A BOLD window into brain wavesDavid Balduzzi, Brady A. Riedner, and Giulio Tononi*Department of Psychiatry, University of Wisconsin, Madison, WI 53705

The brain is never inactive. Neu-rons fire at leisurely rates mostof the time, even in sleep (1),although occasionally they fire

more intensely, for example, when pre-sented with certain stimuli. Coordinatedchanges in the activity and excitability ofmany neurons underlie spontaneousfluctuations in the electroencephalo-gram (EEG), first observed almost acentury ago. These fluctuations can bevery slow (infraslow oscillations, �0.1Hz; slow oscillations, �1 Hz; and slowwaves or delta waves, 1–4 Hz), interme-diate (theta, 4–8 Hz; alpha, 8–12 Hz;and beta, 13–20 Hz), and fast (gamma,�30 Hz). Moreover, slower fluctuationsappear to group and modulate fasterones (1, 2). The BOLD signal underly-ing functional magnetic resonance imag-ing (fMRI) also exhibits spontaneousfluctuations at the timescale of tens ofseconds (infraslow, �0.1 Hz), which oc-curs at all times, during task-perfor-mance as well as during quiet wakeful-ness, rapid eye movement (REM) sleep,and non-REM sleep (NREM). Al-though the precise mechanism underly-ing the BOLD signal is still being inves-tigated (3–5), it is becoming clear thatspontaneous BOLD fluctuations are notjust noise, but are tied to fluctuations inneural activity. In this issue of PNAS,He et al. (6) have been able to directlyinvestigate the relationship betweenBOLD fluctuations and fluctuations inthe brain’s electrical activity in humansubjects.

He et al. (6) took advantage of theseminal observation by Biswal et al. (7)that spontaneous BOLD fluctuations inregions belonging to the same functionalsystem are strongly correlated. As ex-pected, He et al. saw that fMRI BOLDfluctuations were strongly correlatedamong regions within the sensorimotorsystem, but much less between sensori-motor regions and control regions (non-sensorimotor). The twist was that theydid the fMRI recordings in subjects whohad been implanted with intracranialelectrocorticographic (ECoG) electrodesto record regional EEG signals (to lo-calize epileptic foci). In a separate ses-sion, He et al. examined correlations inEEG signals between different regions.They found that, just like the BOLDfluctuations, infraslow and slow fluctua-tions in the EEG signal from sensorimo-tor-sensorimotor pairs of electrodes werepositively correlated, whereas signals fromsensorimotor-control pairs were not.

Moreover, the correlation persisted acrossarousal states: in waking, NREM, andREM sleep. Finally, using several statis-tical approaches, they found a remark-able correspondence between regionalcorrelations in the infraslow BOLD sig-nal and regional correlations in the in-fraslow-slow EEG signal (�0.5 Hz or1–4 Hz). Notably, another report hasjust appeared showing that mirror sites

Spontaneous BOLDfluctuations are not just

noise, but are tied tofluctuations in neural

activity.of auditory cortex across the two hemi-spheres, which show correlated BOLDactivity, also show correlated infraslowEEG fluctuations recorded with ECoGelectrodes (8). In this case, the corre-lated fluctuations reflected infraslowchanges in EEG power in the gammarange [however, no significant correla-tions were found for slow ECoG fre-quencies (1–4 Hz)].

Where Do Infraslow FluctuationsCome from?The results of He et al. (6) highlight sev-eral issues of general relevance in neu-roscience. Although infraslow fluctua-tions are a prominent, constant featureof both BOLD and EEG signals, we stilldo not know where they originate. Onepossibility is that they reflect diffuseinput from a subcortical source that isf luctuating in the infraslow range. Forexample, the firing of neurons in themidbrain reticular formation waxes andwanes with a period of �10 s duringboth wakefulness and sleep (9). Alterna-tively, neurons may slowly modulatetheir level of activity because of intrinsicchanges in excitability, in the activity ofionic pumps, of neurotransmitter trans-porters, and of glial cells (2). Last, mod-eling the overall organization of cortico-cortical connectivity suggests thatinfraslow, system-level f luctuations inactivity may be an emergent networkproperty, not reducible to properties ofindividual neurons (10).

What Wires Together Fires TogetherWhatever the source of infraslow fluctu-ations, the He et al. study (6) makes it

clear that both BOLD and ECoG fluc-tuations display a pattern of regionalcorrelations, or functional connectivity,which closely reflects those regions’ ana-tomical connectivity (11, 12). Inverting awell known adagio, what wires together,fires together. Indeed, it seems that itcould not be otherwise. If neurons areconnected in a certain way, and if theyare spontaneously active, functional con-nectivity is bound to reflect anatomicalconnectivity, just like traffic patternsmust reflect the underlying roadmap.For example, because sensorimotor re-gions are more strongly connected toregions within the sensorimotor system,rather than without, if spontaneous ac-tivity in a sensorimotor area slowly fluc-tuates up for whatever reason, it willtend to increase firing in other sensori-motor areas more reliably than else-where, leading to increased functionalconnectivity. The wire together–fire to-gether principle is bound to apply atmultiple spatial and temporal scales.Consider neurons that are coactivatedduring learning tasks and become morestrongly connected, in line with Hebbianprinciples (fire together, wire together).After learning, the same neurons showan increase in correlated firing whenthey are spontaneously active, both inquiet wakefulness and during sleep (wiretogether, fire together) (13, 14).

What Is Spontaneous Activity for, and IsIt a Distinct Mode?Whatever the significance of infraslowfluctuations, the He et al. study (6) oncemore raises the question of what mightbe the role of spontaneous activity inthe adult brain. The steady depolariza-tion and firing of neurons, even whenthe brain is supposedly ‘‘at rest,’’ alsocalled the ‘‘default mode’’ of activity(15), consumes approximately two-thirdsof the brain’s already disproportionateenergy budget (16), so it better dosomething useful. For instance, sponta-neous activity may be important for thebrain’s trillions of synapses, perhaps bykeeping them exercised or consolidatingand renormalizing their strength. An-other notion is that spontaneous activity

Author contributions: D.B., B.R., and G.T. wrote the paper.

The authors declare no conflict of interest.

See companion article on page 16039.

*To whom correspondence should be addressed. E-mail:gtononi@wisc.edu.

© 2008 by The National Academy of Sciences of the USA

www.pnas.org�cgi�doi�10.1073�pnas.0808310105 PNAS � October 14, 2008 � vol. 105 � no. 41 � 15641–15642

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may be necessary to maintain a fluidstate of readiness that allows the cortexto rapidly enter any of a number ofavailable states or firing patterns—akind of metastability (17). Theoreticalwork suggests that the repertoire ofavailable states is maximal under mod-erate spontaneous activity, and shrinksdramatically with either complete inac-tivity or hyperactivity (18). But whatkind of neural states? One possibility isthat the cortex is like a sea undulatinggently, and that evoked or task-relatedresponses would be like small ripples onits surface. This possibility is consistentwith fMRI studies, because spontaneousslow fluctuations in BOLD are as largeor larger than those evoked by stimuli(11). Also, it would fit nicely with thetrial-to-trial variability of behavioral re-sponses (19). Another possibility is thatthere are distinct modes of neuronalactivity, such as a READY mode and aGO mode (and possibly an inhibited,STOP mode). Spontaneous activitywould then be the READY mode ofneuronal firing signaling the absence ofpreferred stimuli (an ongoing, low-levelbuzz). By contrast, in the GO mode,neurons, or local populations of neu-rons, would signal the presence of a pre-ferred stimulus by firing at much higher

rates for short periods of time (a briefand loud shout). Unit recording studieshave provided plenty of evidence thatneurons respond strongly and distinctlyto specific stimuli. In this view, the cor-tex would be more like a sea pierced bysharp islands. On the other hand, theslow hemodynamic response functionunderlying the BOLD signal may makefMRI partly blind to the distinction be-tween slow, low-amplitude fluctuationsin firing and fast, high-amplitude burstsof activity (4). If there are two modes ofneural activity, it bears keeping in mindthat neurons in the READY modewould be as necessary as neurons in theGO mode in specifying different cogni-tive states, just as the background is asnecessary as the foreground.

Gamma and ConsciousnessGamma activity has often been singledout as being especially relevant to con-sciousness, and just as often it has beenmired in methodological controversies(20). In their article, He et al. (6), tak-ing advantage of clean intracranial sig-nals, report that correlations betweenpairs of regions in terms of BOLD sig-nal, and correlations in EEG power inthe gamma range (50–100 Hz), werethemselves correlated. However, they

were correlated only in wakefulness andREM sleep, but not in deep NREMsleep. Because deep NREM sleep is thetime when consciousness tends to fade,maybe the drop in gamma power corre-lations has something to do with thedrop of consciousness. However, it maywell be that the drop in gamma powercorrelations is just a symptom of some-thing more fundamental. During deepNREM sleep, the spontaneous activityof neurons throughout the cortex is re-peatedly interrupted, after just a fewhundred milliseconds, by brief DOWNstates during which neurons becomeprofoundly hyperpolarized (1). Thisbistability of neurons, due to changes inneuromodulators, is likely to make itdifficult for correlations in gammapower to establish themselves acrossdistant brain regions, hence accountingfor their symptomatic decrease. Thesame bistability, by reducing the numberof available states, may be responsiblefor the fading of consciousness duringdeep NREM sleep, in contrast to themetastability of wakefulness and REMsleep. So, although the brain may alwaysbe on, it may not always be ready.

ACKNOWLEDGMENTS. This work was supportedby National Institutes of Health Director’s Pio-neer Award and the J.S. McDonnell Foundation.

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