Penelope A. Lewis1 and Vincent Walsh2

Our brains measure timecontinuously. We are aware ofhow long we have been doing aparticular thing, how long it hasbeen since we last slept, and howlong it will be until lunch ordinner. We are ready, at anymoment, to make complexmovements requiring musclecoordination with microsecondaccuracy, or to decodetemporally complex auditorysignals in the form of speech ormusic. Our timing abilities areimpressive, diverse and worthy ofinvestigation. But they are notvery well understood.

Many models of time perceptionhave been put forward (forexample, see [1–3]), collectivelypostulating a wide variety ofdifferent mechanisms. Regardlessof their diversity, the models allagree that temporal information isprocessed in many ways: it isremembered, compared to othertemporal information, combinedwith sensory information, and usedin the production of motor outputs.

The holy grail of timing researchis to understand the ‘time-dependent process’: a mechanismequivalent to a piezoelectriccrystal in a man-made clock orthe movement of a shadow on asundial. This has proven anelusive goal, to the extent thatideas about how this mechanismmight work remain near the levelof conjecture. Researchers havehad great difficulty in pinningtiming-related activity in the brainto any specific type of function.This is largely because most timemeasurement tasks draw uponmore than one process, making itdifficult to tease the variouscomponents apart. In their recentstudy, Janssen and Shadlen [4]have shown how single unitrecording can be used to partiallybypass this issue.

Janssen and Shadlen [4]recorded time-sensitiveresponses in the lateral inferiorparietal (LIP) cortex of themacaque. They trained twomonkeys to perform a visual delaytask: the monkeys first fixated alight, then, in response to a ‘go’signal, moved their eyes to a

peripheral visual target as quicklyas possible (Figure 1). The delaybetween target onset and ‘go’signal varied according to twoschedules: a bimodal schedule inwhich the ‘go’ cue could comeearly or late, but not between 0.75and 1.75 seconds, and a unimodalschedule in which it camebetween 0.5 and 2 seconds. Theschedules were presented inalternating blocks. The observedneural spike frequency in LIPcorrelated with the expectancy —‘hazard function’ — of the ‘go’ cue

6. Johnston, R.J., and Hobert, O. (2003). AmicroRNA controlling left/right neuronalasymmetry in Caenorhabditis elegans.Nature 426, 845–849.

7. Stark, A., Brennecke, J., Russell, R.B.,and Cohen, S.M. (2003). Identification ofDrosphila MicroRNA Targets. PLoS Biol.1, 1–13.

8. Lai, E.C. (2004). Predicting and validatingmicroRNA targets. Genome Biol. 5, 115.

9. Bartel, D.P. and Chen, C.Z. (2004).Micromanagers of gene expression: thepotentially widespread influence ofmetazoan miRNAs. Nat. Rev. Genet. 5,396–400.

10. Hobert, O. (2004). Common logic oftranscription factor and miRNA action.Trends Biochem. Sci. 29, 462–468.

11. Giraldez, A.J., Cinalli, R.M., Glasner,M.E., Enright, A.J., Thomson, M.J.,Baskerville, S., Hammond, S.M., Bartel,D.P., and Schier, A.F. (2005). MicroRNAsregulate brain morphogenesis inzebrafish. Science, epub ahead of print[DOI: 10:1126/Science. 1109020].

12. Murchison, E.P., and Hannon, G.J.

(2004). miRNAs on the move: miRNAbiogenesis and the RNAi machinery.Curr. Opin. Cell Biol. 16, 223–229.

13. Wienholds, E., Koudijs, M.J., van Eeden,F.J., Cuppen, E., and Plasterk, R.H.(2003). The microRNA-producing enzymeDicer1 is essential for zebrafishdevelopment. Nat. Genet. 35, 217–218.

14. Ciruna, B., Weidinger, G., Knaut, H.,Thisse, B., Thisse, C., Raz, E., andSchier, A.F. (2002). Production ofmaternal-zygotic mutant zebrafish bygerm-line replacement. Proc. Natl. Acad.Sci. USA 99, 14919–14924.

15. Schier, A.F. (2001). Axis formation andpatterning in zebrafish. Curr. Opin.Genet. Dev. 11, 393–404.

16. Kanellopoulou, C., Muljo, S.A., Kung,A.L., Ganesan, S., Drapkin, R., Jenuwein,T., Livingston, D.M., and Rajewsky, K.(2005). Dicer-deficient mouse embryonicstem cells are defective in differentiationand centromeric silencing. Genes Dev.19, 489–501.

17. Chang, S., Johnston, R.J., Frokjaer-Jensen, C., Lockery, S., and Hobert, O.

(2004). MicroRNAs act sequentially andasymmetrically to control chemosensorylaterality in the nematode. Nature 430,785–789.

18. Chen, C.Z., Li, L., Lodish, H.F., andBartel, D.P. (2004). MicroRNAs modulatehematopoietic lineage differentiation.Science 303, 83–86.

19. Bernstein, E., Kim, S.Y., Carmell, M.A.,Murchison, E.P., Alcorn, H., Li, M.Z.,Mills, A.A., Elledge, S.J., Anderson, K.V.,and Hannon, G.J. (2003). Dicer isessential for mouse development. Nat.Genet. 35, 215–217.

Department of Biochemistry andMolecular Biophysics, Center forNeurobiology and Behavior, ColumbiaUniversity, College of Physicians andSurgeons, New York, New York 10032,USA. E-mail: or38@columbia.edu

DOI: 10.1016/j.cub.2005.05.006

Dispatch R389

Time Perception: Components ofthe Brain’s Clock

We know the human brain contains some kind of clock, butdetermining its neural underpinnings and teasing apart its componentshave proven difficult. New work on the parietal cortex illustrates howsingle unit recording may be able to help.

Figure 1. The task used by Janssen andShadlen [4].

The monkey made eye movements tothe red target as soon as the fixationpoint dimmed. Only trials in which thetarget appeared in the response field ofthe LIP neuron were reported. A bracketdemarcates the random waiting timebetween target onset and ‘go’ signal.(Reproduced with permission [4].)

Go-signal

Target offset

Fixation

Time

Rando

m w

ait tim

e

Current Biology

for each of the two delayschedules.

These results build upon thefindings of an earlier paper fromthe same group [5] in which LIPneurons were recorded during atemporal discrimination task.Monkeys fixated duringpresentation of a standard timeinterval, as defined by a light,followed by a variable probeinterval defined in the samemanner. They then indicated thatthe probe was longer than thestandard by saccading to aperipheral green target, or shorterby saccading to a peripheral redtarget (Figure 2). Recordings fromLIP neurons showed that thosewith the short (green) light in theirreceptive field responded at ahigh frequency until the durationof the standard had elapsed, atwhich time their responsegradually decreased. Neuronswith the long (red) light in theirreceptive field gradually increasedresponding, such that theirresponse rates eventually‘crossed over’ and exceededthose of the green light neurons.

Taken together, these datasetsdemonstrate that neurons inmacaque LIP can respond totemporal information. The originof that information and thepurpose of such responsesremain open for debate. If you aresearching for the holy grail andyou come across a shiny goldencup, it is natural to speculate thatthis is your object. Shadlen andcolleagues have done so by

suggesting that the neurons theyobserved measure time: “.. themonkey could base its judgementof time on the discharge ofneurons with properties like theones we observe” [5]. One of theirarguments in favour of thisinterpretation is that the gradualchange from high to low firingrates precludes input from anoutside timer because the smoothshift in responding is inconsistentwith information from a discreetdecision. This pattern does not,however, exclude the involvementof input from a graded externaltiming signal [6].

In the more recent paper,Janssen and Shadlen [4] admitthat they “cannot determinewhether the timing-relatedanticipatory activity arises in areaLIP or is simply passed to LIPfrom other structures that havebeen implicated in intervaltiming”. Their results show thatLIP responds along anexpectation function or ‘hazardrate’ predicting the time of eyemovements. It is unlikely that acentral clock, providing timesignals to a variety of brainregions for a variety of purposes,would compute such a function.These data therefore suggesteither a localized parietal timer foreye movements or at least alocalized calculation of the hazardrate based upon external timingsignals. From the perspective ofthose not involved in finding thegolden cup, the latter possibilityappears just as likely as the

former. It therefore seemsimprudent to assume that theseneurons actually measure timeuntil more evidence isforthcoming. Furthermore, thepattern of response in these cellsis not consistent with activitypatterns predicted by networkmodels of timing, for which onemight expect either a periodicsignal similar to the ticking of aclock [1,3] or a gradual andpredictable ramping up or downof activity [2]. The authors haveproposed no mechanism for sucha function, and no mechanism isobvious from the literature ateither the cellular or network level.Because LIP is widely connected,temporal information could easilybe passed to it from other parts ofthe brain, a scenario which wouldbe in better keeping with the largeexisting literature implicatingstructures such as cerebellum [7],basal ganglia [7,8], SMA [9] anddorsolateral prefrontal cortex[10,11] as the seat of timemeasurement. Thus, there is littleevidence to suggest that this isthe true grail, and quite a bit tosuggest that it is not.

If LIP neurons do not measuretime, what is the function of theirtemporally sensitive response?The most obvious possibility is arole in preparation for eyemovements. This is certainlyworth considering given that theneurons in question wereselected because they respondedduring preparation for suchmovements. Leon and Shadlen [5]argue against this explanation,pointing out, amongst otherthings, that they did not find acorrelation between the responsefunctions of these neurons andeye movements. The subsequentdemonstration by Janssen andShadlen [4] of a correspondencebetween activity in these cellsand the expectation that amovement will be cuedundermines this argument, asdoes the observation that neuralresponse frequency or‘expectation’ is reflected inmovement response times.

Taken together with the clearadaptive advantage conveyed bya tendency to prepare movementonly when a cue to move isexpected, these data provide

Current Biology Vol 15 No 10R390

Figure 2. The time-discrimination task used byLeon and Shadlen [5].

A central, blue fixation pointturned white for either 316or 800 ms (the standardcue). After delay of between500 and 1000 ms, the cueagain turned white for avariable period (the testcue). Following a secondvariable delay between 100and 1000 ms the bluefixation point disappearedand the monkey made asaccade to one of the twoperipheral targets, indicatingwhether the monkey hadjudged the test cue to belonger (red) or shorter(green) than the standardcue.

Go

Delay (0.1 - 1 s)

Fixation

Time

Delay (0.5 -1 s)

Standard cue

Test cue

Longor

Short ?

Current Biology

substantial support for thepossibility that the LIP activity inquestion is associated withpreparation for eye movement.The alternative interpretationoffered by Janssen and Shadlen[4], “the intention-related signalsseen in our experiments couldunderlie a shift in spatial attentionthat is not in competition with aneye movement plan” [4], is notobviously compelling. However, arelated scenario in which thesecells code for intentionalityregarding a response, withoutbeing involved in a specific motorplan or tied to a specific motoraffector, should also beconsidered.

The likelihood that LIP neuronsdo not actually measure time, andthat their temporally sensitiveresponding codes instead for eyemovement, do not render thesefindings uninteresting to the fieldof time measurement. The parietalcortex is frequently activated inneuroimaging studies of timing —for example, see [8,12], but seealso review [11] — and damage tothis region [13], as well astemporary disruption viatranscranial magnetic stimulation,have both been shown to causetemporal deficits. A number ofauthors have speculated aboutthe role of parietal cortex intemporal processing, with somepapers [8,14] suggesting anattentional function, whileanother[15] suggests a system forcalculating magnitude. Until now,little has been known about howthese involvements could bemanifest at the neural level.

The demonstration by Janssenand Shadlen [4] that individual LIPneurons can respond to visuo-temporal information confirmsthat temporal information isavailable to the parietal cortex.These findings also provide noveland welcome insight into whatthis area may be doing in timemeasurement tasks, suggestingthat the role of parietal cortex inmultisensory integration and theplanning of action extends to themodality of time. Thus, byexploring temporal processing inthe parietal cortex with single unitrecording, Shadlen’s group hastaken a useful step towardsdescribing the type of temporal

processes performed in thatregion. Their work is also novelbecause it illustrates the potentialof single unit recording as a toolfor discrimination between thedifferent forms of temporalprocessing: perception, memory,preparation for movement, and soon. Similar work in otherstructures associated with timingmay lead to even greater insights.Thus, Shadlen and colleaguesmay not have found the holy grailof timing research, but they havecertainly discovered a treasuretrove of information which willundoubtedly lead to a betterunderstanding of this system. Andreally, its about time.

References1. Gibbon, J. (1977). Scalar expectancy

theory and Weber’s law in animal timing.Psychol. Rev. 84, 279–325.

2. Staddon, J.E., and Higa, J.J. (1999). Timeand memory: towards a pacemaker-freetheory of interval timing. J. Exp. Anal.Behav. 71, 215–251.

3. Grossberg, S., and Schmajuk, N.A.(1989). Neural dynamics of adaptivetiming and temporal discriminationduring associative learning. Neural Netw.2, 79–102.

4. Janssen, P., and Shadlen, M.N. (2005). Arepresentation of the hazard rate ofelapsed time in macaque area LIP. Nat.Neurosci. 8, 234–241.

5. Leon, M.I., and Shadlen, M.N. (2003).Representation of time by neurons in theposterior parietal cortex of the macaque.Neuron 38, 317–327.

6. Walsh, V. (2003). Time: the back-door ofperception. Trends Cogn. Sci. 7,335–338.

7. Ivry, R.B., and Spencer, R.M. (2004). Theneural representation of time. Curr. Opin.Neurobiol. 14, 225–232.

8. Rao, S.M., Mayer, A.R., and Harrington,D.L. (2001). The evolution of brainactivation during temporal processing.Nat. Neurosci. 4, 317–323.

9. Macar, F., Vidal, F., and Casini, L. (1999).The supplementary motor area in motorand sensory timing: evidence from slowbrain potential changes. Exp. Brain Res.125, 271–280.

10. Onoe, H., Komori, M., Onoe, K., Takechi,H., Tsukada, H., and Watanabe, Y.(2001). Networks recruited for timeperception: a monkey positron emissiontomography (PET) study. Neuroimage 13,37–45.

11. Lewis, P.A., and Miall, R.C. (2003).Distinct systems for automatic andcognitively controlled timemeasurement: evidence fromneuroimaging. Curr. Opin. Neurobiol. 13,250–255.

12. Coull, J.T., Vidal, F., Nazarian, B., andMacar, F. (2004). Functional anatomy ofthe attentional modulation of timeestimation. Science 303, 1506–1508.

13. Harrington, D.L., Haaland, K.Y., andKnight, R.T. (1998). Cortical networksunderlying mechanisms of timeperception. J. Neurosci. 18, 1085–1095.

14. Macar, F., Lejeune, H., Bonnet, M.,Ferrara, A., Pouthas, V., Vidal, F., andMaquet, P. (2002). Activation of thesupplementary motor area and ofattentional networks during temporalprocessing. Exp. Brain Res. 142,475–485.

15. Walsh, V. (2003). A theory of magnitude:common cortical metrics of time, spaceand quantity. Trends Cogn. Sci. 7,483–488.

1Institute of Science and Culture, 187The Terrace, Wellington, New Zealand.E-mail: plewis@fil.ion.ucl.ac.uk2Institute of Cognitive Neuroscience &Department of Psychology, UniversityCollege London, 17 Queen Square,London WC1N 3AR, UK.

DOI: 10.1016/j.cub.2005.05.008

Dispatch R391

Christof Niehrs

The Spemann-Mangold organizerof vertebrate embryos plays aparamount role duringembryogenesis by releasing acocktail of molecules that inducethe embryonic axes and variouscell fates. Bone morphogeneticprotein (BMP) antagonists are animportant class of such inducers,as was discovered in Xenopus,where their over-expression hasdramatic effects, such as inducing

a secondary embryonic axis. Bycontrast, studies in highervertebrates — such as chickenand mouse — have yielded lessimpressive results and have led toa controversy over how importantBMP antagonists really are andwhat their precise role is. In a boldapproach, Khoka et al. [1] havenow knocked down in parallelthree BMP antagonists inXenopus embryos and observedramatic effects on embryonicaxis formation.

Axis Formation: Redundancy Rules

The role of BMP antagonists in the Spemann-Mangold organizer ofvertebrate embryos is a controversial issue. A study using combinedknock down of multiple antagonists finally reveals dramatic effects.