Tuesday, July 8, 2008

A little more about fMRI (and NO as well)

Dude! People read this blag!

Er... at least two persons read this blag! Awesome!

And on top of that, at least one of them can explain blood oxygen level dependent fMRI signals better than I can:
The BOLD fMRI signal observed in brain activation is from a measurement of the relative quantities of oxy and deoxyhemoglobin. Vasodilation increases blood flow in the activated regions and that changed oxy/deoxy ratio is what is observed.
You can't sum it more simply and accurately than that. I looked at Baylor College's "What is fMRI?" page and found a slightly more detailed summary. It works on the principal of neurovascular coupling - basically, when an area of your brain becomes active, the blood vessels in that area dilate (presumably in order to get more fuel - food and oxygen - to the active cells). When the blood vessels dilate, more oxygenated blood rushes into that area. The relatively higher concentrations of oxygenated blood compared to deoxygenated blood in that area can be detected with a functional magnetic resonance imaging device - an fMRI.

But wait! There's more!
Vasodilation is controlled by NO.

The regions of activation observed in BOLD fMRI are actually regions of NO, where the prompt neurogenic NO release is high enough to cause vasodilation by activating sGC. That NO does things besides vasodilation. Those things are not understood. I think that those things are actually more important than the increased O2 consumption.

It is well established that the O2 delivery by the increased blood flow exceeds the metabolic requirements of the activated region.
NO, or Nitric Oxide, is a gaseous chemical messenger in your body. It is well-known (to dorks like me) as the endothelium-derived relaxing factor. Now if you knew that the endothelium is the technical name for the tissue lining your blood vessels, you could reason that NO is produced by your blood vessels and "relaxes". Which is absolutely spot-on.

Production of NO in this specific context can be set off by a bunch of factors, mainly the ones that would indicate that you needed more blood-flow capacity (strain, certain immune system factors). It seems to act by setting off a G-protein cascade ending with phosphorylating a handful of proteins, with the effect (very generally speaking) of relaxing the smooth muscle around the blood vessel, and thus dilating the vessel.

NO does have differing effects on different tissues (as could be said about pretty much any substance), and it is certainly true that we do not know all of NO's possible effects.

There is apparently an international conference on NO/cGMP interactions, with a lot of stuff posted online if you'd care to slog through it. The takeaway message is: physiology is fuckin' complicated.

While poking around the internet pondering this, I found this paper from the Journal of Neuroscience online. The experiments involved neurovascular coupling, and one focuses on NO specifically as a modulator. The result: when NO is removed (by inhibiting its production), you see only vasodilation in rat retinal neurons. In this case NO acts to cause vasoconstriction in neural blood vessels.

That may sound weird, but the mechanism for how blood vessels dilate in the body may be drastically different from how blood vessels dilate in the brain. Mostly because the brain has special needs. Delicate system of interconnected neurons, and all that. Maybe couldn't handle the strains if the blood vessels just regulated themselves willy-nilly. The paper suggests that glia, the support cells in the brain, have an important role in regulating blood flow.

NO is itself a used as a neurotransmitter both in the brain and in the rest of your body. And it has a buttload of known or hypothesized effects, which you could peruse at your leisure if you're so inclined.

Thank you for the comment, daedalus2u!

1 comment:

  1. That was an interesting paper on retina vasodilation. I especially liked the last few sentences of the second to last paragraph.

    It is difficult to predict what the spatial distribution of glial-evoked vasodilations and vasoconstrictions will be in vivo. The distribution will depend on a number of factors that could not be reproduced in our experiments, including the spatial distribution of neuronal activation, the resting level of NO, and the spatial distribution of NO production.

    That sums up some of the limitations of their in vitro experiments. They didn't mention that they didn't reproduce the special distribution of NO sinks either. They used Ringer's solution instead of blood. That eliminates hemoglobin which is the major sink of NO. In vitro stuff is so hard to make realistic when dealing with systems that are massively coupled. Note they were limited in what they could measure to levels less than 70 nM/L. ~10 nM/L is a more realistic maximum, where sGC becomes ~50% activated (depending on the details). The levels they looked at are probably not relevant in vivo under "normal" conditions. Constriction at such high NO levels might represent some sort of pathological condition, perhaps a local abscess? In vivo the vasodilation that occurs before such levels are reached brings in hemoglobin which removes NO.

    Those NO sensors are extremely tricky. They are very sensitive to noise, temperature fluctuations, you name it, they are sensitive to it. I am not sure how to interpret their data and extend it to other tissue compartments under more physiologic conditions.

    Vasodilation in the brain probably uses every mechanism that the rest of the body uses, and maybe some more. It is much easier for more complex regulation of existing pathway(s) to evolve than for a de novo pathway to evolve (by many orders of magnitude). The brain does have the fastest response time, presumably it has to have the fastest vascular response time too. You are probably correct that the brain can't afford to have blood vessels regulated willy-nilly. They are probably all very tightly regulated. Perhaps that is part of why cerebral spinal fluid is so different than plasma or blood. It has to be to facilitate the right NO diffusion, lifetime, and other properties to allow the proper regulation of vasodilation.

    Vasodilation at some NO levels and vasoconstriction at other levels makes some sense. The rigid skull makes the brain have a fixed total volume. Dilation at one region has to be balanced by constriction at another.

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