction are currently unknown. A competition assay, based on a validated chemical kinetic model of steroid hormone action, is now used to identify two new factors (BRD4 and negative elongation factor (NELF)-E) and to define their sites and mechanisms of action. BRD4 is a kinase involved in numerous initial steps of gene induction. Consistent with its complicated biochemistry, BRD4 is shown to alter both the maximal activity (Amax) and the steroid concentration required for half-maximal induction (EC50) of GR-mediated gene expression by acting at a minimum of three different kinetically defined steps. The action at two of these steps is dependent on BRD4 concentration, whereas the third step requires the association of BRD4 with P-TEFb. BRD4 is also found to bind to NELF-E, a component of the NELF complex. Unexpectedly, NELF-E modifies GR induction in a manner that is independent of the NELF complex. Several of the kinetically defined steps of BRD4 in this study are proposed to be related to its known biochemical actions. However, novel actions of BRD4 and of NELF-E in GR-controlled gene induction have been uncovered. The model-based competition assay is also unique in being able to order, for the first time, the sites of action of the various reaction components: GR < Cdk9 < BRD4 ≤ induced gene < NELF-E. This ability to order factor actions will assist efforts to reduce the side effects of steroid treatments.
Li Y, Chow CC, Courville AB, Sumner AE, Periwal V. Modeling glucose and free fatty acid kinetics in glucose and meal tolerance test. Theor Biol Med Model. 2016 Mar 2;13:8. doi: 10.1186/s12976-016-0036-3.
Quantitative evaluation of insulin regulation on plasma glucose and free fatty acid (FFA) in response to external glucose challenge is clinically important to assess the development of insulin resistance (World J Diabetes 1:36-47, 2010). Mathematical minimal models (MMs) based on insulin modified frequently-sampled intravenous glucose tolerance tests (IM-FSIGT) are widely applied to ascertain an insulin sensitivity index (IEEE Rev Biomed Eng 2:54-96, 2009). Furthermore, it is important to investigate insulin regulation on glucose and FFA in postprandial state as a normal physiological condition. A simple way to calculate the appearance rate (Ra) of glucose and FFA would be especially helpful to evaluate glucose and FFA kinetics for clinical applications.
A new MM is developed to simulate the insulin modulation of plasma glucose and FFA, combining IM-FSIGT with a mixed meal tolerance test (MT). A novel simple functional form for the appearance rate (Ra) of glucose or FFA in the MT is developed. Model results are compared with two other models for data obtained from 28 non-diabetic women (13 African American, 15 white).
The new functional form for Ra of glucose is an acceptable empirical approximation to the experimental Ra for a subset of individuals. When both glucose and FFA are included in FSIGT and MT, the new model is preferred using the Bayes Information Criterion (BIC).
Model simulations show that the new MM allows consistent application to both IM-FSIGT and MT data, balancing model complexity and data fitting. While the appearance of glucose in the circulation has an important effect on FFA kinetics in MT, the rate of appearance of FFA can be neglected for the time-period modeled.
Another brilliant op-ed by Franz de Waal in the Times.