The outer layer of the cerebral hemispheres of the brain

The cerebral cortex (Latin for bark, rind, shell) is a mul-tilayered, convoluted sheet of tissue overlaying the cerebral hemispheres. In humans it is 3-4 mm thick, covering -2600 cm2. It contains at least 1010 neurons and about the same number of glia cells. From a phylogenetic perspective, three types of cortices are discerned: archicortex ("hippocampal formation), paleocortex (olfactory, enthorhinal, and peri"amyg-daloid cortex), and neocortex. The neocortex forms the bulk of the mammalian cerebral cortex, and is critical for the most advanced mental abilities of our species.1

Multiple macroscopic and microscopic "criteria are used in the cartography of the cortex (Jones and Peters 1984-94; White 1989; Mountcastle 1997). First and foremost, the cortex can be described as composed of lobes, the major ones being the frontal, temporal, parietal, and occipital (Figure 10a). The cortex can also be mapped on the basis of function and functional hierarchy (sensory, motor, and 'association cortex'; or primary and higher-order cortex; or unimodal, polymodal, and supramodal cortex2). Finer parcellation into areas is based on cellular architectonics. The most popular map, containing 52 areas, was introduced by Brodmann about 100 years ago. The cytoarchitecture of the cortex is usually described in term of laminar and columnar organization. A six-layer classification, I-VI, first introduced by Brodmann, is conventionally used to describe the laminar structure of the neocortical sheet (Figure 10b). Further subdivision of the major layers is added, e.g. VIa-c. Layer I is the one immediately beneath the pia matter, and layer VI the closest to the white matter. The layers contain pyramidal cells, which are the most abundant neurons in the cortex, and various types of nonpyramidal neurons. The arrangement of afferents and efferents in each layer depends on the area and the species, but in general, thalamocortical afferents end predominantly in the middle layers, whereas cortico-cortical afferents synapse on to neurons in layers I-IV. Several diffused neuromodulatory systems (e.g. "acetyl-choline, "dopamine, "noradrenaline) reach the cortex mostly in layers I and VI. In most cases, cortical neurons in layers II-III project to other cortical areas and those in deeper layers project to subcortical structures. The other organizational principle in the cortex is the division into columns. The column, 0.1-0.5 mm wide, is regarded by many authors as the universal organizational and computational unit of the cortex (Mountcastle 1997).3 Most of the axonal arbour of cortical neurons lies within the cortical column (Douglas et al. 1995). Even in layers that are major recipients of thalamic input, the great majority of the "synapses still mediate information from within the column (Ahmed et al. 1994). Another interesting observation is that about 85% of the synapses of the excitatory neurons synapse on to other excitatory neurons. The computational theory and algorithms ("level) beyond all this gigantic collection of recurrent mini-circuits is still mostly an enigma.

Fig. 10 (a) A macroscopic view of the cerebral cortex: simplified drawing of the lateral surface of the human brain, showing the major cortical lobes.The primary visual cortex is in the occipital lobe, and higher-order visual areas reside in the occipital, temporal, and parietal lobes. The primary and higher-order auditory cortex is in the temporal lobe; primary and higher-order somatosensory areas in the parietal lobe; and primary and higher-order motor cortex in the frontal lobe. The primary taste area is in the insular cortex, which is in the medial wall of the lateral sulcus (groove) that separates the frontal from the temporal lobe, and is invisible on this lateral view, and higher-order taste cortex is in the orbitofrontal cortex. The olfactory (piriform) cortex, on the ventrolateral surface of the brain, which is also invisible in this view, is an ancient part of the cortex (paleocortex). Areas that subserve higher cognitive functions, including *planning, *prospective memory, and *working memory, are in the frontal lobe. (b) A microscopic view of the cortex: Left, stained frontal section of the rat primary visual cortex, showing nerve cell bodies in different cortical layers. WM, white matter. (From Peters 1985.) Right, simplified diagram of elements of cortical circuits. BC, basket cell; CH, chandelier cell; DP, deep pyramidal neuron; SI, superficial inhibitory neuron; SP, superficial pyramidal neuron; ST, stellate cell. Shown also are major afferent and efferent pathways. CTX, cortex; SUBCTX, subcortical areas; TH, thalamus. Open triangles—excitatory synapses; closed triangles—inhibitory synapses. The great majority of the connections of cortical cells are formed with other cortical cells. (After Shepherd 1988.)

Fig. 10 (a) A macroscopic view of the cerebral cortex: simplified drawing of the lateral surface of the human brain, showing the major cortical lobes.The primary visual cortex is in the occipital lobe, and higher-order visual areas reside in the occipital, temporal, and parietal lobes. The primary and higher-order auditory cortex is in the temporal lobe; primary and higher-order somatosensory areas in the parietal lobe; and primary and higher-order motor cortex in the frontal lobe. The primary taste area is in the insular cortex, which is in the medial wall of the lateral sulcus (groove) that separates the frontal from the temporal lobe, and is invisible on this lateral view, and higher-order taste cortex is in the orbitofrontal cortex. The olfactory (piriform) cortex, on the ventrolateral surface of the brain, which is also invisible in this view, is an ancient part of the cortex (paleocortex). Areas that subserve higher cognitive functions, including *planning, *prospective memory, and *working memory, are in the frontal lobe. (b) A microscopic view of the cortex: Left, stained frontal section of the rat primary visual cortex, showing nerve cell bodies in different cortical layers. WM, white matter. (From Peters 1985.) Right, simplified diagram of elements of cortical circuits. BC, basket cell; CH, chandelier cell; DP, deep pyramidal neuron; SI, superficial inhibitory neuron; SP, superficial pyramidal neuron; ST, stellate cell. Shown also are major afferent and efferent pathways. CTX, cortex; SUBCTX, subcortical areas; TH, thalamus. Open triangles—excitatory synapses; closed triangles—inhibitory synapses. The great majority of the connections of cortical cells are formed with other cortical cells. (After Shepherd 1988.)

A few "generalizations that emerge from the functional neuroanatomy of the cortex are of potential relevance to memory. First, although different areas of the cortex share the basic design of local circuits, the particular afferent and efferent destinations of discrete cortical areas turn the cortex functionally nonhomo-geneous. This differentiation, evident already from the macroscopic functional map of the cortex (Figure 10a), imposes gross limits on the distribution of storage of each item in memory, especially if this item is modality specific, such as a visual scene, tone, or taste. The adult cortex is hence not really equipotential, as was inferred from certain early attempts to search for the "engram. Second, at the same time, long-range connections in the cortex provide it with the potential to subserve rich associativity, potentially permitting the same item in memory to be ultimately accessed and "retrieved via different "cues. And third, the configuration of afferents and efferents of cortical columns fits neatly to subserve processing of target information (thalamic input), "context (diffused systems input, corticocortical connectivity), and "associations (corticocortical connectivity). However, the relevance of this hardware configuration to the computation and encoding of discrete "stimuli, context, and associations, respectively, is yet unclear.

Ample evidence shows that the cortex indeed subserves some types of learning and memory. This evidence is either suggestive, or correlational, or proves necessity, but in no case so far does it prove sufficiency and exclusiveness ("criterion). Sufficiency and exclusiveness, we should remember, are hardly to be expected: the cortex interacts with other brain systems in locating, associating, construing, and assessing information about the world.

1. The cortex is highly *plastic. Remarkable morphological and functional plasticity is evident in "development as well as in the adult brain in response to sensory stimuli and injury (e.g. Krech et al. 1960; Wiesel 1982; Sadato et al. 1996; Buonomano and Merzenich 1998; Crair et al. 1998; "map). This plasticity is a candidate vehicle for learning and memory.

2. The cortex is rich in synaptic components that subserve learning. These components can be shown to be altered with learning, and further, their disruption in cortex blocks learning, "consolidation, and "experimental extinction of memory (e.g. Berman and Dudai 2001; "coincidence detector; "CREB, "immediate early genes, "glutamate; "long-term potentiation; "protein kinase; "receptor).

3. Cortical lesions impair learning and memory. This can be shown by inducing circumscribed lesions in animals or by observing the effect of brain damage in human patients (e.g. Luria 1966; Penfield and Rasmussen 1968; Shallice 1988; Squire and ZolaMorgan 1991; Suzuki et al. 1993; Mishkin and Murray 1994; "amnesia, "planning, "working memory).

4. The activity of specific cortical areas is altered in *acquisition and retrieval of memory. This can be shown by "functional neuroimaging (e.g. Nyberg et al. 1996; Karni et al. 1998; Kelley et al. 1998; Wagner et al. 1998a,b; Wheeler et al. 2000).

5. The activity of cortical neurons correlates with the acquisition and retention of memory. The activity of nerve cells in unimodal, polymodal, and supramodal cortex in the "monkey and in the "rat was found to be specifically correlated with mnemonic performance in a variety of tasks (e.g. Funahashi et al. 1989; Schoenbaum and Eichenbaum 1995; Fuster 1995a,fc; Quirk et al. 1997; Zhou and Fuster 1997; Erickson and Desimone 1999; Super et al. 2001). Two general types of findings are noteworthy (Eichenbaum 1997b): (a) cortical neurons can modulate their response to the target stimulus over the course of learning, and retain the change afterwards, and (b) cortical neurons can sustain or reactivate responses over the task in the absence of the stimulus (Figure 11).

The particular role(s) of the cortex in learning and memory is far from being understood. Such understanding requires, among others, deciphering the neuronal code(s) used by the cortex in registration and reactivation of "internal representations (for a selection of approaches, see Abeles 1991; Gawne and Richmond 1993; Konig et al. 1996; Shadlen and Newsome 1994; "cell assembly). In the meantime, it might be useful to think about memory in cortex in the following way: "percepts are formed in modality specific cortex, or in a combination of such cortici, and are registered in collaboration with activity in supramodal cortex and extracortical circuits, such as limbic circuits in the case of "declarative information, striatal circuits in the case of "skill and "habit, and neuromodulatory pathways ("neurotransmitter) in all these cases. Upon consolidation, the representation may become independent of some of the circuits that were obligatory for its encoding and registration (e.g. hippocampus in declarative memory). The representation may also invade new circuits, hence become associated with additional representations. The registered information is ultimately distributed over the relevant unimodal and polymodal cortical areas. Retrieval of the information may require

Fig. 11 Mnemonic performance of cortical neurons in the monkey. (a) Spike frequency histogram (i.e. activity level measure) of a unit in the inferotemporal cortex during a delayed matching to sample task ('delay task). The 'subject selected one of several colours to match a sample presented before the delay. The unit increased its activity only during the delay if the sample was red (solid line, shaded histogram) but not green (broken line, superimposed on the red response histogram). S, sample, M, match. (After Fuster and Jervey 1982.) (b) Spike frequency histograms of two units in the dorsolateral prefrontal cortex during a visuospatial delayed response task, in which the monkey learned which of two identical wooden blocks covers a baited food well. The upper unit increased firing in the 'cue period, during which the monkey observed the baiting and covering of the wells, and in the choice period, following the delay. In contrast, the lower unit increased activity during the delay. (After Fuster 1973.) One interpretation of the data is that the neurons in both cortici (which are depicted in the insets, respectively) retain task-specific information.

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activation, co-ordination, and monitoring by the supramodal cortex, particularly the prefrontal cortex. In retrieval, cortical areas that have subserved the acquisition of the information in the first place, may become activated again. This reactivation, however, is unlikely to generate a representation identical to the one at the moment of acquisition. This is because the information has been pruned and associated over time, and, furthermore, is affected by the context of retrieval, which is contributed by exogenous stimuli as well as by the spontaneous, endogenous activity of the cortex at the moment of retrieval. Hence, we may use many "metaphors to describe the cortex, but a hard disk is clearly not a suitable one.

Selected associations: Cell assembly, Conscious awareness, Engram, Functional neuroimaging, Recall

1 For the sake of convenience, 'cortex' will be used throughout this text to refer to the neocortex, or the neocortex and paleocortex (archicor-tex is discussed separately under 'hippocampus). The accurate term is, however, cerebral cortex, as the 'cerebellum also has a cortex.

2Modal refers to sensory modality. As to the notion of association cortex, it can be traced back to the observation that some cortical areas did not display sensory or motor response in lesion or stimulation experiments. These areas were first called 'silent areas' and later 'association areas' because it was thought that they associate the sensory and motor information. The term association cortex is losing favour, and in any case should not be taken to imply that only these areas perform associations; all cortical areas are probably capable of some or another type of associations.

3The concept of cortical column is based on structural and functional observations. Neuroanatomy has shown that columns of nerve cells are discrete structural units. Cellular physiology has shown that vertical aggregates of cortical neurons could be discerned on the basis of their response to a certain 'stimulus 'dimensions. Columns can also be detected nowadays by 'functional neuroimaging (Kim et al. 2000). The concept of cortical column appeals to 'reductionists because it reinforces the notion that cortical function can be dissected into elementary modules. There are, however, voices who oppose this atomistic approach to cortical function (e.g. Fuster 2000a).

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