NATUREVol 45312 June 2008 REVIEWS of a hanges of coric qular and may cdnetcxcitationorht on might (up n in re torv n black.All g which or cortice rtical ax net excitator rtical output In thesam uperficial ortic utpu ve but would the decrea MRI sign inhibited hereas the the be paths originating am pul 。2 The initial infor ed an and s-reg rtical interactions The co the repres and high-tone reque sits res and SNR reflect the activityof se systems Electrophysiology s bination of anatomical and and nals them the ation-inhibition netw orks and fMR n th aning active is sub nent of a functi 9. inhibition teralccitatiol these conditio ps obtained ith C)2-de yglucose(2DG nen nd thly and onstrated hat the ation of blood flow CBF)(that that area is sufficie t to s the fMRIdau e th sumes an in as he spiking of many or stimulus the re e rates w suppression o All rights reserved degree of input convergence, and the activity patterns of postsynaptic neurons. The same concept also broadly applies to the afferents of the cerebral cortex34, wherein the thalamic or corticocortical axons ter￾minating in layer IV can be envisaged as drivers, and other feedback afferents terminating in the superficial layers as modulators. It can also be applied to the cortical output, whereby the projections of layer VI back to the primary relays of the thalamus are modulatory, whereas the cortico-thalamo-cortical paths originating in layer V of cortex, reaching higher-order thalamic nuclei (for example, pul￾vinar), and then re-entering cortex via layer IV, are drivers33. The initial information reaching a cortical region is elaborated and evaluated in a context-dependent manner, under the influence of strong intra- and cross-regional cortical interactions. The cortical output reflects ascending input but also cortico-thalamo-cortical pathways, whereas its responsiveness and SNR reflect the activity of feedback, and likely input from the ascending diffuse systems of the brain-stem. The neuromodulation (see ‘Neurotransmission and neuromodulation’ in Supplementary Information) afforded by these systems, which is thought to underlie the altered states of cognitive capacities, such as motivation, attention, learning and memory, is likely to affect large masses of cells, and potentially induce larger changes in the fMRI signal than the sensory signals themselves. Excitation–inhibition networks and fMRI. The organization dis￾cussed above evidently complicates both the precise definition of the conditions that would justify the assignment of a functional role to an ‘active’ area, and interpretation of the fMRI maps. Changes in excitation–inhibition balance—whether they lead to net excitation, inhibition, or simple sensitivity adjustment—inevitably and strongly affect the regional metabolic energy demands and the concomitant regulation of cerebral blood flow (CBF) (that is, they significantly alter the fMRI signal). A frequent explanation of the fMRI data sim￾ply assumes an increase in the spiking of many task- or stimulus￾specific neurons. This might be correct in some cases, but increases of the BOLD signal may also occur as a result of balanced proportional increases in the excitatory and inhibitory conductances, potential concomitant increases in spontaneous spiking, but still without a net excitatory activity in stimulus-related cortical output. In the same vein, an increase in recurrent inhibition with concomitant decreases in excitation may result in reduction of an area’s net spiking output, but would the latter decrease the fMRI signal? The answer to this question seems to depend on the brain region that is inhibited, as well as on experimental conditions. Direct haemodynamic measurements with autoradiography sug￾gested that metabolism increases with increased inhibition35. An exquisite example is the inhibition-induced increase in metabolism in the cat lateral superior olive (LSO). This nucleus, which contains the representations of low-, middle- and high-tone frequencies, receives afferents from both ears: over a two-neuron pathway from the ipsilateral ear and over a three-neuron pathway from the contra￾lateral ear. Furthermore, it has no presynaptic axo-axonic endings that might mediate presynaptic inhibition via excitatory terminals. Electrophysiology showed that the LSO afferents from the ipsilateral ear are excitatory whereas the afferents from the contralateral ear are inhibitory. This unusual combination of anatomical and physio￾logical features suggests that if one ear is surgically deafened and the animal is exposed to a high-frequency pure tone, a band of tissue in the LSO on the side opposite to the remaining active ear is sub￾jected to strictly inhibitory synaptic activity without complications by presynaptic inhibition, concurrent lateral excitation, disinhibi￾tion/excitation, or other kinds of possibly excitatory action. Under these conditions, maps obtained with [14C]2-deoxyglucose (2DG) autoradiography36 demonstrated clear increases in metabolism in the contralateral LSO37, suggesting that the presynaptic activity in that area is sufficient to show strong energy consumption despite the ensuing spiking reduction. Similar increases in metabolism during the reduction of spike rates were observed during long-lasting micro￾stimulation of the fornix, which induces sustained suppression of pyramidal cell firing in hippocampus38. a b E I I II III IVB IVC V VI IVA Thalamus Up Down Net excitation Net inhibition Increase Decrease Increase Decrease? (circuit dependent) Baseline fMRI response GABA cells Glu cells Figure 2 | Principles of excitation–inhibition circuits. a, Model of a canonical cerebral microcircuit (adapted from ref. 71). Three neuronal populations interact with each other: supragranular–granular and infragranular glutamatergic spiny neurons, and GABAergic cells. Excitatory synapses are shown in red and inhibitory synapses in black. All groups receive excitatory thalamic input. The line width indicates the strength of connection. The circuit is characterized by the presence of weak thalamic input and strong recurrence (see text for details). Glu, glutamatergic. b, Potential proportional and opposite-direction changes of cortical excitation (E) and inhibition (I). Responses to large sustained input changes may occur while maintaining a well balanced excitation–inhibition (up and down). The commonly assumed net excitation or inhibition might occur when the afferents drive the overall excitation–inhibition balance in opposite directions. The balanced proportional changes in excitation–inhibition activity, which occur as a result of neuromodulatory input, are likely to strongly drive the haemodynamic responses. NATUREjVol 453j12 June 2008 REVIEWS 873 ©2008 Macmillan Publishers Limited. All rights reserved