Breakthroughs in cognitive neuroscience: Highlighting influential research from the past 20 years
This series will explore influential papers in cognitive neuroscience, as measured by the number of times they are cited each year. The papers featured are a sampling of many important works in the field over the past 20 years. This is the third in the series. Read the first and second stories.
Whether day-dreaming, reminiscing on the week’s events, or thinking of others, our brain takes on a resting state. This resting state activates what is called the default-mode network, which occurs when we are not actively engaged in an external task. Over the past decade, studying this network has led to a wealth of discoveries about not only how the brain acts in a resting state but also about cognitive impairment diseases. Research on this network could one day lead to shorter clinical trials for drugs aimed to curb these diseases, such as Alzheimer’s.
A big boost in this work came in 2004, with a paper in Proceedings of the National Academy of Sciences (PNAS) that described how the default-mode network in healthy aging adults compared to that in Alzheimer’s patients. Using fMRI, they found that in those with Alzheimer’s disease, connectivity in the default mode network was reduced. Specifically, the researchers found disrupted connectivity between the posterior cingulate and the hippocampus, speculating that it could account for the reduced brain metabolism often indicative of early stage Alzheimer’s.
“Our paper has been well-received in part because we were able to combine several distinct threads of interest into a single study,” says Michael Greicius of the Stanford School of Medicine, lead author of the PNAS paper. Coming out just a few years after Marc Raichle coined the term “default-mode,” the paper brought together research of interest to cognitive neuroscientists, and the Alzheimer’s research and human brain mapping communities.
The default mode network is especially intriguing, he says, as it functionally brings together several different brain regions — the hippocampus, posterior cingulate, and inferior parietal cortices — linked to Alzheimer’s disease. “There is something satisfying, unifying, and intuitive in seeing all these regions targeted, together, as a network,” Greicius says.
Since 2004, several research groups have expanded on the original findings. Researchers, for example, have now found decreased default-mode network connectivity in mild cognitive impairment patients, in healthy older controls that harbor amyloid plaques indicative of early Alzheimer’s, and in healthy older controls that carry an ApoE4 risk gene for Alzheimer’s. “These studies all suggest that functional connectivity deficits in Alzheimer’s can be detected many years before people actually develop dementia,” says Greicius whose lab is currently studying how gender affects the role of the ApoE4 gene.
In other work in 2009, Bill Seeley and colleagues showed that Alzheimer’s is just one of several neurodegenerative diseases that appear to target specific networks. “In other words, the notion that a specific disease like Alzheimer’s marches along a specific brain network like the default-mode network may be a universal feature of neurodegenerative diseases,” Greicius says.
All of this work may ultimately help treat patients suffering from Alzheimer’s and other neurodegenerative diseases. Right now, when a pharmaceutical company is testing whether an experimental drug is hitting the target, they have to wait a year or more to see if a patient’s behavior has improved or stabilized with the active drug compared to the placebo. With an fMRI during a patient’s resting state, however, companies could check after only 2-3 months to see if activity in the default- mode network has improved with the drug versus the placebo — thus considerably speeding up clinical trials.
“It is conceivable that resting-state fMRI might one day be useful at the single-patient level as a diagnostic test in Alzheimer’s, but there’s a lot of work that needs doing before that can happen,” Greicius says. “Beyond its potential clinical applications in Alzheimer’s, understanding the default-mode network in healthy people should lead to some important insights into the network properties of short-term memory function,” he says “With the field’s focus on the hippocampus and medial temporal lobe structures, the role of the posterior cingulate cortex and inferior parietal lobes in memory function has been sorely underappreciated.”
Greicius points out that the default-mode network is only one of dozens of different resting-state networks. “What is becoming increasingly clear is that resting-state fMRI is an incredibly powerful methodology that can provide critical insights into a host of networks related to a host of brain functions like vision, language, emotional processing, and motor function,” he says. “More generally, I think resting-state fMRI, in conjunction with other types of imaging and non-imaging data, will allow us to ask and answer a myriad of compelling questions regarding the genetic and environmental underpinnings of the brain’s vast and complex network architecture.”
-Lisa M.P. Munoz
Media contact: Lisa M.P. Munoz, CNS Public Information Officer,