CORE CONCEPTS CORE CONCEPTS Core Concept: Resting-state connectivity Helen H. Shen baseline activity that actually decreased Science Writer when subjects engaged in a variety of cognitive tasks. “It said something important about the In the early days of functional magnetic res- approach that promises to help researchers ongoing activity of the brain, and the fact that onance imaging (fMRI), researchers mostly study the functional organization of both it is not just sitting there waiting for someone analyzed how brain areas responded to a the healthy and abnormal brain, particularly in a white coat to come along and tell you stimulus, whether a light, a noise, or some in children and others who cannot complete what to do,” says Raichle. sort of cognitive task. But as a graduate stu- challenging cognitive tasks. (See Perspective Intrigued by what the brain might be dent at the Medical College of Wisconsin in page 14105.) doing during supposedly inactive periods, Milwaukee, Bharat Biswal had an unusual re- Biswal’s 1995 paper, which is now recog- Raichle and others began to explore this so- quest of his fMRI test subjects: climb into the nized as a seminal resting-state fMRI study, called “default mode network,” which seemed scanner and do, well, nothing. received little attention at first (1). But in to be involved in high-level cognitive pro- Biswal expected that the spontaneous neu- 2001, neuroscientist Marcus Raichle and his cesses, such as self-awareness and memory. ronal chatter at rest would be more or less colleagues at Washington University in St. Michael Greicius, a behavioral neuroscientist random and unstructured. Instead, he saw Louis sparked widespread interest in the ap- at Stanford University in California, soon fol- ’ structure, organization, correlations among proach when they described a previously un- lowed on Raichle s work by demonstrating groups of brain regions that were known to that at rest, the individual components of known brain network that appeared to play ’ function together. Different regions of the a key role in a baseline, or default, mode the brain s default mode network show cor- related oscillations, just as Biswal had seen for brain’s sensorimotor system fluctuated slowly of the brain (2). Unlike the sensorimotor the sensorimotor network (3). and synchronously in the absence of any and several other brain networks, which were “That series of papers really increased the explicit task. It was the first step toward initially identified by their activation during ” “ ” profile of the research, says Biswal, now a the study of resting-state connectivity, an tasks, this mystery network displayed high professor at the New Jersey Institute of Tech- nology 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, itmeantthatneuroscientistswouldbeableto 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 fluctua- tions 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 andexpandedontheearlyfindings.Research showed that the correlated activity ran along structural networks of nerve fibers in the brain, and that surgically severing connec- tions between areas could disrupt resting- Upper state network activity, all suggesting that the The default mode network, shown here in resting-state fMRI scans ( ), includes the correlations reflected a genuine and funda- Lower posterior cingulate cortex, hippocampus, and the medial prefrontal cortex. ( ) Diffusion mental aspect of neuronal communication tensor imaging, an MRI technique that highlights the brain’s white matter, reveals nerve fibers (4–6). The precise function of the default connecting these brain regions (posterior cingulate cortex in red; medial prefrontal cortex in mode network remains a matter of debate, yellow; hippocampus in green and pink). Adapted from ref. 5, with permission from Oxford but its component brain regions are in- University Press. volved in such processes as self-referential www.pnas.org/cgi/doi/10.1073/pnas.1518785112 PNAS | November 17, 2015 | vol. 112 | no. 46 | 14115–14116 Downloaded by guest on September 28, 2021 thinking, emotional processing, and recall- self-admiring and embarrassed behaviors be- scientists do hope to use resting-state con- ing memories. tween 14 and 20 months, and learn to recog- nectivity to help improve treatments for Besides the sensorimotor and default mode nize their own reflections between 20 and neuropsychiatric patients who have already networks, many other brain networks have 24 months of age (12). been diagnosed by other means. now been observed at rest, including those Resting-state imaging may also provide At Harvard Medical School in Boston, involved in vision, hearing, and memory (7). new insights into how brain connectivity Massachusetts, neurologist Michael Fox is in- In each of these cases, the same regions that goes awry. Disruption of the default mode vestigating the networks involved in therapeu- fire together during tasks seem to hum along network, for example, has been associated tic brain stimulation, a set of techniques used ’ together at rest, maintaining a signature of with Alzheimer s disease, depression, autism, to treat Parkinson’s disease, depression, and their functional organization. The slow, syn- and schizophrenia (13). In the case of au- other conditions. Researchers still have only — chronized oscillations within each network tism, both task-based and some resting-state a vague understanding of how these tech- — which are independent of each other are studies have also revealed abnormal patterns niques alleviate neurological symptoms, and also remarkably robust, persisting even dur- “Being able to use resting- why certain stimulation sites are most effective. ing sleep and under anesthesia (8, 9). “If you want to try to understand how In recent years, acceptance of the approach state to scan young kids brain stimulation propagates and affects a has taken off. And in 2010, when the NIH network, you’ve got to understand what that launched the Human Connectome Project— and people with a range of network looks like,” says Fox. A recent rest- a large-scale, five-year effort to map the brain abilities is a great thing ing-state connectivity study by his group sug- networks of more than 1,000 people—the ” for the field clinically. gests that different stimulation sites that work agency selected resting-state fMRI as one — of the core techniques for the project. “That Lucina Uddin for the same disorder often belong to the same brain network, whereas ineffective sites was a big signal from the field at large that of connectivity in several other networks, appear not to be connected (15). The finding, resting-state connectivity is ready for prime including those involved in working mem- ” says Fox, suggests that in the future, resting- time, says Greicius. ory, language, emotion processing, and social state connectivity maps could be used to pre- With resting-state fMRI, neuroscientists cognition (14). dict whether certain sites will be effective in can study brain activity in young children “We’re still in the early phases of discovery,” or patients who would otherwise be unable to says cognitive neuroscientist Lucina Uddin, an individual patient, or to locate new candi- complete long experiments or perform com- who studies autism in children at the Univer- date sites for stimulation. plex cognitive tasks. And unlike task-based sity of Miami in Florida. With task-based Applications for resting-state connectivity “ ’ imaging, which typically highlights a single imaging having dominated the field for de- continue to expand. IdontthinkIhadan- brain network associated with any given task, cades, a shortage of data exists from children ticipated that later on there would be so ” resting-state fMRI allows researchers to observe and people with severe autism symptoms, much interest in this work, says Biswal. ’ many networks at once. The simplicity of the who often cannot complete a standard psy- Raichle and others credit the technique s “ procedure and its relatively short duration (often chological experiment in the scanner. “Being simplicity and versatility. You can study new- – taking about 5 10 min compared with 30 min able to use resting-state to scan young kids born children and watch them develop, and or more for many task-based studies), has also andpeoplewitharangeofabilitiesisagreat you can jump to the other end of the spectrum made it easier for researchers to replicate each thing for the field clinically,” says Uddin. and study people that are aging and not per- ’ other s experiments and compare results. So far, fMRI biomarkers for diagnosing forming well,” he says. “It’sreallyopenedthe Neuroscientist Wei Gao, at Cedars-Sinai individuals with autism or neurodegenerative door to studying the functional organization of Medical Center in Los Angeles, is one of diseases have proven difficult to develop. But the brain.” several investigators using resting-state fMRI in sleeping infants to study how brain networks form and evolve during develop- 1 Biswal B, Yetkin FZ, Haughton VM, Hyde JS (1995) Functional 8 Sämann PG, et al. (2011) Development of the brain’s default ment. Whereas some circuits, such as the connectivity in the motor cortex of resting human brain using echo- mode network from wakefulness to slow wave sleep. Cereb Cortex sensorimotor network and the auditory net- planar MRI. Magn Reson Med 34(4):537–541. 21(9):2082–2093. 2 Raichle ME, et al. (2001) A default mode of brain function. Proc 9 Vincent JL, et al. (2007) Intrinsic functional architecture in the work, appear fairly well-established at birth, – Natl Acad Sci USA 98(2):676–682.