Sci was incredibly excited to see this paper come out. It’s got lots of stuff going for it, and all its powers combined were enough to send Sci bouncing around in her seat and sending emails to Ed Yong saying “OMG COOL PAPER!!”.
What’s it got, you say? It’s got the meaning of life, the universe, and that pesky MRI signal.
Lee et al. “Global and local fMRI signals driven by neurons defined optogenetically by type and wiring” Nature, 2010.
Ah, the pretty brain picture. But what does it MEAN?
By now, I’m sure you’ve all heard of BOLD fMRI. fMRI is functional magnetic resonance imaging, and BOLD stands for “blood oxygen level-dependent”. So what that breaks down to (basically) is that fMRI uses magnetic resonance to form images of the anatomy of your brain. When you make MRI functional by adding a BOLD signal, it not only reveals the anatomy of your brain, it also shows where blood oxygen is being heavily used, and thus which regions of your brain show “activity” during certain tasks. For instance, your occipital cortex, which is very important in the processing of vision, “lights up” with a BOLD signal when you are viewing something. Blood rich in oxygen is being recruited to the area and oxygen is being used.
But for a long time now (well, a long time since the invention of MRI), scientists have been skeptical. MRI is great in that it’s very non-invasive (Sci has done time in many MRIs are a graduate student, and though the noise is annoying, it’s certainly not invasive), and in that it can show us the anatomy of the brain (or any other area, for that matter, or at least whatever area you can fit into the scanner). But the BOLD signal has been a thorn in the side of neuroscientists for some time. We know that there is “activity” and that blood, with oxygen, is going to the area and being used, but what does this MEAN?!
Now, you might say “well, that’s dumb, of course it means that brain area is involved in whatever thing you’re doing”. Well, yes, but HOW. There are excitatory, inhibitory, and modulatory groups of neurons in the brain. You might have activity in one area when you’re performing a task, but is that excitatory activity? Or is that inhibitory activity that is inhibiting something else to allow excitation? Or is it even more complicated than that? Scientists don’t know. So all they can really do is say that a certain area of the brain which gives off a BOLD signal in response to a certain task is “activated”. They can’t say HOW.
And of course, the media doesn’t like this. Heck, science doesn’t like this. It’s like being given a random assortment of exactly half of the pieces of a puzzle. And so this has led to a tendency to over-interpret fMRI data. Scientists often try not to do this, but we’re only human, and we love our pet hypotheses. But even if the scientists don’t do this, the media often does, saying that “OMG activity in this area means you’re psycho!” or something. When in reality, all we have is activity in an area, which corresponds to a task, and with no real idea as to what it DOES.
The scientists in this paper have found a way to interpret the fMRI signal. They figured it out using optogenetics, which is the new hotness in neuroscience techniques these days, and really does seem like something out of a Sci-fi novel.
Here’s how it works: There are certain channels in cells (the ones we are concerned with are from green algae) which can respond to LIGHT. These are called channelrhodopsins. When they are hit by light of a specific wavelength (in the case of this paper, 473nM, which is a blue, the channels will open and ions will move in and out. In the case of some of these channels, the ions moving in and out will cause the cell the channel is on to fire.
Looks kind of like this:
A few years ago, Karl Deisseroth (who may win some BIG PRIZES for this discovery, he’s already a rockstar of neuroscience) discovered that you could take the gene that encodes this light-responding channel, and place it into a virus. You could then use carefully targeted viral infection to infect a local area of neurons with this virus, implanting the channel into the cells.
And guess what happened then?
Looks cool, yeah? Above you can see these viruses placed into the primary motor cortex of a rat. When you stimulate with light, the now-light responding cells will FIRE in response to the light! When you put this into the motor cortex, you will get a motor response, like in this video:
Here you can see a mouse, who has a viral mediated infection of light responding channels in his motor cortex. He’s just sniffin around and hanging out, but when he gets a jolt of blue light (which you can see), he starts to run, because his cortex has been activated.
(Is that the freakin’ coolest thing or what?!? We’re on the way to having our own little mouse armies that you can control with LASERS ATTACHED TO THEIR HEADS!)
This technique is called optogenetics, and is already the next big thing. Using optogenetics, you can stimulate very specific parts of the brain using light, and see what happens. You can also link these light-responding channels to very specific receptors, and see what happens when ONLY those receptors in specific areas of the brain are activated. It’s really massively cool, and you’re probably going to be seeing huge numbers of papers coming out about this (well, tons already HAVE, but a lot more WILL).
Now, on to this paper.
So we know that the problem with the fMRI BOLD signal is that we know where the blood is going, but we don’t know what neurons specifically are being activated. So what you really need to do is be able to specifically activate a bunch of neurons in a specific area, and then check the BOLD signal.
Well, with these light controlled channels and viruses to insert them into the brain, that isn’t so hard, now is it?!
Here you can see what happened in rats that had light-responsive channels in their motor cortex. The rats were anesthetized and lying asleep in the scanner (getting a rat to hold still for this sort of thing is a significant challenge). Then, they gave the rat pulses of light. And the BOLD signal leaped up (Figure E) each time they did.
So, what’s so great about that? Well it shows definitively that the BOLD signal (and thus blood flow and oxygen usage) are directly correlated with actual neuron firing, because every time these neurons fired, the BOLD signal went up.
What is also really cool about this is that the virus infected only excitatory neurons with the light-responsive channels, showing that the BOLD signal also correlates with excitatory neuron firing in the brain. To drive this home, the authors ALSO infected a bunch of inhibitory cells with this same light-responsive channels. This time, when they shone a light, they got DECREASES in BOLD signal which corresponded with increased stimulation of inhibitory neurons. This means that not only does the BOLD signal correlate with excitatory neuron activity, is also negatively correlates with inhibitory neuron activity.
So this is massively cool enough. It implies that when we are looking at a BOLD signal in a patient, we are looking at primarily excitatory neuron activity. This means, for the first time, we can begin to interpret the BOLD fMRI signal. Of course, there could be other neurons activated as well which are neither excitatory nor inhibitory, but it’s a start.
BUT, the scientists for this paper didn’t stop there! They also looked at where the neurons they were stimulating WENT. They could do this because the virus that infected the neurons with the light-responsive channels allowed the channels to be expressed all over the neurons. Thus, when the cells were stimulated with light, the whole thing was activated, and if you attach a GFP (green fluorescent protein) to your light channels, you get something like this:
You can see that light stimulation activates certain neurons, and causes the neurons that are activated to glow all along their length. This means that, not only do you know which neurons you’ve activated, but you also know WHERE they go! They confirmed this by checking the electrical signals of the neurons, checking the signals where it started, as well as where it projected to. This could be really important in neuroanatomy, allowing us to look very carefully and very specifically at neuronal projections in the brain, where exactly they are going, and, with optogenetics, what exactly they are doing when they get there.
But the really cool finding here is that, for the first time, we may have come a little closer to understanding what those BOLD fMRI signals mean. We can’t put virus-delivered light-activated channels into the human brain, and we don’t have the specificity to do it for every cell type, but we do have a start. And by carefully mapping the specific regions of animal brains using this technique, right down to the specific cell types, we may one day be able to determine what exactly your brain scans are showing you.
Lee, J., Durand, R., Gradinaru, V., Zhang, F., Goshen, I., Kim, D., Fenno, L., Ramakrishnan, C., & Deisseroth, K. (2010). Global and local fMRI signals driven by neurons defined optogenetically by type and wiring Nature, 465 (7299), 788-792 DOI: 10.1038/nature09108