YOUTUBE, ZEUS CHIRIPAThe relevance and reliability of blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) data have been hotly debated for years, not least because it is still unclear what aspects of brain activity the technique is picking up. “In many ways, this would seem to be an unacceptable method for neuroscience,” said Ed Bullmore from the University of Cambridge, at a Royal Society-organized gathering of neuroscients late last month. “But if you’re interested in humans, there isn’t much of a choice.” Bullmore and colleagues had convened in Buckinghamshire, U.K., to discuss what, exactly, BOLD fMRI results can tell us.
“What we do know, of course, is what MRI measures,” said Robert Turner, director emeritus of the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig, Germany. MRI measures the magnetization of hydrogen protons in water molecules excited by pulses of radio waves that lead their spins to temporarily align. “Over the next few tens of milliseconds,” Turner noted, “their orientations fan out again, and the magnetization we measure will quickly decrease.”
But what can this tell us about brain activity?
When hemoglobins—the iron-rich oxygen-carrying proteins in our blood—run out of oxygen, Turner explained, “they become paramagnetic,” disturbing the local magnetic field. This makes the protons spin out of phase more rapidly.” One might think this means BOLD fMRI highlights oxygen consumption by active neurons, but in reality, such activity is rarely measured.
What BOLD does reveal is what usually happens next: fresh blood rushes into the area, flushing out paramagnetic deoxyhemoglobin and replacing it with new, oxygenated hemoglobin. Since this does not interfere with the proton spins, the result is a larger fMRI signal. So BOLD fMRI reflects a combination of changes in blood flow and oxygen consumption within the brain—not neuronal activity itself.
“This means that if BOLD shows you a large blob of activity, that doesn’t necessarily mean that all the neurons in that region are spiking,” said David Attwell of University College London, one of the meeting’s organizers. “So what we really need to know is how neurons are influencing bloodflow.”
To find out, Attwell and his colleagues are studying postmortem slices of rodent brain to better understand the interactions between neurons, blood vessels, and supporting cells such as astrocytes and pericytes. These cells wrap around the vasculature and likely affect its response to local neural activity.
Research on living animals, on the other hand, has suggested that endothelial cells lining the brain’s blood vessels may also play an active role in coordinating such responses, as they are known to do elsewhere in the body. “The wave of vessel dilation resulting in increased bloodflow travels much faster and farther than could be explained by astrocytes and pericytes alone,” said Elizabeth Hillman of Columbia University in New York City, whose lab has developed an optical method to look into rat brains directly. “Moreover, if we disable parts of the endothelium, we can see that wave come to a halt.”
More recently, the Hillman lab unexpectedly uncovered what seems to be a convincing link between neural and vascular activity. “While trying to disprove that resting state activity in the brain could teach us about neural connections we have actually been able to observe seemingly spontaneous neural activity that correlates with bloodflow quite tightly,” Hillman told The Scientist, “which would be hard to show with the very precise single-neuron measurements many neuroscientists prefer, but when you zoom out and look at the larger picture, the synchrony is hard to deny—and believe me, we’ve tried very hard to explain these results away.”
If these unpublished findings stand up to the scrutiny of Hillman’s colleagues, this would be reassuring news for neuroscientists using BOLD fMRI to study neural activity.
But in some brains, BOLD may not work at all, Hillman cautioned. “In the developing brain of young animals, for example, we find that BOLD activity is very unusual,” she said. “Initially, the bloodflow response doesn’t seem to be attuned to neural activity at all, so fMRI may be as good as blind.”
Diseased brains can also skew results. “Pathology may affect the BOLD signal in the absence of any changes in neurons themselves,” said Bojana Stefanovic of Toronto’s Sunnybrook Research Institute. In patients who suffered a stroke, for example, the amount of water may be reduced where cells have died, and increased by oedema in some of the surrounding tissues. The brain’s bloodflow may also be altered by disruptions to the vasculature, for example, or the formation of scar tissue.
The best way to deal with this depends on the research question, Stefanovic told The Scientist. “There’s this idea that if we can link BOLD to neuronal activity—that would be nirvana,” she said. “Clinicians, however, are looking for measures with a clear link to symptoms. And, fortunately, there is no shortage of disease effects BOLD can sense.”
Cognitive neuroscientist Geraint Rees of University College London sounded a similar note. “If whatever BOLD is measuring reproducibly correlates to the behavior I’m interested in, such as attention or consciousness, I am less worried about the physiological details behind it,” he said. “Which does not mean, of course, I don’t consider them interesting—otherwise, I wouldn’t be here.”
Meanwhile, researchers are developing methods to measure human neural activity more directly, learning more about BOLD fMRI data along the way. “Thanks to over 30 Parkinson’s patients who agreed to play an investment game while undergoing surgery for the placement of a deep-brain stimulation probe, we were able to directly measure the striatal dopamine response we only knew from rodents and human BOLD,” said Read Montague of the Virginia Tech Carilion Research Institute. “Surprisingly, we found that while BOLD responds to expected reward and actual outcome separately, the dopamine response integrates them into one ‘better or worse’ signal.”Montague’s team would next like to explore whether the same is true for people without Parkinson’s disease, which is known to affect dopaminergic neurons.
For now, however, the researchers’ results demonstrate the benefits of applying other techniques in parallel with BOLD fMRI. Not only might this approach reveal insights BOLD cannot, it might also help neuroscientists better understand the results of past fMRI experiments.