FOR DECADES, neuroscientists were like mental drill sergeants, always directing volunteers to do something: read this word, listen for that sound, add these numbers, tap your finger, and so forth.
As volunteers worked, scanners tracked changes in their brain’s blood flow and oxygen use, which increase when neurons in a brain region become more active. Researchers could compare and contrast the results of slightly different tasks (reading a word aloud versus reading a word silently, for example) to determine which brain regions were essential to particular mental abilities (in this example, speech).
Scientists built a tremendous wealth of knowledge using such approaches, but Marcus E. Raichle, MD, professor of radiology, neurology and neurobiology, and his colleagues had lingering questions.
Raichle noticed, for example, that the brain’s total energy usage only went up a measly 5 percent or so when volunteers performed these tasks. Based on blood flow and oxygen use, he estimated that scientists could not link 60 percent to 80 percent of the brain’s overall energy usage to any kind of conscious mental activity or external events. What was all that energy being used for?
Raichle and his colleagues started calling the mysterious resource consumption the brain’s “dark energy,” naming it after an astronomers’ term for the force that compels the universe to expand faster as they look farther out and further back in time. Like the astronomers, neuroscientists knew something was there by the effect it was having, but they didn’t know what that something was.
In the mid-1990s, Raichle’s group found by accident that energy usage in certain regions of the brain consistently decreased when volunteers began cognitive tasks. This led them to conduct a series of brain scans with a key difference: they asked the volunteers to just relax.
It soon became clear that certain brain regions were more likely to be abuzz with activity when volunteers did nothing and that this activity dropped as participants took up mental tasks. Hints of this background brain activity had earlier been dismissed as “noise,” but over time, Raichle and others established it was part of a previously unrecognized brain system known as the default mode network (DMN). They have amassed evidence that the DMN helps the brain organize memories and prepare for future events, and that impairments in the DMN may be connected to a wide range of neurological disorders, including Alzheimer’s, depression and schizophrenia.
This approach to analysis of brain organization is now called functional connectivity (FC), and it’s opening up new horizons in neuroscience in laboratories at the School of Medicine and around the world.
Popular culture sometimes depicts the brain as a control room or ship’s bridge from which a central authority figure issues all the directions. Steven E. Petersen, PhD, the James S. McDonnell Professor of Cognitive Neuroscience and professor of neurology and psychology, and his colleagues have used FC to look for this “little person up top telling everyone else what to do” in the brain.
To their surprise, they found the human mind has not one but two captains. They are separate networks of brain regions that do not consult each other but still work toward a common purpose: control of voluntary, goal-oriented behavior.
Using conventional brain-scanning techniques, Petersen’s group had earlier identified a set of brain regions that became active just before a volunteer began a variety of tasks. They then used FC to look at when blood flow and oxygen use rose and fell in those regions as volunteers rested. Next, they analyzed the results, employing a mathematical technique called graph theory to draw links between brain regions where those surges and drops often happened in sync.
“You might expect that everything is connected to everything, and you would get sort of a big mess from that analysis and not much information, but that’s not at all what we found,” says Nico U. Dosenbach, MD/PhD, who was a student working in Petersen’s lab during the research.
Instead, two clear master control networks emerged. Typically, the networks consisted of brain regions physically distant from each other.
In a more recent set of experiments, scientists used FC scanning on 210 volunteers ages 7 to 31 to see whether the control networks they had identified changed as the brain matured. (They set the lower age limit at 7 because at that point the brain has mostly finished growing in size.) They found significant differences in the organization of the child’s brain compared to that of adults, but not the utter mess that the parent of an unruly 7-year-old might expect.
“Regardless of how tempting it might be to assume other-wise, a normal child’s brain is not inherently disorganized or chaotic,” Petersen said. “It’s differently organized, with much more emphasis on connections between regions that are physically close to each other than in the adult brain. But a child’s brain is still at least as capable as an adult brain.”
Petersen and his colleagues hope to use what they learn about the brain’s control networks and how they normally develop to better understand and possibly one day seek treatments for developmental disorders and brain injuries.
Part of the challenge of understanding and treating brain injuries has been that physicians can quantify where and to what extent the brain has been damaged, but they can’t always use those measurements to predict how an injury will affect the patient. This has led Maurizio Corbetta, MD, the Norman J. Stupp Professor of Neurology, and others who treat such injuries to look at how brain damage can affect activity in brain regions that are functionally connected to but physically distant from the injury.
“To promote optimal recovery, it’s critical that we map the functional impact of lesions on distributed brain networks that reach beyond the injury site,” Corbetta explains.
In an early proof of this concept, Corbetta and his colleagues looked at spatial neglect, which affects 3 to 5 million brain injury patients annually and causes most patients to have trouble paying attention to their left side.
“After the injury, these patients may forget to shave the left side of their face or seem to be unaware of their left arm,” says Corbetta, the clinical director of the Stroke and Brain Injury Program at the Rehabilitation Institute of St. Louis.
The condition typically results from an injury to the right side of the brain. That a right-side injury disables left-side attention is not surprising; neurologists’ established understanding of the brain puts the brain’s right side in charge of the body’s left side, and vice-versa.
But when scientists used conventional brain-scanning techniques to study spatial neglect patients as they performed visual tasks, they could see that not only had activity in the right side of the brain diminished, the left side of the brain had become significantly busier. Greater overactivation of the left side was linked to greater problems with spatial attention.
In more recent studies, the researchers tested whether FC could be used to predict how stroke damage affects patients. In 23 patients who had recently suffered a stroke on one side of the brain, researchers assessed the strength of the connections in two networks, one for moving the arm and one for paying attention to the environment. Each includes regions in both hemispheres of the brain. Patients with damage to connections linking regions in both hemispheres were more likely to suffer a greater degree of impairment after the stroke.
That meant, for example, that stroke damage on the left side of the brain might lead to problems with control of the right arm, but the losses were worse if the left-side damage disrupted network connections with the right side of the brain.
This and other recent findings have neuroscientists thinking they may need to adjust their picture of how the brain’s hemispheres divide control of the body.
“It’s not wrong to say that one side of your brain controls the opposite side of your body, but we’re starting to realize that it oversimplifies things,” says Alex Carter, MD, PhD, assistant professor of neurology.
To further define and confirm FC’s clinical applicability, researchers are planning additional studies of brain injury patients. They also plan to use FC in long-term studies of the recuperation of such patients.