local action for global vision

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J Physiol 589.14 (2011) pp 3419–3420 3419 The Journal of Physiology PERSPECTIVES Local action for global vision Maxim Volgushev Department of Psychology, University of Connecticut, Storrs, CT 06269, USA Email: [email protected] Active brain cells use oxygen, but exactly how neurone activity drives brain metabolism is poorly understood. A paper by Li & Freeman (2011) in a recent issue of The Journal of Physiology sheds light on this important question, by demonstrating how indistinguishable patterns of local neural responses can be accompanied by distinct patterns of brain oxygen consumption. They cleverly exploit the topographic organisation of sensory cortices, using visual stimuli to manipulate the area of activated cortex, and show that global cortical activation can influence local measurements of neural and metabolic activity. The results are important for understanding the basis of non-invasive measures of brain function. The most common brain imaging techniques are optical imaging of intrinsic signals and functional magnetic resonance imaging (fMRI). These methods measure changes of the blood oxygen level-dependent (BOLD) signal. The BOLD signal is of special importance in brain science, because it can be measured non-invasively in humans using fMRI. Put simply, increased neuronal activity increases energy consumption, producing a decrease in tissue oxygen level (measured as the ‘initial dip’ in the BOLD signal), followed a few seconds later by a reactive increase Figure 1. Spatial relation between region of primary visual cortex activated by the stimuli and regions contributing to the recorded electrophysiological (MUA and LFP) and oxygen level (BOLD) signals of blood and oxygen supply (the ‘positive peak’). Herein, however, lies the problem of using BOLD signals to understand brain function: BOLD signals have slow dynamics and coarse spatial scale. The BOLD signal begins long after stimulus-evoked neuronal responses, when cognitive processes such as stimulus detection and recognition may have already been accomplished. Spatially, the initial dip probably integrates changes of tissue oxygen level over 0.2 mm 2 , and the positive peak integrates over 2 mm 2 (Thompson et al. 2005; Viswanathan & Freeman, 2007), encompassing many thousands of cortical neurones. Thus, neural signals and BOLD signals provide complementary, different-scale views on how the brain operates. Changes of the BOLD signal are known to be related to changes of neuronal activity, but the details of this relationship are controversial (reviewed in Logothetis 2008; Ekstrom, 2009). A key question remains: can similar changes of neuron activity be accompanied by distinct BOLD signals? The paper by Li and Freeman gives a positive answer to this question. The authors recorded from the best-understood sensory cortex: the primary visual cortex of cats. They combined recordings of neuronal multi-unit activity (MUA) and local field potential (LFP) with simultaneous, co-localized measurements of tissue oxygen level. Control neurone responses and BOLD signals were first evoked with patterned visual stimuli: patches of optimally oriented moving gratings. Next, two different stimuli which suppress neuronal responses were tested. In the first protocol (‘surround suppression’), neuronal responses are suppressed by increasing the stimulus diameter. In the second (‘cross-orientation’), neuronal responses are suppressed by superimposing an orthogonal grating on the optimally oriented grating. Although neuronal responses decreased in both cases, the BOLD signals were affected in a strikingly different way. Surround suppression produced an increase of the initial dip, but no change of the positive peak of the BOLD signal. In contrast, the cross-orientation protocol yielded a decrease of the initial dip but an increase of the positive peak. How can we reconcile this apparent contra- diction, where one level of neuronal activity is accompanied by two distinct patterns of brain metabolism changes? Consider what happens when stimulus diameter is increased from 4 deg to 20 deg in the surround suppression test. The strength of thalamic input from the lateral geniculate nucleus (LGN) to the local recording site in the cortex decreases only slightly because LGN neurones are barely sensitive to size change for stimuli over 2 deg diameter (Stone et al. 1979; Ozeki et al. 2009). More importantly, the large stimulus will activate about 60–70% of the cat’s primary visual cortex (Tusa et al. 1978), including long-range projections to the recording site from regions up to several millimetres away (Kisvarday et al. 1997). Activity around the recording electrode will be diminished as global and local inhibitory circuits work to stabilize the cortical network (Ozeki et al. 2009). A magnified BOLD initial dip could result from increased local activity of the inhibitory neurones (as the authors suggest), or as part of a more general increase of oxygen consumption over a very large (hundreds of mm 2 ) activated cortical area (Fig. 1). The BOLD positive peak does not increase with stimulus size, perhaps in part because the effect of local vaso- dilatation is shunted by the simultaneous vasodilatation over large regions of visual cortex. In Li and Freeman’s second protocol of cross-orientation suppression, the neuro- nal activity is modified in a very different way. Responses of LGN neurons will be enhanced by addition of an orthogonal (‘mask’) grating (Freeman et al. 2002; Priebe & Ferster, 2006). However, the plaid-like spatial pattern of LGN inputs is sub-optimal C 2011 The Author. Journal compilation C 2011 The Physiological Society DOI: 10.1113/jphysiol.2011.212670

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J Physiol 589.14 (2011) pp 3419–3420 3419

The

Jou

rnal

of

Phys

iolo

gy

PERSPECT IVES

Local action for global vision

Maxim VolgushevDepartment of Psychology, University ofConnecticut, Storrs, CT 06269, USA

Email: [email protected]

Active brain cells use oxygen, butexactly how neurone activity drives brainmetabolism is poorly understood. A paperby Li & Freeman (2011) in a recent issue ofThe Journal of Physiology sheds light on thisimportant question, by demonstrating howindistinguishable patterns of local neuralresponses can be accompanied by distinctpatterns of brain oxygen consumption.They cleverly exploit the topographicorganisation of sensory cortices, using visualstimuli to manipulate the area of activatedcortex, and show that global corticalactivation can influence local measurementsof neural and metabolic activity. The resultsare important for understanding the basisof non-invasive measures of brain function.

The most common brain imagingtechniques are optical imaging ofintrinsic signals and functional magneticresonance imaging (fMRI). These methodsmeasure changes of the blood oxygenlevel-dependent (BOLD) signal. TheBOLD signal is of special importance inbrain science, because it can be measurednon-invasively in humans using fMRI. Putsimply, increased neuronal activity increasesenergy consumption, producing a decreasein tissue oxygen level (measured as the‘initial dip’ in the BOLD signal), followeda few seconds later by a reactive increase

Figure 1. Spatial relation between region of primary visual cortex activated by thestimuli and regions contributing to the recorded electrophysiological (MUA and LFP)and oxygen level (BOLD) signals

of blood and oxygen supply (the ‘positivepeak’). Herein, however, lies the problemof using BOLD signals to understand brainfunction: BOLD signals have slow dynamicsand coarse spatial scale. The BOLD signalbegins long after stimulus-evoked neuronalresponses, when cognitive processes suchas stimulus detection and recognition mayhave already been accomplished. Spatially,the initial dip probably integrates changesof tissue oxygen level over ∼0.2 mm2, andthe positive peak integrates over ∼2 mm2

(Thompson et al. 2005; Viswanathan& Freeman, 2007), encompassing manythousands of cortical neurones. Thus,neural signals and BOLD signals providecomplementary, different-scale views onhow the brain operates.

Changes of the BOLD signal are known tobe related to changes of neuronal activity,but the details of this relationship arecontroversial (reviewed in Logothetis 2008;Ekstrom, 2009). A key question remains:can similar changes of neuron activity beaccompanied by distinct BOLD signals? Thepaper by Li and Freeman gives a positiveanswer to this question.

The authors recorded from thebest-understood sensory cortex: theprimary visual cortex of cats. Theycombined recordings of neuronalmulti-unit activity (MUA) and localfield potential (LFP) with simultaneous,co-localized measurements of tissueoxygen level. Control neurone responsesand BOLD signals were first evokedwith patterned visual stimuli: patchesof optimally oriented moving gratings.Next, two different stimuli which suppressneuronal responses were tested. In the

first protocol (‘surround suppression’),neuronal responses are suppressed byincreasing the stimulus diameter. In thesecond (‘cross-orientation’), neuronalresponses are suppressed by superimposingan orthogonal grating on the optimallyoriented grating. Although neuronalresponses decreased in both cases, theBOLD signals were affected in a strikinglydifferent way. Surround suppressionproduced an increase of the initial dip, butno change of the positive peak of the BOLDsignal. In contrast, the cross-orientationprotocol yielded a decrease of the initial dipbut an increase of the positive peak.

How can we reconcile this apparent contra-diction, where one level of neuronal activityis accompanied by two distinct patterns ofbrain metabolism changes?

Consider what happens when stimulusdiameter is increased from 4 deg to 20 deg inthe surround suppression test. The strengthof thalamic input from the lateral geniculatenucleus (LGN) to the local recording site inthe cortex decreases only slightly becauseLGN neurones are barely sensitive to sizechange for stimuli over 2 deg diameter(Stone et al. 1979; Ozeki et al. 2009).More importantly, the large stimulus willactivate about 60–70% of the cat’s primaryvisual cortex (Tusa et al. 1978), includinglong-range projections to the recording sitefrom regions up to several millimetres away(Kisvarday et al. 1997). Activity around therecording electrode will be diminished asglobal and local inhibitory circuits workto stabilize the cortical network (Ozekiet al. 2009). A magnified BOLD initial dipcould result from increased local activityof the inhibitory neurones (as the authorssuggest), or as part of a more generalincrease of oxygen consumption over a verylarge (hundreds of mm2) activated corticalarea (Fig. 1). The BOLD positive peak doesnot increase with stimulus size, perhapsin part because the effect of local vaso-dilatation is shunted by the simultaneousvasodilatation over large regions of visualcortex.

In Li and Freeman’s second protocol ofcross-orientation suppression, the neuro-nal activity is modified in a very differentway. Responses of LGN neurons will beenhanced by addition of an orthogonal(‘mask’) grating (Freeman et al. 2002; Priebe& Ferster, 2006). However, the plaid-likespatial pattern of LGN inputs is sub-optimal

C© 2011 The Author. Journal compilation C© 2011 The Physiological Society DOI: 10.1113/jphysiol.2011.212670

3420 Perspectives J Physiol 589.14

for activation of orientation-sensitivecortical neurons at the recording site andtheir activity will be reduced (Priebe &Ferster, 2006), thus leading to the reductionof the initial dip. The overlapping maskstimulus will also activate cortical neuronsthat prefer the orientation of the mask. Thespatial grain of the cortical orientation mapmeans that these neurons would lie outsidethe sensitivity area of electrophysiologicalrecording, and outside the area contributingto the BOLD initial dip. But these neuroneswould lie within a broader area contributingto the vasodilation response, and theiractivity could explain why the BOLDpositive peak is increased.

The results reported by Li and Freemanprovide excellent illustration of twoimportant points. First, they clearly

demonstrate the complexity of relationsbetween neuronal activity and BOLDsignals. Changes of neuronal activitymay arise from activation of differentcircuits and be mediated via differentmechanisms. Although producing thesame final measured level of neuronalactivity, the difference in underlying circuitsmay be reflected by the BOLD signals.Second, the observations show why it isessential to consider large-scale patternsof neuronal activation for understandinglocally measured processes. This illustrativeexample shows the power of combinedelectrophysiological and brain imagingmethods which provide complementary,fine-grain and large-scale perspectives onneuronal activity, and most importantlyhelp to understand how they are related.

References

Ekstrom A (2009). Brain Res Reviews 62,233–244.

Freeman TCB, Durand S, Kiper DC & CarandiniM (2002). Neuron 35, 759–771.

Kisvarday ZF, Toth E, Rausch M & Eysel UT(1997). Cerebral Cortex 7, 605–618.

Li B & Freeman RD (2011). J Physiol 589,3175–3190.

Logothetis N (2008). Nature 453, 869–878.Ozeki H, Finn IM, Schaffer ES, Miller KD &

Ferster D (2009). Neuron 62, 578–592.Priebe NJ & Ferster D (2006). Nat Neurosci 9,

552–561.Stone J, Dreher B & Leventhal A (1979). Brain

Res Reviews 1, 345–394.Thompson JK, Peterson MR & Freeman RD

(2005). J Neurosci 28, 9046–9058.Tusa RJ, Palomer RA & Rosenquist AC (1978).

J Comp Neurol 177, 213–236.Viswanathan A & Freeman RD (2007). Nature

Neurosci 10, 1308–1312.

C© 2011 The Author. Journal compilation C© 2011 The Physiological Society