Skip to main content

It ain't what you don't know that gets you into trouble. It's what you know for sure that just ain't so.

-- Mark Twain

So far, most of the posts in this blog have been focused on building a 'bottom-up' understanding of how the brain works - from how DNA works up to how individual neurons work. Lots of good science to base all of this stuff on. It is difficult to go further 'up the stack' in this way, however.  How do neurons work together to do useful things? How are small-scale networks of neurons structured and how do the neurons interact in order for us to do simple things like rhythmically tap a finger?
 
Are we there yet?
Every decade or two the scientific community gets wildly optimistic that we will be able to fully understand how cognition works and be able to replicate the process in some non-biological system. It's been named many things over the years - cybernetics, artificial intelligence, computational intelligence, cognitive computing (see http://en.wikipedia.org/wiki/Artificial_intelligence for a nice overview).  And yet, with all of the money that has been poured into this research, we still don't have enough information to build a working model of the few hundred neurons in a worm.(Some great work IS going on in this direction, however - see the Open Worm project.)  


Part of the problem is due to sheer complexity - each neuron can have connections that number in the 100's to 10,000s. Part of it is also due to a number of "things we know for sure that just ain't so." This post will take a step back and try to outline a number of "things we've known for sure" for quite a while that, it turns out, "just ain't so".

The things we take for granted...
As you go through the literature on cognition, you come across a number of fundamental assumptions that are either just taken for granted or have been extensively popularized:
  • neurons are the only cells that are involved in cognition.
  • neurons are connected together in a static, unchanging way.
  • emotions are localized within the limbic system.
  • the early visual cortex contains only 'feedforward' connections and acts as a simple filter bank for image processing
  • neurons work the same way in an anesthetized brain as they do in a behaving brain 
Every now and then, however, you come across some ground-breaking work that takes a fresh look at what is REALLY happening.   Lets take a fresh look at some of these pre-conceived notions, and at how science in general got stuck on them.

Re: Neurons are the only cells that are involved in cognition.
From the excellent book "The Other Brain" - R. Douglas Fields
"How will understanding glia change our understanding of the mind?  Today we know that glia constitute another brain that was ignored for a century or more, a brain new to science.  There, all along, the other brain was simply overlooked.  Why?

To begin with, the wrong tools were used to explore it.  The electrodes of neuroscientists are deaf to glial communication.  Yet the glial brain was indeed communicating; it just works differently from the neuronal brain, communicating in different ways and on different time scales.  But the lack of tools is not the complete answer to why neuroscientists missed half the brain until now.
...
It was our thinking that failed us.  We thought we knew how the brain worked.  Dazzled by the electric neuron, neuroscientists tightened their foucs intensely on this one cell type, virtually ignoring all others even though the other cells are superior in number and diversity to neurons.  Our unconscious biases clouded our perception.  The glial brain simply went unseen.
...
Understandably, research on the "unimportant" cells did not fare well in the fierce competition for precious funds doled out by government committees to support scientific research.  Findings on the "unimportant" cells also lacked the "significance" required for publication in the mainstream journals.
  Suddenly this siutation has changed.  We are experiencing a scientific revolution sparked by a revelation:  We now know that the other brain [glia] works independently but cooperatively with the neuronal brain.
...
The rapid "within an eye blink" functions of our nervous system are actually a narrow slice of cognition.  Many brain functions develop and operate slowly.  Emotions and feelings, cycles of attention, cognitive changes with growth and aging, acquisition of complex skills like playing the guitar operate over time scales where glia excel and control neuronal function.  These slowly changing aspects of brain function are relatively unexplored.  Some would argue that these are the most interesting aspects of the mind.


  Our artificial conceptual division separating the other brain from the neuronal brain is eroding, and as it dissolves, we are recognizing a new brain. The links from glia to disease are obvious: seizure, infection, stroke, neurodegenerative disease, cancer, demylelinating disease, and mental illness all involve many different types of glia, but glia regulate and remodel the brain in health as well as in sickness.  Here the questions that are central to research on the neuronal brain are only now being asked of the other brain.  How plastic are glia?  Do they learn, sleep, age, differ in males and females, become impaired by disease?  How many different kinds of glia are there?
...
   Astrocytes also cover enormous territories in the brain.  An oligodendrocyte ensheathes scores of axons.  Microglia move at will through large regions of the brain.  a single astrocyte can engulf 100,000 synapses.  It seems unliely that one astrocyte is monitoring and dictating the transmission of information individually across the thousands of synapses it surveys.  A more likely possibility is that astrocytes (and other glia) couple large groups of synapses or neurons into functional groups.  This would vastly increase the power and flexibility of information processing in our brains beyond the simple changes in strength of individual synapses along a neural circuit.  Glia give the brain a new dimension of information porocessing.


     The physical dimensons and also the mechanism of communication suggest that glia cover an enormous domain of operation.  The chemical means of cell-cell communication used by glia diffuses widely and across the hardwired lines of neuronal connections.  These features equip glia to control information processing in the brain on a fundamentally different and more global scale than the point-to-point synaptic contacts of neurons.  Such higher level oversight is likely to have significant implications for information processing and cognition.


Re: Neurons are connected together in a static, unchanging way.
From an aside Henry Markram, EPFL/BlueBrain made on "Microcircuit plasticity" 48 minutes into his presentation The Emergence of Intelligence in the Neocortical Microcircuit (video):
"We patched 6 cells, and we see how they're connected so we can define the circuit [they make]. Now we take the pipettes out and we wait 12 hours, and we re-patch it. And what we found is that the circuit was different. Not only after 12 hours but actually after 4 hours. And just to show you how much inertia there is in the current scientific paradigm, [Science magazine] said that this was not interesting. It will come out in PNAS [Proceedings of the National Academy of Sciences] in another 2 months.". (aside: some interesting comments on this work here, including a reference to the PNAS paper). Markram continued: So we do these recordings, and we puff glutamate now [into the circuit] - we actually activate the circuit. We can't still put intelligent stimulus, but we activate the circuit. And when you activate the circuit, here you can see that you have connections appearing and disappearing. This is potentially the substrate that Nobelist Gerry Edelman could use in all kinds of restructuring of the circuitry. Over a 4 hour period you can still see the circuitry is dynamically rewiring. For 50 years we've studied only how synapses are getting stronger and weaker, not how the circuit restructures itself.

    

A somewhat different'rewiring' process involving dendritic spines has also been observed in living, behaving mice. From the HHMI home page for Scientist Karel Svoboda: Karel Svoboda builds windows into the brain—literally, with tiny glass slides he places in the skulls of mice. He peers inside with sophisticated microscopes and watches individual neurons.

"What we've discovered is that new experiences spur new connections in the adult brain," he says. "And that's a mechanism for learning and memory."

While researchers already knew that the adult brain can reorganize in response to new experiences, until Svoboda developed his techniques, no one had seen the process in action.

"We follow individual synapses—the tiny junctions between neurons—day-by-day for a month or more to see if and how new connections form."

Svoboda, who prior to his move to Janelia was an HHMI investigator at Cold Spring Harbor Laboratory, has devised techniques so precise that he can count the number of calcium channels on the tiny spines that reach between neurons to form synapses. Calcium channels can trigger a series of chemical events that ultimately rewires the synapse. Watching the channels' openings and closings provides direct evidence of such activity.

"It's a very powerful technique that can look deep into the brain without disturbing it," he says. "There is something like a hundred billion synapses in the mouse brain and now we have some tricks to locate the same synapse each time we put the mouse under the microscope. It took a while to figure out, but now it's pretty routine."

In a related article, Svoboda provides some of the results that were observed:
"Our first observations of the large-scale structure of neurons, their axons and dendrites, revealed that they were remarkably stable over a month." Dendrites and axons are highly branched structures, where dendrites are the input side of neurons and axons the output side.

"However, when we zoomed in closer, we found that some spines on dendrites appeared and disappeared from day to day," said Svoboda. These spines stipple the surface of dendrites, like twigs from a branch, and form the receiving ends of synapses, which are the junctions between neurons where neurotransmitters are released.

"This finding was quite unexpected, because the traditional view of neural development has been that when animals mature, the formation of synapses ceases, which is indicated by stable synaptic densities," said Svoboda. "However, the flaw in this view has been that a stable density only indicates a balanced rate of birth and death of synapses. It doesn't imply the absence of the formation of new synapses, but it was often interpreted that way...

The researchers also explored whether sensory experiences could affect the turnover of spines. In this set of experiments, they trimmed individual whiskers from the mice, forcing them to experience their environment with a subset of whiskers. This manipulation expands the representation of the intact whiskers at the expense of trimmed whiskers. There was a dramatic effect on spine turn-over.

"We found in these animals that there was a pronounced increase in the rate of birth and death of these synapses, as evidenced by increased turnover of spines," said Svoboda. "This finding indicates that there's a pronounced rewiring of the synaptic circuitry, with the formation of new synapses and the elimination of other synapses," he said...

In one set of experiments, Svoboda's team trimmed the whiskers of their mice. As the mice explored their environment, Svoboda saw "pronounced rewiring." New synapses formed and others disappeared in the part of the brain that receives input from the whiskers.

Re: Emotions are localized within the limbic system:
From the (excellent) book "The Emotional Brain - The Mysterious Underpinnings of Emotional Life" by Joseph LeDoux: The limbic system theory [developed by Paul MacLean in 1952] was a theory of localization. It proposed to tell us where emotion lives in the brain. But MacLean and later enthusiasts of the limbic system have not managed to give us a good way of identifying what parts of the brain actually make up the limbic system.
    MacLean said that the limbic system is made up of phylogenetically old cortex and anatomically related subcortical areas. Phylogenetically old cortex is cortex that was present in very old (in an evolutionary sense) animals. Although these animals are long gone, their distal progeny are around and we dcan look in the brains of living fish, amphibians, birds and reptiles and see what kinds of cortical areas they have and compare these to the kinds of areas that are present in newly evolved creatures - humans and other mammals. When anatomists did this early in the 1900's, they concluded that the lowly animals only have the medial (old) cortex, but mammals have both the medial and lateral (new) cortex.
    This kind of evolutionary neurologic carried the day for a long time, and it was perfectly reasonable for Herrick, Papez, MacLean, and many others to latch on to i. But, by the early 1970s, this view had begun to crumble. Anatomists like Harvey Karten and Glenn Northcutt were showing that so-called primitive creatures do in fact have areas that meet the structural and functional criteria of neurocortex. What had been confusing was that these cortical areas were not exactly in the place that they are in mammals so it was not obvious that they were the same structures. As a result of these discoveries, it is no longer possible to say that some parts of the mammalian cortex were older than other parts. And once the distinction betwen old and new cortex breaks down, the whole concept of mammalian brain evolution is turned on its head. As a result, the evolutionary basis of the limbic lobe, rhinencephalon, visceral brain and limbic system concepts has become suspect.
    Another idea was that the limbic system might be defined on the basis of connectivity with the hypothalamus. After all, this is what led MacLean to the medial cortex in the first place. But with newer, more refined methods, it has been shown that the hypothalamus is connected with all levels of the nervous system, including the neocortex. Connectivity with the hypothalamus turns the limbic system into the entire brain, which doesn't help us very much.
  MacLean also proposed that areas of the limbic system be identified on the basis of their involvement in visceral functions. While it is true that some areas traditionally included in the limbic system contribute to the control of the autonomic nervous system, other areas, like the hippocampus, are now believed to have relatively less involvement in autonomic and emotional functions than in cognition. And other areas not included in the limbic system by anyone (especially areas in the lower brain stem) are primarily involved in autonomic regulation. Visceral regulation ins a poor basis for identifying the limbic system.
    Involvement in emotional functions is, obviously, another way the limbic system has been looked for. If the limbic system is the emotive system, then studies showing which brain areas are involved in emotion should tell us where the limbic system is. But this is backward reasoning. The goal of the limbic system theory was to tell us where emotion is in the brain on the basis of knowing something about the evolution of brain structure. To use research on emotion to find the limbic system turns this criterion around. Research on emotion can tell us where the emotion system is in the brain, but not where the limbic system is. Either the limbic system exists or it does not. Since there are not independent criteria for telling us where it is, I have to say that it does not exist.
    But lets consider the issue of using research on emotion to define the limbic system a little further. MacLean had proposed that the limbic system was the kind of system that would be involved in primitive emotional functions and not in higher thought processes. Recent research is very problematic fort this view. For example, damage to the hippocampus and some regions of the Papez circuit, like the mammillary bodies and anterior thalamus, have relatively little consistent effect on emotional functions but produce pronounced disorders of conscious or declarative memory - the ability to know what you did a few minutes ago and to store that information and retrieve it at some later time and to verbally describe what you remember. These were exactly the kinds of processes that MacLean proposed that the visceral brain and limbic system would not be involved with. The relative absence of involvement in emotion and the clear involvement in cognition are major difficulties for the view that the limbic system, however one chooses to define it, is the emotional brain.

    How, then, has the limbic system theory of emotion survived so long if there is so little evidence for its existence or for its involvement in emotion? There are many explanations that one could come up with. Two seem particularly cogent. One is that, though imprecise, the limbic system term is a useful anatomical shorthand for areas located in the no-man's-land between the hypothalamus and the neocortex, the lowest and highest (in structural terms) regions of the forebrain, respectively. But scientists should be precise. The limbic system term, even when used in a shorthand structural sense, is imprecise and has unwarranted functional (emotional) implications. It should be discarded
    Another explanation for the survival of the limbic system theory of emotion is that it is not completely wrong - some limbic areas have been implicated in emotional functions. Given that the limbic system is a tightly packaged concept (though not a tightly organized, well defined system in the brain), evidence that one limbic area is involved in some emotional process has often been generalized to validate the idea that the limbic system as a whole is involved in emotion. And, by the same token, the demonstration that a limbic region is involved in one emotional process is often generalized to all emotional processes. Through these kinds of poorly reasoned associations, involvement of a particular limbic area in a very specific emotional process has tended to substantiate the view that the limbic system is the emotional brain.
...
  A new approach to the emotional brain is needed.

Re: The early visual cortex contains only 'feedforward' connections and acts as a simple filter bank for image processing
From Computations in the early visual corex - Tai Sing Lee (2003):
In the classical feed-forward, modular view of visual processing, the early visual areas (LGN, V1 and V2) are modules that serve to extract local features, while higher extrastriate areas are responsible for shape inference and invariant object recognition. However, recent findings in primate early visual systems reveal that the computations in the early visual cortex are rather complex and dynamic, as well as interactive and plastic, subject to influence from global context, higher order perceptual inference, task requirement and behavioral experience. The evidence argues that the early visual cortex does not merely participate in the first stage of visual processing, but is involved in many levels of visual computation.
There are also some VERY cool discoveries being made about the role of attention in visual processing, and how attention alters the neural processing of vision. I have a hunch that this concept may apply in other areas like motor control as well. I hope to cover these topics in another post sometime.

Re: Neurons work the same way in anesthetized brains as they do in a behaving brain
From Lamme VAF, Zipser K, Spekreijse H: "Figure-ground activity in primary visual cortex is suppressed by anesthesia." Proc Natl Acad Sci USA 1998, 95:3263-3268 :
Figure–ground-related contextual modulation recorded in V1 from awake and perceiving monkeys is abolished when these animals are anesthetized, whereas RF tuning properties remain unaffected. V1 thus hosts very different types of activity, some of which may not (RF properties) and some of which may very well (contextual modulation) be involved in visual awareness.
Also, see 11:10 mark of David Dalrymple guest lectures in Marvin Minsky's class (http://www.youtube.com/watch?v=xW77lANeJas ), and the book "Beyond Boundaries" by Miguel Nicolelis.

Summary

When you look at all of these considerations together, it becomes apparent why the progress towards a working model of cognition has been so very slow. With the new understandings of the brain that are finally coming to light, hopefully the scientific community can get 'unstuck' from the "nice, easy to understand (and get funding for and get published about) but wrong answers" that have bogged down research for the last few decades and start from a newer, fresher perspective that better reflects the way the brain actually works.

Comments

Popular posts from this blog

Perkinjes and Granules and Schwanns, oh my...

It's tempting to oversimplify things.  Like neurons.  It would be nice if there were one type of neuron, and all you needed to know about how neurons work could be clearly labelled on a diagram of that one type of neuron.  Well, nature LOVES to specialize.  So, before getting deeper into how neurons work, I thought it would be good to take a step back and get some vocabulary in place...The BasicsFrom University of Washington's 'Neuroscience for kids':Neurons come in many different shapes and sizes. Some of the smallest neurons have cell bodies that are only 4 microns wide. Some of the biggest neurons have cell bodies that are 100 microns wide.  Neurons are similar to other cells in the body because: Neurons are surrounded by a cell membrane. Neurons have a nucleus that contains genes. Neurons contain cytoplasm, mitochondria and other "organelles". Neurons carry out basic cellular processes such as protein synthesis and energy production. However, neurons diff…

Neurotransmitters - molecular messages

You often hear about neurotransmitters in the news and in science magazines in a kind of off-hand way that assumes everyone must surely know what these things are. But, um, what are they, exactly?

From Sandra Ackerman's book "Discovering the Brain": To be recognized as a neurotransmitter, a chemical compound must satisfy six conditions: It must be

synthesized in the neuron, stored there, released in sufficient quantity to bring about some physical effect; when administered experimentally, the compound must demonstrate the same effect that it brings about in living tissue; there must be receptor sites specific to this compound on the postsynaptic membrane, as well as a means for shutting off its effect, either by causing its swift decomposition or by reuptake, absorbing it back into the cell.

OK, well, what about hormones? They're chemical messengers too - how are hormones different from neurotransmitters? A hormone, by definition, is a compound produced by an endocrine…

Receptors - getting the message across

From Paul Greengard's Nobel Lecture in 2000:
It is estimated that there are about 100 billion nerve cells in the brain and that on average each of these nerve cells communicates with 1000 other nerve cells. A vigorous debate went on from the 1930s through the 1960s as to whether intercellular communication across the synapses between nerve cells was electrical or chemical in nature. The electrical school of thought held that the nerve impulse or action potential was propagated along the axon to the nerve ending, changed the electrical field across the postsynaptic plasma membrane, and thereby produced a physiological response. The chemical school believed that when the action potential came down the axon to the nerve terminal, it caused the fusion of neuro-transmitter-containing vesicles with the presynaptic plasma membrane, releasing a neurotransmitter, which then diffused across the synaptic cleft and, through activation of a (hypothetical) receptor, produced a physiological resp…