REVIEWS NATUREIVol 453112 June 2008 rd.In fact,w corical moduleare instantiated ina simg basic EIN,referred to cading ove ofthe module,rather than initia ing a sequential activatio k is massive,the loc vol d and end taining ing rd and ding,or up an top-do periods ng-type or functiona apable e of large change in a y while maintai in tive on brain fun ion,it is the backwar tly in of hig (up) error signal be rea bral ing natural sleet th to s on basa and b are,respect and rked mitan Cortical utput ha s thalamicand he and reduction or cessation of firi ion of the upsta y and rge uctar uits t e fol t feat s:(1)th boriaonaandvcrticalco ctions within and be cortic ample,due Very few of the p ramid are thalamocortical (less that and less than 5%a when th on s Ils bei ④r large sustaine input c nd back to and induced tion k interposed amon ting of a variet activit visual cortex es on to their nata,and hav only local con rvat CARA synapt ells)targ ta and p of the integ other ole.chandelie sting the nal-t ratio (SNR either as d epe ha erio activity concomitant metabolic his in and imp ant dr odultor distinction wa nitially c ich ferents in the majo in all ortical the basis of th ara xon term 872 C2008 Macmillan Publishers Limited.All rights reservedin different areas of cortex is anything but straightforward. In fact, we now know that the traditional cortical input–elaboration–output scheme, commonly presented as an instantiation of the tripartite perception–cognition–action model, is probably a misleading over￾simplification16. Research shows that the subcortical input to cortex is weak; the feedback is massive, the local connectivity reveals strong excitatory and inhibitory recurrence, and the output reflects changes in the balance between excitation and inhibition, rather than simple feedforward integration of subcortical inputs17. In the context of this review, the properties of these excitation–inhibition networks (EIN) deserve special attention, and are briefly discussed below. Feedforward and feedback cortical processing. Brain connectivity is mostly bidirectional. To the extent that different brain regions can be thought of as hierarchically organized processing steps, connec￾tions are often described as feedforward and feedback, forward and backward, ascending and descending, or bottom-up and top-down18. Although all terms agree on processing direction, endowing back￾ward connections with a role of engineering-type or functional ‘feed￾back’ might occasionally be misleading, as under a theoretical generative model perspective on brain function, it is the backward connections that generate predictions and the forward connections that convey the traditional feedback, in terms of mismatch or pre￾diction error signals19. In the sensory systems, patterns of long-range cortical connectivity to some extent define feedforward and feedback pathways20. The main thalamic input mainly goes to middle layers, whereas second￾order thalamic afferents and the nonspecific diffuse afferents from basal forebrain and brain-stem are, respectively, distributed diffusely regionally or over many cortical areas, making synapses mainly in superficial and/or deep layers. Cortical output has thalamic and other subcortical projections originating in layers VI and V, respectively, and corticocortical projections mostly from supragranular layers. The primary thalamic input innervates both excitatory and inhib￾itory neurons, and communication between all cell types includes horizontal and vertical connections within and between cortical layers. Such connections are divergent and convergent, so that the final response of each neuron is determined by all feedforward, feed￾back and modulatory synapses17. Very few of the pyramid synapses are thalamocortical (less than 10–20% in the input layers of cortex, and less than 5% across its entire depth; in the primary visual cortex the numbers are even lower, with the thalamocortical synapses on stellate cells being about 5%21), with the rest originating from other cortical pyramidal cells. Pyramidal axon collateral branches ascend back to and synapse in superficial layers, whereas others distribute excitation in the horizontal plane, forming a strongly recurrent excitatory network17. The strong amplification of the input signal caused by this kind of positive feedback loop is set under tight control by an inhibitory network interposed among pyramidal cells and consisting of a variety of GABAergic interneurons22,23. These can receive both excitatory and inhibitory synapses on to their somata, and have only local con￾nections. About 85% of them in turn innervate the local pyramidal cells. Different GABAergic cells target different subdomains of neu￾rons22,24. Some (for example, basket cells) target somata and proximal dendrites, and are excellent candidates for the role of gain adjustment of the integrated synaptic response; others (for example, chandelier cells) target directly the axons of nearby pyramidal neurons, and appear to have a context-dependent role25—they can facilitate spik￾ing during low activity periods, or act like gatekeepers that shunt most complex somatodendritic integrative processes during high activity periods (for example, see up- and down states below). Such nonlinearities might generate substantial dissociations between subthreshold population activity and its concomitant metabolic demand and the spiking of pyramidal cells. Modules and their microcircuits. A large number of structural, immunochemical and physiological studies, in all cortical areas examined so far, suggested that the functional characteristics of a cortical module are instantiated in a simple basic EIN, referred to as a canonical microcircuit17 (see also Fig. 2a). Activation of a micro￾circuit sets in motion a sequence of excitation and inhibition in every neuron of the module, rather than initiating a sequential activation of separate neurons at different hypothetical processing stages. Re￾excitation is tightly controlled by local inhibition, and the time evolu￾tion of excitation–inhibition is far longer than the synaptic delays of the circuits involved. This means the magnitude and timing of any local mass activation arise as properties of the microcircuits. Computational modelling suggested that EIN microcircuits, con￾taining such a precisely balanced excitation and inhibition, can account for a large variety of observations of cortical activity, includ￾ing amplification of sensory input, noise reduction, gain control26, stochastic properties of discharge rates27, modulation of excitability with attention28, or even generation of persisting activity during the delay periods of working memory tasks29. The principle of excitation–inhibition balance implies that micro￾circuits are capable of large changes in activity while maintaining proportionality in their excitatory and inhibitory synaptic conduc￾tances. This hypothesis has been tested directly in experiments exam￾ining conductance changes during periods of high (up) and low (down) cortical activity. Alternating up states and down states can be readily observed in cerebral cortex during natural sleep or anaes￾thesia30, but they can be also induced in vitro by manipulating the ionic concentrations in a preparation so that they match those found in situ. Research showed that the up state is characterized by persist￾ing synaptically mediated depolarization of the cell membranes owing to strong barrages of synaptic potentials, and a concomitant increase in spiking rate, whereas the down state is marked by mem￾brane hyperpolarization and reduction or cessation of firing31,32. Most importantly, the excitation–inhibition conductances indeed changed proportionally throughout the duration of the up state des￾pite large changes in membrane conductance31,32. Microcircuits therefore have the following distinct features: (1) the final response of each neuron is determined by all feedforward, feed￾back and modulatory synapses; (2) transient excitatory responses may result from leading excitation, for example, due to small synaptic delays or differences in signal propagation speed, whereupon inhibi￾tion is rapidly engaged, followed by balanced activity31,32; (3) net excitation or inhibition might occur when the afferents drive the overall excitation–inhibition balance in opposite directions; and (4) responses to large sustained input changes may occur while main￾taining a well balanced excitation–inhibition. In the latter case, experimentally induced hyperpolarization of pyramidal cells may abolish their spiking without affecting the barrages of postsynaptic potentials (see ref. 31 and references therein). It is reasonable to assume that any similar hyperpolarization under normal conditions would decrease spiking of stimulus-selective neurons without affect￾ing presynaptic activity. In visual cortex, recurrent connections among spiny stellate cells in the input layers can provide a significant source of recurrent excitation26. If driven by proportional excitation– inhibition synaptic currents, the impact of their sustained activity might, once again, minimally change the spiking of the pyramidal cells. This last property of microcircuits suggests that changes with balanced excitation–inhibition are good candidates for mechanisms adjusting the overall excitability and the signal-to-noise ratio (SNR) of the cortical output. Thus microcircuits—depending on their mode of operation—can, in principle, act either as drivers, faithfully transmitting stimulus-related information, or as modulators, adjust￾ing the overall sensitivity and context-specificity of the responses28. Figure 2b summarizes the different types of excitation-inhibition changes and their potential effect on the haemodynamic responses. This interesting and important driver/modulator distinction was initially drawn in the thalamus33, in which the afferents in the major sensory thalamic relays were assigned to one of two major classes on the basis of the morphological characteristics of the axon terminals, the synaptic relationships and the type of activated receptors, the REVIEWS NATUREjVol 453j12 June 2008 872 ©2008 Macmillan Publishers Limited. All rights reserved