Young and old: fMRI and brain blood flow

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  • Published: Jul 1, 2016
  • Author: David Bradley
  • Channels: MRI Spectroscopy
thumbnail image: Young and old: fMRI and brain blood flow

fMRI mantra

Spikes in neuronal activity in young mice do not spur corresponding boosts in blood flow — a discovery that stands in stark contrast to the adult mouse brain. Credit: Hillman Lab/Zuckerman Institute

The mantra in functional magnetic resonance imaging (fMRI) is that in the adult brain, increases in neural activity lead to increases in local blood flow. It is on this fact that so many studies that discuss brain regions "lighting up" during particular behaviour or activities hinge. Now, US scientists have demonstrated that what holds for the adult brain may not be true for the infant brain, in mice at least.

Writing in the Journal of Neuroscience, Elizabeth Hillman of Columbia University's Mortimer B. Zuckerman Mind Brain Behavior Institute and Mariel Kozberg, Ying Ma, Mohammed Shaik and Sharon Kim, explain how spikes in the activity of neurons in young mice do not spur corresponding rise in blood flow. The finding is perhaps counterintuitive given fMRI studies being done in adult mice and humans, given that we know that the adult brain almost always increases blood flow, and thus have to assume that those blood flow increases are important for meeting the brain's energy needs, Hillman explains. Nevertheless, the work beggars the question as to how the developing brain meets its energy needs if blood flow is not always increased when brain activity in a particular region rises. It also suggests that science may need to reconsider how best to track brain development and whether fMRI is fit for purpose in such studies. On the plus side, the work might also offer new insights into improving care for infants, should the results translate from mouse to infant humans.

Hind paw insight

"In the adult brain, neuronal activity triggers a localized increase in blood flow. This relationship between neuronal activity and blood flow has long been assumed to be present from birth, but our findings in mice suggest the opposite: that instead it develops over time," explains Hillman. "Our study further suggests that this process is an essential part of building a healthy brain and could represent an unexplored factor in brain disorders that emerge in early childhood."

"The fact is, that there is plenty of literature studying human brain, both for fMRI studies and near infrared spectroscopy (NIRS) that pointed to newborn responses being different - generally inverted," Hillman told SpectroscopyNOW. "While some papers claim otherwise, it was this body of literature that drew us to take a closer look using our optical imaging techniques in a well-controlled mouse model." The research paper's first author Kozberg points out that previously, "No one knew how to interpret blood-flow responses in the developing brain." The present study has spotted the difference between adult and newborn brain and answered questions regarding whether the differences were in neural activity itself, or whether they lie in the relationship between activity and local blood flow changes.

To answer those questions, the team developed a new optical imaging technique that simultaneously recorded neuronal activity and blood flow in the brains of mice of different ages (from newborn up to adult), tracking how the brain responded when they stimulated each animal's hind paw.

More power to fMRI

"When we started to get data we were amazed by what we could see," explains Kozberg. Stimulating the hind paw caused a strong neuronal response, but this response was localized to one region. As the animals got older, the neuronal response began to spread. At ten days of age, stimulating the right paw first sparked activity on the left side of the brain before travelling to the right side, corresponding to the development of connections between the two hemispheres of the brain. "We realized we were actually watching cells form connections with each other throughout the brain: the development of neural networks," adds Hillman.

The second finding was that in the youngest mice, neuronal activity did not trigger an increase in blood flow, as occurs in the adult mouse brain. But as the animals matured, and their neural networks became more established, the brain's blood-flow response gradually got stronger over time until the animal was fully grown.

"It was like the brain was gradually learning to feed itself," says Hillman. This, she says, makes sense. "It is hardly surprising that blood vessels - and the machinery linking them to brain activity - would mature in step with the development of neural activity itself." But, if the job of blood vessels is to supply the brain with oxygen-rich blood how can the brain of a newborn be functioning and growing without subsequent increases in blood flow? To answer this question, the team turned to flavoprotein imaging, which measures how the newborn brain used oxygen.

"In the youngest animals, we confirmed that neurons were indeed consuming oxygen, but without a rush of fresh blood, they seemed to run out of fuel," explains Kozberg. "We further found that the neural activity actually caused localized drops in oxygen levels, known as hypoxias." The explanation may lie in the fact that a newborn mammal has to make a stark transition from the womb where it is provided with oxygen and nutrients via the umbilical cord to suddenly getting its oxygen via its lungs. Alternatively, the hypoxia seen in infant mice suggest this is a normal developmental process."We know that a lack of oxygen can trigger the growth of blood vessels," says Kozberg. "So, in this case, neural activity in the newborn brain might actually be guiding blood vessels to grow in the right places."

The next step will be to look at hundreds of fMRI scans from newborns and from children of different ages to look for the same signs of neurovascular development in human infants. Rather than rendering fMRI less useful than it currently is as was hinted above, Hillman hopes this result will provide greater insights into how to measure the developing brain. It might lead to "new fMRI-based metrics of normal and abnormal trajectories of brain development," she says. "Deeper insights into the mechanisms of neurovascular development could actually render fMRI it an even more powerful tool for studying the growing brain."

Related Links

J Neurosci 2016, online: "Rapid postnatal expansion of neural networks occurs in an environment of altered neurovascular and neurometabolic coupling"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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