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NEUROSCIENCE

The Brain'sDarkEnergyBrain regions active when our minds wander may hold a key to

understanding neurological disorders and even consciousness itselfBy Marcus E. Raichle

KEY CONCEPTS Neuroscientists have long

thought that the brain'scircuits are turned offwhen a person isat rest.

Imaging experiments,however, have shown thatthere is a persistent levelof background activity.

This default mode, as it iscal led, may be critical inplanning future actions.

Miswiring of brain regionsinvolved in the defaultmode may lead to disor-ders ranging from Alz-heimer's to schizophrenia.

-The Editors

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Imagineou are almost dozing in a lounge chairoutside, with a magazine on your lap. Sudden-ly, a fly lands on your arm. You grab the mag-azine and swat at the insect. What was going onin your brain after the fly landed? And what wasgoing on just before? Many neuroscientists havelong assumed that much of the neural activity in-side your head when at rest matches your sub-dued, somnolent mood. In this view, the activityin the resting brain represents nothing more thanrandom noise, akin to the snowy pattern on thetelevision screen when a station isnot broadcast-ing. Then, when the fly alights on your forearm,the brain focuses on the conscious task of squash-.ing the bug. But recent analysis produced by neu-roimaging technologies has revealed somethingquite remarkable: a great deal of meaningful ac-tivity is occurring in the brain when a person issitting back and doing nothing at all.

It turns out that when your mind is at rest-when you are daydreaming quietly in a chair,

say, asleep in a bed or anesthetized for surgery-dispersed brain areas are chattering away to oneanother. And the energy consumed by this everactive messaging, known as the brain's defaultmode, is about 20 times that used by the brainwhen it responds consciously to a pesky fly oranother outside stimulus. Indeed, most thingswe do consciously, be it sitting down to eat din-ner or making a speech, mark a departure fromthe baseline activity of the brain default mode.

Key to an understanding of the brain's defaultmode has been the discovery of a heretofore un-recognized brain system that has been dubbedthe brain's default mode network (DMN). Theexact role of the DMN in organizing neural ac-tivity is still under study, but i t may orchestratethe way the brain organizes memories and vari-ous systems that need preparation for futureevents: the brain's motor system has to be revvedand ready when you feel the tickle of a fly onyour arm. The DMN may playa critical role in

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synchronizing all parts of the brain so that, likeracers in a track competition, they are all in theproper "set" mode when the starting gun goesoff. If the DMN does prepare the brain for conscious activity, investigations of its behavior mayprovide clues to the nature of conscious experience. Neuroscientists have reason to suspect,moreover, that disruptions to the DMN may underlie simple mental errors as well as a range ofcomplex brain disorders, from Alzheimer's disease to depression.

Probing Dark EnergyThe idea that the brain could be constantly busyis not new. An early proponent of that notionwas Hans Berger, inventor of the familiar electroencephalogram, which records electricalactivity in the brain with a set of wavy lines on agraph. In seminal papers on his findings, pub-

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lished in 1929, Berger deduced from the ceaseless electrical oscillations detected by the devicethat "we have to assume that the central nervoussystem is always, and not only during wakefulness, in a state of considerable activity."

But his ideas about how the brain functionswere largely ignored, even after noninvasive imaging methods became a fixture in neurosciencelaboratories. First, in the late 1970s, came positron-emission tomography (PET), which measures glucose metabolism, blood flow and oxygen uptake as a proxy for the extent of neuronalactivity, followed in 1992 by functional magneticresonance imaging (fMRI), which gauges brainoxygenation for the same purpose. These technologies are more than capable of assaying brainactivity, whether focused or not, but the designof most studies inadvertently led to the impression that most brain areas stay pretty quiet untilcalled on to carry out some specific task.

Typically neuroscientists who run imagingexperiments are trying to pinpoint the brain regions that give rise to a given perception or behavior. The best study designs for defining suchregions simply compare brain activity duringtwo related conditions. If researchers wanted tosee which brain areas are important during reading words aloud (the "test" condition) as opposed to viewing the same words silently (the"control" condition), for instance, they wouldlook for differences in images of those two condit ions.And to see those differences clearly, theywould essentially subtract the pixels in the passive-reading images from those in the vocal image; activity of neurons in the areas that remain"lit up" would be assumed to be the ones necessary for reading aloud. Any of what is called intrinsic activity, the constant background activity, would be left on the cutting-room floor. Representing data in this way makes it easy toenvision areas of the brain being "turned on,"during a given behavior, as if they were inactiveuntil needed by a particular task.

Over the years, however, our group, and others, became curious about what was happeningwhen someone was simply resting and just letting the mind wander. This interest arose froma set of hints from various studies that suggestedthe extent of this behind-the-scenes activity.

One clue came from mere visual inspectionsof the images. The pictures showed that areas inmany regions of the brain were quite busy inboth the test and the control conditions. In partbecause of this shared background "noise," differentiating a task from the control state by look-

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ing at the separate raw images is difficult if notimpossible and can be achieved only by applyingsophisticated computerized image analysis.

Further analyses indicated that performing aparticular task increases the brain's energy consumption by less than 5 percent of the underlying baseline activity. A large fraction of the overall activity-from 60 to 80 percent of all energyused by the brain-occurs in circuits unrelatedto any external event. With a nod to our astronomer colleagues, our group came to call this intrinsic activity the brain's dark energy, a reference to the unseen energy that also representsthe mass of most of the universe.

The question of the existence of neural darkenergy also arose when observing just how littleinformation from the senses actually reachesthe brain's internal processing areas. Visual information, for instance, degrades significantlyas it passes from the eye to the visual cortex.Of the virtually unlimited information available in the world around us, the equivalent of 10billion bits per second arrives on the retina atthe back of the eye. Because the optic nerve attached to the retina has only a million outputconnections, just six million bits per second canleave the retina, and only 10,000 bits per secondmake it to the visual cortex.

After further processing, visual informationfeeds into the brain regions responsible for forming our conscious perception. Surprisingly, theamount of information constituting that conscious perception is less than 100 bits per second. Such a thin stream of data probably couldnot produce a perception if that were all thebrain took into account; the intrinsic activitymust playa role.

Yet another indication of the brain's intrinsicprocessing power comes from counting the number of synapses, the contact points between neurons. In the visual cortex, the number of synapses devoted to incoming visual information is lessthan 10 percent of those present. Thus, the vastmajority must represent internal connectionsamong neurons in that brain region.Discovering the Default ModeThese hints of the brain's inner life were wellestablished. But some understanding was needed of the physiology of the brain's intrinsic activity-and how it might influence perception andbehavior. Happily, a chance and puzzling observation made during PET studies, later corroborated with fMRI, set us on a path to discoveringthe DMN.

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A CLUE TOTHE NEW VIEWResearchers have known for somet ime that on ly a trick le of informat ionfrom the virtually inf inite flood in thesurrounding environment reachesthe brain's processing centers.A lthough six mil lion b its are transmi tted through the opt ic nerve, forinstance, on ly 10,000 bits make i tto the brain's visual-processing area,and only a few hundred are involvedin formulating a conscious perception-too little to generate a meaningful perception on their own. Thef inding suggested that the bra inprobably makes constant predictionsabout the outside environment inant ic ipat ion of pal try sensory inputsreaching i t f rom the outside wor ld ,

.1.: i1111:[IJ:fl0#Marcus E. Raichle is professorof radiology and neurology at theWashington University School ofMedicine in St. louis. For manyyears Raichle has led a team thatinvestigates human brain functionusing posit ron-emission tomography and funct iona l magneticresonance imaging. He was electedto the Institute of Medicine in 1992and to the National Academy ofSciences in 1996,

In the mid-1990s we noticed quite by accidentthat, surprisingly, certain brain regions experienced a decreased level of activity from the baseline resting state when subjects carried out sometask. These areas-in particular, a section of themedial parietal cortex (a region near the middleof the brain involved with remembering personal events in one's l ife, among other things)-registered this drop when other areas were engagedin carrying out a defined task such as readingaloud. Befuddled, we labeled the area showingthe most depression MMPA, for "medial mystery parietal area."

A series of PET experiments then confirmedthat the brain is far from idling when not engaged in a conscious activity. In fact, the MMP Aas well as most other areas remains constantlyactive until the brain focuses on some novel task,at which time some areas of intrinsic activity decrease. At first, our studies met with some skepticism. In 1998 we even had a paper on such findings rejected because one referee suggested thatthe reported decrease in activity was an error inour data. The circuits, the reviewer asserted,were actually being switched on at rest andswitched off during the task. Other researchers,however, reproduced our results for both themedial parietal cortex-and the medial prefrontal cortex (involved with imagining what otherpeople are thinking as well as aspects of ouremotional state). Both areas are now consideredmajor hubs of the DMN.

The discovery of the DMN provided us witha new way of considering the brain's intrinsic activity. Until these publications, neurophysiologists had never thought of these regions as a system in the way we think of the visual or motorsystem-as a set of discrete areas that communicate with one another to get a job done. The ideathat the brain might exhibit such internal activity across multiple regions while at rest had escaped the neuroimaging establishment. Did theDMN alone exhibit this property, or did it existmore generally throughout the brain? A surprising finding in the way we understand and analyze fMRI provided the opening we needed toanswer such questions.

The fMRI signal is usually referred to as theblood oxygen level-dependent, or BOLD, signalbecause the imaging method relies on changes inthe level of oxygen in the human brain inducedby alterations in blood flow. The BOLD signalfrom any area of the brain, when observed in astate of quiet repose, fluctuates slowly with cyclesoccurring roughly every 10 seconds. Fluctua-

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tions this slowwere considered to bemere noise,and sothe data detected by the scanner were simply eliminated to better resolve the brain activityfor the particular task being imaged.

The wisdom of discarding the low-frequencysignals came into question in 1995, when BharatBiswal and his colleagues at the Medical CollegeofWisconsin observed that evenwhile a subjectremained motionless, the "noise" in the area ofthe brain that controls right-hand movement fluctuated in unison with similar activity inthe areaon the opposite side ofthe brain associated withleft-hand movement. In the early 2000s MichaelGreicius and his co-workers at Stanford University found the same synchronized fluctuations inthe DMN in a resting subject.

Because of the rapidly accelerating interest inthe DMN's role in brain function, the finding bythe Greicius group stimulated a flurry ofactivity

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in laboratories worldwide, including ours, inwhich all ofthe noise, the intrinsic activity of themajor brain systems, was mapped. These remarkable patterns of activity appeared even under general anesthesia and during light sleep, asuggestion that they were a fundamental facet ofbrain functioning and not merely noise.It became clear from this work that the DMNis responsible for only a part, albeit a criticalpart, of the overall intrinsic activity-and thenotion of a default mode of brain function extends to all brain systems. In our lab, discoveryofa generalized default mode came from first examining research on brain electrical activityknown as slow cortical potentials (SCPs), inwhich groups ofneurons fire every 10 seconds orso. Our research determined that the spontaneous fluctuations observed in the BOLD imageswere identical to SCPs:the same activity detectedwith different sensing methods.We then went on to examine the purpose ofSCPs as they relate to other neural electrical signals. As Berger first showed and countless others have since confirmed, brain signaling consists ofa broad spectrum of frequencies, rangingfrom the low-frequency SCPs through activity inexcess of 100 cyclesper second. One ofthe greatchallenges in neuroscience is to understand howthe different frequency signals interact.It turns out that SCPshave an influential role.Both our own work and that of others demonstrate that electrical activity at frequencies abovethat of the SCPs synchronizes with the oscillations, or phases, of the SCPs. As observed recently by Matias Paiva and his colleagues at theUniversity of Helsinki, the rising phase of anSCP produces an increase in the activity of signals at other frequencies.

The symphony orchestra provides an apt metaphor, with its integrated tapestry ofsound arising from multiple instruments playing to thesame rhythm. The SCPsare the equivalent oftheconductor's baton. Instead of keeping time for acollection of musical instruments, these signalscoordinate access that each brain system requires to the vast storehouse of memories andother information needed for survival in a complex, everchanging world. The SCPs ensure thatthe right computations occur in a coordinatedfashion at exactly the correct moment.

But the brain ismore complex than a symphony orchestra. Each specialized brain systemone that controls visual activity, another that actuates muscles-exhibits its own pattern ofSCPs. Chaos is averted because all systems are

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not created equal. Electrical signaling from somebrain areas takes precedence over others. At thetop of this hierarchy resides the DMN, whichacts as an tiber-conductor to ensure that the cacophony of competing signals from one systemdo not interfere with those from another. Thisorganizational structure is not surprising, because the brain is not a free-for-all among independent systems but a federation of interdependent components.Atthe same time, this intricate internal activ

ity must sometimes give way to the demands ofthe outside world. To make this accommodation, SCPsin the DMN diminish when vigilanceis required because of novel or unexpected sensory inputs: you suddenly realize that you promised to pick up a carton of milk on the drivehome from work. The internal SCP messagingrevives once the need for focused attention dwindles. The brain continuously wrestles with theneed to balance planned responses and the immediate needs of the moment.Consciousness and DiseaseThe ups and downs of the DMN may provideinsight into some of the brain's deepest mysteries. It has already furnished scientists with fascinating insights into the nature of attention, afundamental component of conscious activity.In 2008 a multinational team of researchersreported that bywatching the DMN, they couldtell up to 30 seconds before a subject in a scanner was about to commit an error in a computertest. Amistake would occur if, at that time, thedefault network took over and activity in areasinvolved with focused concentration abated.And in years to come, the brain's dark energy

may provide clues to the nature of consciousness. Asmost neuroscientists acknowledge, ourconscious interactions with the world are just asmall part of the brain's activity. What goes onbelow the level of awareness-the brain's darkenergy, for one-is critical in providing the context forwhat we experience in the small windowof conscious awareness.Beyond offering a glimpse of the behind-thescenes events that underlie everyday experience,

study of the brain's dark energy may providenew leads for understanding major neurologicalmaladies. Mental gymnastics or intricate movements will not be required to complete the exercise. A subject need only remain still within thescanner while the DMN and other hubs of darkenergy whir silently through their paces.Already this type of research has shed new

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MORE TOEXPLORE

Spontaneous Fluctuations in BrainActivity Observed with FunctionalMagnet ic Resonance I magi ng.Michael D. Fox and Marcus E.Raichlein Nature Reviews Neuroscience, Vol.8, pages 700-711; September 2007.Disease and the Brain's Dark Ener-gy. Dongyang Zhang and Marcus E.Raichle in Nature Reviews Neurology,Vol. 6, pages 15-18; January 2010.Two Views of Brain Function.Marcus E.Raichle in TrendsinCognitive Science (in press).

light on disease. Brain-imaging studies havefound altered connections among brains cells inthe DMN regions of patients with Alzheimer's,depression, autism and even schizophrenia. Alzheimer's, in fact, may one day be characterizedas a disease of the_DMN. A projection of thebrain regions affected byAlzheimer's fits neatlyover a map of the areas that make up the DMN.Such patterns may not only serve as biologicalmarkers for diagnosis but may also provide deeper insights into causes of the disease and treatment strategies.Looking ahead, investigators must now try to

glean how coordinated activity among and within brain systems operates at the level ofthe individual cells and how the DMN causes chemicaland electrical signals to be transmitted throughbrain circuits. New theories will then be neededto integrate data on cells, circuits and entire neural systems to produce a broader picture of howthe brain's default mode of function serves as amaster organizer of its dark energy. Over timeneural dark energy may ultimately be revealedas the very essence of what makes us tick.

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