Core Concept: Resting-state connectivity.

In the early days of functional magnetic resonance imaging (fMRI), researchers mostly analyzed how brain areas responded to a stimulus, whether a light, a noise, or some sort of cognitive task. But as a graduate student at the Medical College of Wisconsin in Milwaukee, Bharat Biswal had an unusual request of his fMRI test subjects: climb into the scanner and do, well, nothing. Biswal expected that the spontaneous neuronal chatter at rest would be more or less random and unstructured. Instead, he saw structure, organization, correlations among groups of brain regions that were known to function together. Different regions of the brain’s sensorimotor system fluctuated slowly and synchronously in the absence of any explicit task. It was the first step toward the study of “resting-state connectivity,” an approach that promises to help researchers study the functional organization of both the healthy and abnormal brain, particularly in children and others who cannot complete challenging cognitive tasks. (See Perspective page 14105.) Biswal’s 1995 paper, which is now recognized as a seminal resting-state fMRI study, received little attention at first (1). But in 2001, neuroscientist Marcus Raichle and his colleagues at Washington University in St. Louis sparked widespread interest in the approach when they described a previously unknown brain network that appeared to play a key role in a baseline, or default, mode of the brain (2). Unlike the sensorimotor and several other brain networks, which were initially identified by their activation during tasks, this mystery network displayed high baseline activity that actually decreased when subjects engaged in a variety of cognitive tasks. “It said something important about the ongoing activity of the brain, and the fact that it is not just sitting there waiting for someone in a white coat to come along and tell you what to do,” says Raichle. Intrigued by what the brain might be doing during supposedly inactive periods, Raichle and others began to explore this socalled “default mode network,” which seemed to be involved in high-level cognitive processes, such as self-awareness and memory. Michael Greicius, a behavioral neuroscientist at Stanford University in California, soon followed on Raichle’s work by demonstrating that at rest, the individual components of the brain’s default mode network show correlated oscillations, just as Biswal had seen for the sensorimotor network (3). “That series of papers really increased the profile of the research,” says Biswal, now a professor at the New Jersey Institute of Technology in Newark. The findings suggested that networks of brain regions that activate or deactivate together during tasks maintain signatures of their connectivity that can be detected and studied even at rest. Potentially, it meant that neuroscientists would be able to map the brain’s basic wiring diagram without the use of specially designed tasks. The idea generated intense interest, but also a healthy dose of skepticism from many neuroscientists. “It just seemed too good to be true, and too easy,” says Greicius. “People started to wonder if it could really be neural.” Many researchers initially questioned whether the rhythmic, synchronized fluctuations observed during the resting-state could be artifacts of other bodily functions, such as breathing or heartbeats. But those doubts gradually faded as more studies replicated and expanded on the early findings. Research showed that the correlated activity ran along structural networks of nerve fibers in the brain, and that surgically severing connections between areas could disrupt restingstate network activity, all suggesting that the correlations reflected a genuine and fundamental aspect of neuronal communication (4–6). The precise function of the default mode network remains a matter of debate, but its component brain regions are involved in such processes as self-referential The default mode network, shown here in resting-state fMRI scans (Upper), includes the posterior cingulate cortex, hippocampus, and the medial prefrontal cortex. (Lower) Diffusion tensor imaging, an MRI technique that highlights the brain’s white matter, reveals nerve fibers connecting these brain regions (posterior cingulate cortex in red; medial prefrontal cortex in yellow; hippocampus in green and pink). Adapted from ref. 5, with permission from Oxford University Press.