Neuronal Correlates to Consciousness. the _Hall of Mirrors_ Metaphor

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Research Report

Neuronal correlates to consciousness. The “Hall of Mirrors”metaphor describing consciousness as an epiphenomenon of multiple dynamic mosaics of cortical functional modules

Luigi Francesco Agnat ia,⁎ , 1, 2, Diego Guidolinb, 1, Pietro Cortellic , 2, Susanna Genedanid,

Camilo Cela-Conde

e

, Kjell Fuxe

f

aFondazione IRCCS San Camillo, Venezia Lido, ItalybDepartment of Molecular Medicine, University of Padova, Padova, ItalycDepartment of Neurological Sciences, Alma Mater Studiorum, University of Bologna, ItalydDepartment of Biomedical Sciences, University of Modena and Reggio Emilia, Via Campi 287, Modena, ItalyeUniversity of the Balearic Islands, Palma de Mallorca, Spainf Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden

A R T I C L E I N F O A B S T R A C T

Article history:

Accepted 4 January 2012

Available online 11 January 2012

Humans share the common intuition of a self that has access to an inner ‘theater of mind’

(Baars, 2003). The problem is how this internal theater is formed. Moving from Cook's view

(Cook, 2008), we propose that the ‘sentience’ present in single excitable cells is integratedinto units of neurons and glial cells transiently assembled into “functional modules”

(FMs) organized as systems of encased networks (from cell networks to molecular

networks). In line with Hebb's proposal of ‘cell assemblies’, FMs can be linked to form

higher-order mosaics by means of reverberating circuits. Brain-level subjective awareness

results from the binding phenomenon that coordinates several FM mosaics. Thus,

consciousness may be thought as the global result of integrative processes taking place at

different levels of miniaturization in plastic mosaics. On the basis of these neurobiological

data and speculations and of the evidence of ‘mirror neurons’ the ‘Hall of Mirrors’ is

proposed as a significant metaphor of consciousness.

This article is part of a Special Issue entitled: Brain Integration.

© 2012 Elsevier B.V. All rights reserved.

Keywords:

Consciousness

Cellular sentience

Functional module mosaic

Mirror neuron

Internal theater

Hall of Mirrors

1. Introduction

Humans seem to share a common intuition of a ‘self ’ that has

access to conscious sensations, inner speech, images and

thoughts (self-consciousness). This intuition may be

metaphorically described as a “theater of mind” (Baars et al.,

2003), and conscious events can be defined as those brain

activities a subject can accurately report in optimal conditions

(Baars et al., 2003). Once the assumption of a chemico-

physical basis of consciousness has been accepted, we are

B R A I N R E S E A R C H 1 4 7 6 ( 2 0 1 2 ) 3 – 2 1

⁎ Corresponding author at: Fondazione IRCCS San Camillo, Via Alberoni, 70, Venezia Lido, Italy. Fax: +39 041 731330.E-mail address: [email protected] (L.F. Agnati).

1 These authors equally contributed to the paper.2 Dedicated to Professor Angelo Pierangeli (1932–2010) and to Professor Pasquale Montagna (1950–2010), University of Bologna.

0006-8993/$ – see front matter © 2012 Elsevier B.V. All rights reserved.doi:10.1016/j.brainres.2012.01.003

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http://dx.doi.org/10.1016/j.brainres.2012.01.003



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confronted with the question of how brain activity leads to

conscious experiences, i.e., what are the neuronal correlates

of consciousness (NCC). As Chalmers emphasizes, the search

for NCCs is the cornerstone of the recent resurgence of the

science of consciousness (Chalmers, 2000). NCCs have become

important in the wake of the enthusiasm generated by neuro-

imaging techniques, which correlate specific cognitive tasks

with the activation of restricted brain areas, making therelationships between psychology and neurobiology more

realistic and fruitful (Monti et al., 2010). This research effort

allowed to show that conscious perceptual processing

involves the sequential activation of cortical networks at

several brainlocationswith theonset of oscillatory synchronous

activity (Gray et al., 1989a, 1989b). Hence, studies on conscious-

ness must explore both a temporal and spatial dimension.

As far as the temporal dimension of conscious events is

concerned, Pöppel and Logothetis (1986) investigated reaction

times to visual stimuli, and proposed that perceptual proces-

sing operates in basic unitsof 30 ms, while conscious episodes

composing the “conscious present” can be extended to

periods of 2 or 3 s (Pöppel, 1994). Studies in humans based

on the event-related potential (ERP) paradigm allow an esti-

mate of the temporal dynamics of conscious perceptual pro-

cessing. ERP measures the temporal location of brain events

correlated with conscious processing evoked by stimulus pre-

sentation. These studies indicate that the ERP P300 and N400

components are related to working memory and/or attention

functions that probably involve conscious processing (Coull,

1998; Knight, 1997). The corresponding brain events occur

from 300 to 400 ms after stimulus presentation. According

to Pereira and Furlan (2009), these data suggest that 200 ms

can be a good estimation of the minimum temporal duration

from stimuli presentation to the formation of a conscious

percept.

Therefore, the neuronal activity required to support

conscious processing would need to be sustained from 200 ms

to 2/3 s. Consistently, studies on subliminal perception

(Murphy and Zajonc, 1993) reveal that a visual stimulus pre-

sented for only 5 ms and followed by a mask is not consciously

perceived, although it may have unconscious priming effects.

This implies that a threshold input firing for perceptual con-

sciousness has not been reached (Pereira and Furlan, 2010).

Since such an appropriate temporal dynamics (from

200 ms to 2/3 s) of conscious events is the result of processes

linking a large network of brain systems (Buzsáki, 2007;

Laureys, 2005), it follows that the spatial dimension (i.e. the

brain's morpho-functional organization) is a key feature to

consider in order to derive deductions on the communication

modes involved in brain integrative processes leading to

conscious percepts.

In the present review aspects of the brain's morpho-

functional organization corresponding to increasing levels of

integration will be addressed(also basedon data andhypotheses

proposed by our group). In particular, the following issues

and their relevance for consciousness formation will be

analyzed:

1. Recent findings on the special features of neurons and

astrocytes (Agnati et al., 1995; Allman et al., 2005; Pereira

and Furlan, 2010; Premack,2007 ) and the possibleexistence

of a proto-consciousness phenomenon founded on the

mechanism of cell ‘sentience’ (Cook, 2008; Sevush, 2006);

2. The Volume and Wiring Transmission (VT, WT) modes of

communication processes in the brain (Agnati et al.,

2005a, 2010a) will be briefly examined since they are the

fundamental neurobiological mechanisms that allow the

dynamic formation of cell assemblies and the integration

of their activity.3. The concept of mosaics of computational elements will be

introduced (Agnati et al., 1982, 1990, 2007a, 2008). In particu-

lar, the cellular mosaic (Functional Module, FM) formed by

neuron–astroglialinteractionswill be analyzed andproposed

to be capable of a first-level integrative sentience;

4. Mechanisms for large-scale integration of FMs into

mosaics of higher-order leading to the formation of the neu-

ronal correlates of consciousness allowing the integration of

different percepts will be analyzed from the neurobiological

perspective.

Finally, these aspects will be used to propose a new inter-

pretative metaphor of consciousness, namely the brain as a

‘Hall of Mirrors’.

2. Special features of neurons and astrocytesin the human brain

A neurobiological approach to the human capacity for

auto-reflection should start at the lower level to clarify the

fundamental question of what neural substrates make a

human being human (DeFelipe et al., 2002). Plainly, these

investigations focused on the amount of neurons and synaptic

contacts, the presence of some type of special neurons, the

properties of astrocytes and, of major potential interest, a

comparison of possible specific features in some transmitter-

identified neuronal systems such as monoamine systems

(for details see Fuxe et al., 2010).

2.1. Neuronal aspects specific to the human brain

Let us start by examining some data on the peculiarities of

neurons present in the human brain.

2.1.1. Quantitative evaluations of neural and synaptic densities

A crucial quantitativedifference in neuronaldensity (neurons/

mm3 in layers I–VI) distinguishes the human brain from other

species. Neuronal density in the cerebral cortex is lower in

humans (24186/mm3) than in rats (54483/mm3) and mice

(120315/mm3), whereas the number of synapses per neuron

is higher in humans (29807) than in rats (18018) and mice

(21133) (DeFelipe et al., 2002). The number of dendritic spines

of basal dendrites of layer III pyramidal neurons also differs

in mouse and human temporal cortex. The mean number

(mean± SEM) of spines per 10 μm segment is 10.9±0.5 for

cells in temporal cortex of mice and 14.2±0.4 with respect to

the temporal cortex of humans (Benavides-Piccione et al.,

2002). Study of the size of spine heads revealed that the

mean area in the temporal cortex of mice was smaller than

in humans (mean±SEM: 0.37±0.01 μm2 and 0.59±0.01 μm2,

respectively) and the spine necks in the temporal cortex of

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mice were shorter (0.73±0.01μm) than those of humans (0.94±

0.01 μm) (Benavides-Piccione et al., 2002).

From a functional standpoint, data on the density of spines

are in agreement with the observation of a higher number of

synapses in humans than in mice or rats. The larger volume

of the spine head again indicates a more efficient transfer of

information between neurons in the human brain as spine

head volume is directly proportional to postsynaptic density,the number of postsynaptic receptors, the pre-synaptic

number of docked synaptic vesicles and the rapidly releasable

pool of neurotransmitters. In addition, spines with longer

necks show longer time constants of calcium compartmental-

ization than spines with shorter necks. All these data can be

interpreted to reflect that thehuman brain containsthe highest

density of local circuits (Alonso-Nanclares et al., 2008; DeFelipe

et al., 2002) , which are likely involved in memory processes

(Douglas et al., 1995; Goldman-Rakic, 1995; Romo et al., 1999;

Wang, 2001 see Fig. 1). It should be noticed that a high density

of synaptic contacts per neuron allows several alternative path-

ways in the high density local circuits of the human brain.

2.1.2. Special types of neurons

The qualitative and quantitative aspects of special types of

neurons like the giant Betz nerve cells of the primate motor

cortex, and especially the von Economo neurons (or spindle

neurons) are worthy of attention. The giant Betz nerve cells

of the primate motor cortex are not clustered but evenly

distributed in the inner pyramidal cell layer (layer V), where-

as clusters of large giganto-cellular nerve cells exist in layer V

of the primary motor cortex of giraffe and sheep ( Badlangana

et al., 2007). This observation is certainly interesting, but for

the moment has no clear functional correlate with the pecu-

liar features of motor control in primates. More interesting

for their possible functional correlates are the observations

on the qualitative and quantitative aspects of the von

Economo neurons (VENs) since they serve to differentiate

the human brain from other species (Allman et al., 2005;

Premack, 2007).

VENs have also been described in the cortex of the

elephant (Hakeem et al., 2009) and in the cetacean brain

(Butti et al., 2009) hencein animalspecies that pass the ‘mirror

test’ of being able to recognize themselves in a mirror (de Veer

et al., 2003; Gallup, 1970; Plotnik et al., 2006).The VENs are large, bipolar cells located in layer 5 of the

anterior cingulate, fronto-insular and dorsolateral (dysgranular)

prefrontal cortex (Fajardo et al., 2008).

They are distinguished from pyramidal cells because VENs

have only a single large basal dendrite, whereas pyramidal

cells have an array of smaller basal dendrites extending

from the cell body. Among the morphological and functional

human differences, Premack (2007) cites evidence showing

that our species has many more and larger VENs than apes.

In particular, the perimeters of VENs are far wider: an average

of 51 μm in humans compared with 36 μm in chimpanzees

and in monkeys. This increase is produced by an enlarged

dendritic tree and higher density of synapses, leading to an

increased density of local circuits. As mentioned above,

human VENs are located in only two parts of the brain, the

anterior cingulate cortex and the fronto-insular cortex.

These areas appear to be involved in socially crucial tasks,

such as empathy, feelings of guilt, and embarrassment. In

addition, human columns (see below) in the left planum tem-

porale – an area involved in language and perhaps music – are

organized differently from those of chimpanzees and rhesus

monkeys. However, they may alternatively represent a struc-

tural plasticity process to cope with the demands of achieving

integration and communication in very large brains.

It is interesting to note that VENs develop late in ontogeny.

They first appear in very small numbers in the 35th week of

gestation, and the adult number is attained only at 4 years of

Fig. 1 – Schematic example showing how increasing the number of synaptic contacts per neuron also increases the number of

potentially available reverberant circuits. As illustrated, a higher number of synapses per neuron allows several alternative

pathways to be exploited for signal reverberation.

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age. In all great apes and in postnatal human brains, VENs are

around 30%more numerous in the fronto-insular cortexof the

right hemisphere compared with their number in the corre-

sponding cortex of the left side. It may therefore be surmised

that VEN predominance in the right hemisphere in the

postnatal period is related to the right hemisphere specializa-

tion – in humans, at least – to the social emotions that are of

basic importance for self-consciousness. VENs may also beinvolvedin the fast intuitive assessment of complex situations

(Allman et al., 2005).

2.2. Astrocytic aspects specific to the human brain

Astrocytes are also excitable cells and play important roles in

information processing as can be deduced from evolutionary

data showing increasing numbers and a more complex

organization of astrocytes in the human brain. The astrocyte/

neuron ratio increases in evolution from 1:25 in the leech to

3:2 in the human brain (Pereira and Furlan, 2010). These data

likely implicate these cells in the evolution of increasingly

complex brain functions.

2.2.1. Special types of astrocytes

Of major interest are recent findings by Oberheim et al. (2006,

2009) indicating the existence of different types of astrocytes,

besides the classical protoplasmic and fibrous astrocytes, the

so-called ‘varicose projection astrocytes’ that seem exclusive

to the human brain.

These cells present more spiny processes than exhibited

by typical protoplasmic astrocytes and extend one to five,

essentially unbranched, millimeter long fibers within the

deep layers of the cortex.

The evenly spaced varicosities suggest specialized struc-

tures or compartmentalization of cellular elements along the

great distance of the fibers. These astrocytes are connected to

each other and with protoplasmic astrocytes by gap junctions,

forming a brain-wide network allowing long-distance commu-

nication across cortical layers or even between gray and white

matter (Oberheim et al., 2009).

2.3. Possible existence of a proto-consciousness founded on

single-cell ‘ sentience’

According to Cook (2008) and Sevush (2006), a single-neuron

theory of consciousness can be proposed. In particular, Cook

analyses the capability of neurons, as excitable cells, of

sensing the extracellular environment during action potential

generation. In particular, these authors suggest that a sort of

neuronal sentience emerges as a consequence of themomentary

“openness” of the plasma membrane to the external world

during the action potential. This is not “feeling ” in the sense

of “a human being having emotional experiences”, but it is

“feeling ” at the cellular level: the neuron in isolation senses its

extracellular fluid by making contact with its surrounding

world (e.g. by absorbing a small part of the local ionic charge)

as it goes about its cognitive business of synaptic communica-

tions (Cook, 2008). Thus, in a very simplified way, Cook's

proposal canbe summarized by stating that whilethe synaptic

interconnections in a neuronal network are the biological sub-

strate of the proto-phenomenon of cognition, the ion-flows

during the action potential are the biological substrate of the

proto-phenomenon of sentience.

It can also be surmised that the ‘sensing capability’ of

neurons is likely broader than that proposed above since these

cells can derive information on their external environment

not only by ion-fluxes but also via extrasynaptic receptors that

decode a variety of ‘volume transmission’ signals (see below

and Agnati et al., 2010a).Similar concepts could apply to astrocytes as well. In fact,

they can “sense” their environment, converting such an infor-

mation into detailed wavelike patterns of calcium ions and

ATP signaling that can be directly communicated to other

astrocytes and neurons (Pereira and Furlan, 2010).

As a consequence, a peculiar combination of “cognition”

and “sensitivity” is present in the nervous tissue (Guidolin et

al., 2011), not only in neurons but also in glial cells, probably

representing, in agreementwith Cook'sproposal,a prerequisite

for the emergence of the highest functions performed by the

CNS, such as subjectivity and consciousness.

To further illustrate this point, other systems in which the

above two characteristics are not simultaneously present can

briefly be considered.

On the one side, it is well known that networks of artificial

devices with fixed activation thresholds, and connected by

simple excitatory or inhibitory “synapses” are able to perform

any cognitive task that can be adequately defined (Koblauch

et al., 2010; McCulloch and Pitts, 1943; Penrose and Gardner,

1999). Thus, at least in principle, all forms of information pro-

cessing (i.e. cognition) could be performed by such a circuitry.

However, whether something like subjectivity and conscious-

ness could emerge from such a computational system is far

from being obvious (Freeman, 1997; Werner, 2007).

On the other side, there are excitable cells, such as cardio-

myocytes, sharing with neurons the possibility to sense their

external environment, since they are opened to ion-fluxes

during their electrical activity. However, the lack of adequate

connectivity schemes, primarily the lack of both excitatory

and inhibitory connections, prevents the emergence of either

cognitive functions or subjectivity.

Summing up, a comment and three considerations can be

added to Cook's interesting proposal (see Fig. 2):

a.) The comment: to be properly tuned and to have long-

lasting effects the sentience of a neuron needs a term

of comparison and likely has to impinge on a core

neuronal structure. Thus, we suggest two environments

should be considered: the extracellular fluid as the

classical internal milieu andthe cytoplasm. TheEnergide

(formed by the nucleus, microtubules and other satellite

structures) is the basic unit of living organisms (see

Baluška et al., 2006). Thus, the Energide (i.e., the core

structure of the cell) interacts with the cytoplasm that,

in turn, interacts with the interstitial fluid, and hence

with themedium classically known as theinternalmilieu

(Agnati et al., 2009a). In neurons the cytoplasm around

the Energide may represent the term of comparison for

neuronal sentience. It could also be surmised that in

view of the fundamental functions carried out by the

Energide, especially by the nucleus, long-lasting effects

on a neuron's sentience are the result of the modulatory

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actions of the ‘private’ internal medium (i.e., the cyto-

plasm around the nucleus) on the Energide.

b.) First consideration: the presence of receptors for trans-

mitters outside the synapse and not only at soma and

dendritic level, but also at axonal levels (Aoki et al.,

1998; Riad et al., 2000; Semyanov and Kullmann, 2002)

points to the possible important role of ‘volume trans-

mission’ (see below and Agnati et al., 2010a) in the

sentience of single neurons by modulating not only thecomposition of the cytoplasm and the activation of

molecular networks, but also the generation of action

potentials at soma-dendritic level and hence the bio-

chemical features of the cytoplasm around the Energide.

c.) Second consideration: according to the ‘Tide Hypothesis’

(Agnati et al., 2005a), the piston-likemovements of the en-

tire brain towards the occipital foramen cause pulsatory

distortions of the cell membranes. Thus, mechano-

sensitive ion channels present at neuronal (Zurborg et al.,

2007) and astrocyte (Ostrow and Sachs, 2005) membrane

level are stimulated. Their activation can affect the ion

movements across the plasma membranes and hence

both the generation of action potentials (i.e., sentience of neurons) and the integrative action of astrocyte networks.

d.) Third consideration: visceral homeostatic processes can

affect brain function via neuronal visceral (especially

vagal) afferences or endocrine signals. It should also be

noted that astrocytic networks are in a privileged loca-

tion to respond to blood and cerebrospinal fluid signal-

ing mediated by endothelial and ependymal cells

respectively. These signals include small molecules

like hormones and neuropeptides.

All these aspects should be entertained in investigating the

integrative actions of the brain since they underpin the global

sentience that represents subjective awareness.

3. Wiring and Volume Transmission and thesupra-cellular organization of the cortex

A basic feature of all processes leading to consciousness is the

existence of communication modes between cells leading to

the formation of supracellular forms of organization allowing

the integration of information.

3.1. Communication modes in the brain

3.1.1. Wiring Transmission (WT)

This is basically a signaling process along a physically well-

delimited channel like a ‘wire’. Two types of WT have been

studied in detail, chemical synaptic transmission and gap-

junctions (for an updated discussion see Agnati et al., 2010a).

WT allows interneuronal connections in the millisecond

range and, in some instances, it even allows a sort of transient

syncytial functional organization of the CNS (Agnati et al.,

2007b; Hameroff, 2010). However, as mentioned above,

astrocyte networks arealsoconnected by WT since gapjunctions

between chains of astrocytes have been described. Thus, where-

as neurons are interconnected through chemical and electrical

synapses and their excitable response are basically electrical

signals, astrocytes are interconnected via gap junctions and

their excitable responses are basically intracellular calcium

waves (Oberheim et al., 2009; Pereira and Furlan, 2010).

Furthermore, the existence of three-dimensional molecular

networks has been proposed, mainly made of proteins and car-

bohydrates, which can be organized in a large Global Molecular

Network (GMN) pervading the intra- and extracellular environ-

ment of the central nervous system. The GMN might transmit

signals and connect different compartments through interac-

tions between extra- and intracellular molecular networks.

Thus, the GMN may be involved in the integrative actions of

Fig. 2 – Schematic representation of a neuron. Signal transmission is the essential function of the neuron, but what flows down

the axon is a sudden process of adjustment of the membrane potential. It is associated with a material flow of ions orthogonal to

the direction of signal transmission. According to Cook (2008) these two cellular processes could represent the protophenomenon

of cognition and sentience respectively. The scheme points out the key role that the comparison between the extra-cellular fluid

(i.e., the classical ‘internal milieu’ ) and the cytoplasm, the ‘private’ cellular internal environment around the Energide (see Baluška

et al., 2006 ) may have to realize such a cell sentience. Furthermore, the possible contribution of Volume Transmission (VT) signalsof both chemical and physical nature (as, for instance, the pressure waves caused by the arterial blood pressure pulses in cerebral

arteries) to the process is indicated. For further details, see text.

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the brain also in view of its plastic structure, in fact its extra-

cellular part is continuously under the remodeling action of

the matrix metalloproteinases (Agnati et al., 2006).

3.1.2. Volume Transmission (VT)

This is a diffuse mode of signalingprocess that hassimilarities

with radio broadcasting (for an updated discussion see Agnati

et al., 2010a). Thus, diffusible chemical signals can affect entirebrain regions. In this context the electromagnetic fields (EMFs)

could also be mentioned. The brain's endogenous electromag-

netic fields are generated by the fields induced by neuron

firing and the fields generated by the movement of ions into

and out of cells and within extracellular channels (McFadden,

2002; Pockett, 2000). Pressure waves due to arterial pulses in

the brain arteries may also operate as VT signals and/or affect

VT signal diffusion and mechano-sensitiveion channelsin the

plasma membranes of neurons and astrocytes (Agnati et al.,

2005a). Thus, this type of signaling can give a beat-to-beat

connection between cardiac activity and the functional state

of entire brain areas.

3.2. Supra-cellular organization of cortical neurons and

astrocytes

In 1938 Lorente de Nò (1938) suggested that the cortex is

organized in cortical cylinders composed of vertical chains of

neurons crossing all cortical layers and having specific afferent

fibers as their axis. These cylinders represent units of operation

(DeFelipe et al., 2002; Lorente de Nò, 1938). This concept wasfur-

ther developed by Mountcastle's investigations demonstrating

that neuronsare arranged vertically (or radiallyin theconvolut-

ed cerebrum) in the form of columns spanning the width of the

primate somatosensory cortex and responding to a single

receptive field in the periphery (Mountcastle et al., 1957; Rakic,

2008).

As stated by Rakic (2008), cortical columns can be considered

functional units consisting of an array of iterative neuronal

groups extending radially across the cortical cellular layers.

Rakic points out that it has been assumed that neurons within a

given column are stereotypically interconnected in the vertical dimen-

sion, share extrinsic connectivity, and hence act as basic functional

units subserving a set of common static and dynamic cortical opera-

tions that include not only sensoryand motor areas but also association

areas subserving the highest cognitive functions.

Even though there is no consensus on a single anatomical

columnar entity (da Costa and Martin, 2010), the concept of column is still supported by experimental evidence (Hubel

and Wiesel, 1977). Thus, when a physiological investigation

is carried out through the cortex of primates, ungulates and

carnivores in a trajectory perpendicular to its surface, it is

generally possible to detect a remarkable constancy in the

receptive field properties of the neurons regarding one set of

stimulus features (see Fig.3. and Carreira-Perpiñán and

Goodhill, 2002; da Costa and Martin, 2010; Miyawaki et al.,

2008). Of special relevance is the evidence of ontogenetic

columns and the proven validity of the radial unit hypothesis

as the basis for understanding the evolutionary expansion of

the cortex (Rakic, 2008).

However, some authors claim that the term ‘column’ does

not actually correspond to any single structure within the

cortex. Thus, it is impossible to find a canonical microcircuit

corresponding to the classical cortical column (Crick and

Koch, 2005; Rockland, 2010).

The concept could be clarified, on the basis of anatomical

findings (Peters and Sethares, 1996), by distinguishing mini-

columns (diameter of about 50 μm) from macrocolumns

(diameter in the range of 300–500 μm). A further theoretical

development of this important distinction can be found in a

recentpaper by Rinkus (2010) who proposes that minicolumns

do have a generic functionality, which only becomes clear

when seen in the context of the function of the higher level,

subsuming unit, the macrocolumn. Thus, Rinkus proposes

that a macrocolumn's functions are to store sparse distributed

representations of its inputs and to recognize those inputs;

while the generic function of the minicolumn is to enforce

macrocolumnar code sparseness.

Fig. 3 – Example of the organization of the visual cortex in functional columns (see Carreira-Perpiñán and Goodhill, 2002 ).

A. Schematic view of an area of visual cortex representing a particular place in the visual field. It appears organized as a

pinwheel of columns each reacting to a specific orientation of the edges at that visual field position. B. The surface of the visual

cortex appears as a topologically mapped mosaic. The different shades of gray indicate patches that have different orientation

preferences. Topologically arranged columns can similarly be identified for other characteristics of the visual field, such as

color and spatial frequency (see Miyawaki et al., 2008 ).

8 B R A I N R E S E A R C H 1 4 7 6 ( 2 0 1 2 ) 3 – 2 1



Astrocytes can play an important role in the functional

organization of the cerebral cortex from specific interactions

with single synaptic contacts to modulatory interactions

with entire neuronal networks (Oberheim et al., 2009; Pereira

and Furlan, 2010).

The concept of ‘tripartite synapse’ has been introduced

since the extremity of a protoplasmic astrocyte process

wraps the synapticcleft in mostglutamatergic central synapses.It should be noted that astrocytes express membrane receptors

to neurotransmitters and can release their own chemical

messengers (gliotransmitters). Thus, they establish a cross-talk

with both pre- and post-synaptic neurons. It is important to

emphasize that VT and WT have a specialized point of contact

at the level of tripartite synapses hence it is possible to assess

that astrocyte networks regulate neural functions and vice

versa (Giaume et al., 2010).

Several astrocytes participate in this functional unit (i.e.,

the tripartite synapse) and are coupled with each other by

gap junctions forming a network that can support large-

scale integrative functions in the brain via a continuous

cross-talk with neurons. Thus, neuron–astroglial networks

do exist (see Agnati and Fuxe, 1984 the concept of ‘complex

cellular networks’) controlling not simply dynamic glucose

delivery (Rouach et al., 2008), but also cognitive information

processing (Robertson, 2002). In particular, astrocytes

connected via gap junctions represent not only a pathway

for direct intercellular exchange of ions,nutrientsand signaling

molecules (Parpura et al., 2004), but can even be an active

computing mechanism. This proposal is supported by findings

demonstrating that gap junction channels are regulated by

extra- and intracellular signals and allow exchange of

information, so that astrocyte networks can operate as a Turing

B-likedevicesince the gap junctions can beset inthe ‘pass-mode’

or in the ‘interrupt mode’ (Agnati and Fuxe, 2000; Giaume et al.,

2010).

4. The concept of functional module and its

integrative sentience

Altogether the abovementioned data give some evidence for

the existence of elementary processing units functionally

located between and hence bridging single cells and system

levels (Cutsuridis et al., 2009; Graybiel and Grillner, 2006).

They can be called ‘functional modules’ (FM) and can be

defined as micro-circuits in which nerve cells (neurons and

astrocytes) are organized into specific patterns to carry out a

specific processing activity (see Shepherd, 2011). As discussed

above, the ‘functional module’ concept is basicallyin agreement

with both Rinkus' (Rinkus, 2010) proposal andBuxhoeveden and

Casanova's (Buxhoeveden and Casanova, 2002) assumption that

cortical morphofunctional units (columns) have no fixedanatomical borders but only functional boundaries since the

precise combination of inhibition and excitation ‘creates’ units

of different size and function.

Following our group's previous proposal of the brain as a

system of nested networks (Agnati and Fuxe, 1984; Agnati et

al., 2007a, 2007b, 2008), it may also be surmised that within a

FM the information processing could occur at different levels

of miniaturization from the cell network level down to the

molecular network level (see Fig. 4). It follows that the final,

integrated, activity of the FM would emerge from the complex

Fig. 4 – Schematic representation of a functional module (FM). As illustrated, in the CNS it is possible to distinguish a horizontal

organization (mosaic pattern) and a vertical (hierarchical) organization, following a “Russian doll” pattern ( Agnati and Fuxe,

1984 ).

9B R A I N R E S E A R C H 1 4 7 6 ( 2 0 1 2 ) 3 – 2 1



dynamics of this hierarchical system of relations. In this

respect, of particular interest for the present discussion are

theso called ‘synaptic clusters’ (SC), in which multiple synapses

act cooperatively to modulate their strength (Golding et al.,

2002; Shepherd, 1979). Each FM can have one or more SC, often

organized around the dendritic spines and partially isolated

from the surrounding environment by glial cells (Cutsuridis et

al., 2009; Golding et al., 2002). SC were shown to be very plasticentities from both the structural (Holtmaat et al., 2005) and the

functional (Welzel et al., 2010) point of view. As a matter of

fact, it has been reported that plastic changes induced by Long

Term Potentiation (LTP) at one synaptic contact lower the

threshold for the induction of LTP at neighboring synapses at

a stimulation strength that did not cause any plastic changes

under control conditions. Theextent of this sensitized plasticity

zone spans about 10 μm of dendrite and lasts for 10 min and is

presumably due to the diffusional spread of the Ca2+ activated

small GTPase Ras to neighboring spines (Harvey and Svoboda,

2007). These characteristics allow the SC to act as a sort of

‘intelligent layer ’ between the activity at the cellular level and

the integrative functions performed at the molecular level by

supramolecular complexes such as those formed at the cell

membrane by G protein-coupled receptors, owing to direct

receptor –receptor interactions (see Agnati et al., 2010b; Fuxe et

al., 2007a; Kenakin et al., 2010 for reviews).

To summarize, we could illustrate the general structure of

a FM as a hierarchical assemblage of mosaics of different

miniaturization, where the term ‘mosaic’ (see Agnati et al.,

2009b) is defined as in figurative art, i.e. as the process of

making pictures by inlaying small bits of colored stones

(tesserae). Thus, it indicates how from a given set of elements

(cells, synapses or molecules in this case) it is possible to

achieve different patterns endowed with different emergent

properties (e.g. of computational type). It may be surmised

that recurrent (Hebb, 1949) WT- and/or VT-based communica-

tion processes within the different levels of miniaturization

may also help in keeping information on-line and hence

allow those integrative processes requiring a certain time

interval (see above) to reach the threshold of consciousness.

With reference to the abovementioned Cook's proposal

(Cook, 2008, see Section 2.3), this schematic representation

of the integrative processes occurring within each FM

indicates that FM could represent the first integrative level

of proto-cognition and proto-consciousness, i.e. a structure

able to convert the incoming fragments of sensation into a

particular ‘fragment of perception’ ( John, 2002).

As pointed out by some authors (see Cutsuridis et al., 2009;

Graybiel and Grillner, 2006), examples of such FM include

cortical minicolumns, glomeruli in the olfactory systems,

networks for the storage and recall of memories in the hippo-

campus and the prefrontal cortex, and neural microcircuits

generating different aspects of motor behavior. The presence

of this organization of the human brain can be discussed in

the frame of Jacob's (1977) proposal on evolution working not

as an engineer but as a tinkerer. Jacob claims that evolution

tinkers together contraptions in a natural selection process

that acts by adding direction to changes, orienting chance, and

slowly and progressively producing more complex structures,

new organs, and new species. Thus, novelties come from previ-

ously unseen associations of already available material.

In agreement with this proposal, it is suggested that FMs in

the human brain can be seen as the result of a tinkering

process carried out at different time-scales:

a.) long-term scale, by evolution

b.) intermediate-termscale, by life-long individual experience

c.) short-term scale, by the moment-to-moment external

and/or internal inputs impinging on each individual

human brain.

Evolution by natural selection gave rise to a human brain

having, at least in some areas, special FMs thanks to the

particular features of VENs, the high density and peculiar

biochemical characteristics of synaptic contacts, and the

presence of varicose projection astrocytes (see Section 2.2).

Moreover, it can be conjectured that special functional rules

for recruitment of computational elements and information

handling are present in the human brain and even if they

are genetically determined, they may differ to some extent

from subject to subject and can be made more efficient by

appropriate educational training.

5. Fundamental mechanisms for ‘large-scale’integration in the brain

The set of FMs corresponding to sensory inputs generates a

“fractured” representation of the world. The issue of perceptual

unit needs mechanisms that allow these different sensory

components to be gathered into one global image. In other

words, to provide the fine texture of consciousness and the

global nature of a momentary cognitive instant of experience,

a cooperative process is required. In line with the classical

Hebb hypothesis on the possible existence of cell assemblies

interconnected via reverberating circuits (Hebb, 1949; Wang,

2001), we propose that different FMs can be transiently inter-

connected to form a higher-order mosaic, representing the

further integrative step in the chain leading to cognition and

consciousness. It has been suggested ( John, 2002) that not only

a ‘binding phenomenon’, but also a ‘background tone’ (both

exploiting the communication processes of WT and VT) is

needed to integrate the information handled by the FMs.

5.1. Formation of the neuronal correlates of consciousness:

the background tone and the binding phenomenon

Classical paradigms relate neural activity to controlled sensory

stimuli, to the motor responses following stimulation of the

motor system or, more generally, to physiological responses in

controlled cognitive conditions. Besides these results, several

studies have investigated the temporally coherent activity in

cortical areas in the absence of overt goal-directed behavior. In

humans, this resting state has been suggested not simply to

represent “noise”, but rather to implicate spontaneous and

transient processes involved in task-unrelated imagery and

thought. The resting statenetworksnot associatedwith sensory

or motor regions, such as the medial prefrontal, parietal and

posterior and anterior cingulate cortices, seem to be most

engaged when persons are not involved in overt goal-directed

behavior. Thus, these networks have been thought to underlie

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certain aspects of conscious introspection, being specific to

humans (Ghosh et al., 2008).

However, other authors have recently shown that the

spatiotemporal patterns of the resting state also exist in anes-

thetized monkeys, thus demonstrating that they do not

reflect a state of consciousness (Shmuel and Leopold, 2008).

These dynamic resting states have been considered to

manifest the intrinsic characteristics of the underlying brainstructure, being useful for keeping the system in a highly

competitive state between different sub-networks that are

later used during different tasks (Deco et al., 2009). Following

this view, it can be suggested that the resting state might

represent the background tone on which binding mechanisms

(i.e. mechanisms capable of integrating different perceptions,

emotions, thoughts and memories in an unified conscious

experience) operate.

Different binding mechanisms have been proposed to

solve the problem of how our brain integrates information

distributed among billions of spatially separated neurons to

generate the unity of conscious experience. In the late 1980s,

Wolf Singer and colleagues (Gray et al., 1989a, 1989b) found a

specific, phase-synchronized EEG in cats' visual cortex which

was strongly correlated to a particular visual stimulation.

The phase synchrony they found in the gamma frequency

band (from 30 to 90 Hz) of the EEG becameknown as “coherent

40 Hz”. Subsequent studies have shown gamma synchrony in

various brain locations correlating with conscious perception.

This synchrony has been regarded as the electrophysiological

marker of the binding of different unconscious components in

a unified conscious percept. Location and distribution of

gamma synchrony within the brain can change dynamically,

shifting on timescales of hundreds of milliseconds or faster

(Hameroff, 2010).

However, this mechanism has been criticized as an expla-

nation of the crucial marker of the binding phenomenon. For

example, gamma band synchrony occurs in brains of both

conscious and unconscious animals in response to visually

presented objects (Canales et al., 2007).

Large-scale integration, or ‘binding ’, has then been

suggested to involve fluctuations around the background

state (Edelman and Tononi, 2000; John, 2002). What leads to

a binding of the fragmented information into a coherent

process would be the identification (by neuronal coincidence

detectors in the cortex) of synchrony within and coherence

among brain regions which deviate from the ground state. In

this respect, oscillations of local field potentials (in the beta,

alpha and theta/delta frequencies) also play an important

role in facilitating synchronization and coherence ( John, 2002).

In this context, a potentially important contribution of

astrocytes to the binding process was emphasized by

(Pereira and Furlan (2009). Accordingto their theory, thetrans-

fer of information patterns embodied in local field potentials

to astrocytic calcium waves would facilitate a “binding ” of

spatially distributed patterns into unitary conscious episodes.

According to the concept of FM illustrated in Section 4, a

view could also be proposed, in which the ‘background tone’

and the ‘binding phenomenon’ are considered as different

aspects of the collective dynamics of FMs. In fact, it can be sur-

mised that the background tone simply reflect reverberating

activity playing the leading role of continuously assembling

pools of FMs. In the absence of a salient internal and/or exter-

nal input this process results as a spontaneous chaotic activity

(recorded as a noise) present in many brain regions. Under

internal and/or external inputs triggering a binding phenome-

non, a self-organization occurs and this basal state moves

towards an attractor, eventually leading to a dynamic synchro-

nization and hence to the functional assemblage of several FMs

into specific high-order mosaics. A comment by Werner (2007)may be in line with this hypothesis: On the horizon I note promis-

ing new actors to count with in future: I draw attention to computa-

tional simulations of radically novel features of neural microcircuits

which function more like liquids responding to perturbations with

ripples of waves, rather than like digital gates ( … ) If proven real,

such microcircuits would adopt a system dynamics at the boundary

region of ordered and chaotic behavior. They would, thus, belong to

the class of natural systems operating at “ the edge of chaos”, which

are known for their capacity for critical self-organization.

Summing up, the existence of global synchrony in the

brain indicatesthe operationof a tuning mechanism accounting

for the coordination of local circuits and orienting some FMs to

form transient higher-order mosaics, which may represent the

NCCs.

The assemblage is not the result of any ‘conscious process’,

but on the contrary, is a largely unconscious process that

depends on genetically coded as well as learned interaction

rules, which integrate incoming inputs with short and long-

term memories stored in the FMs. In a recent interesting

study by Buzsáki (2010) possible mechanisms allowing the

identification and organization of cell assemblies are exten-

sively reviewed and discussed. FMs are recruited according

to different spatial patterns (locations of the FMs with respect

to each other) and temporal patterns (time sequences of their

activation). These two patterns also regulate the mosaic

networks of different miniaturization inside each FM. An

adaptation is, therefore, possible by shaping and activating

the mosaics to fit the specific task to fulfill.

5.2. The neuroanatomical bases of ‘ large-scale’ brain

integration

A crucial aspect is the characterization of the neuronal

systems selecting FMs and linking them together into the

abovementioned higher-order mosaics representing the

NCCs. Two of these, namely the thalamo-cortical and the

brainstem–subcortical/cortical interconnections will be briefly

described, since they are widely acknowledged to play a key

role in the formation of conscious events. Some comment

will be also deserved to the claustrum and to its proposed

(Crick and Koch, 2005) special integrative role.

5.2.1. Thalamo-cortical interconnections

Thalamo-cortical reverberating circuits are a highly relevant

topic for consciousness processes. Several lines of clinical

experience suggest that if we lack the thalamus, the cortex

is useless, leaving the patient in a state close to total coma.

Thus, as emphasizedby Llinasand Ribary (2001), consciousness

needs a continuous “dialog ” between the thalamus and the

cortex to arise.

As Llinas et al. (1998) pointed out, the thalamus represents

a sort of hub from which any site in the cortex can

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communicate with other sites. The corticothalamic pathway,

therefore, can selectively mediate coherence and synchronicity

of activity between selected groups of interconnected cortical

and thalamic neurons during particular functional states. A

second organizing principle, however, may be equally impor-

tant. It is based on the temporal rather than spatial relation-

ships among groups of neurons and the thalamo-cortical

iterative recurrent activity certainly plays a key role in such aprocess. In fact, as proposed by Llinas et al. (1998) two comple-

mentary loops between the thalamus and the cerebral cortex

work in conjunction to subserve temporal binding:

- a “specific” system formed by sensory or motor nuclei

projecting to layer IV of the cortex. It produces cortical

oscillations by direct activation and feed-forward inhibition

via inhibitory interneurons. These oscillations re-enter the

reticular nucleus of the thalamus via layer-VI pyramidal

cells;- a “non-specific” system, in which intralaminar nonspecific

thalamic nuclei project to cortical layers I and V and to the

reticular nucleus. Layer-V pyramidal cells return oscilla-tions to the reticular nucleus and intralaminar nuclei.

It is apparent from literature that neither of these circuits

alone can generate cognition: damage of the non-specific

system leads to deep disturbances of consciousness, while

damage of the specific system produces loss of some particular

cognitive modality. These observations led to the hypothesis

(Llinas and Ribary, 2001) that the specific system would provide

the content relating to the external world, and the non-specific

system would give rise to the temporal conjunction, or the con-

text (on thebasisof a moreinteroceptive background concerned

with alertness). Togetherthey would generate a single cognitive

experience.

An interesting structural feature of the interconnections

between cortex and thalamus is that a very large percentage

of this connectivity is recurrent, and that much of its activity

is related to such intrinsic connectivity not necessarily related

to the immediacy of sensory input. In particular, the thalamic

input from the cortex is larger than that from the peripheral

sensory system (Llinas et al., 1998). It is, therefore, reasonable

to assume that the brain is essentially a closed systemcapable

of self-generated activity based on the intrinsic electrical

properties of its component neurons and their connectivity.

In this respect Llinas et al. (1998) proposed an analogy with

the spinal cord based on the pioneering work of Brown

(1914) on locomotion. Brown demonstrated that sensory

inputs are mostly modifiers of the intrinsic activity of the

spinal cord since locomotion was still present after bilateral

dorsal root deafferentation, hence after the total removal of

sensory inputs. On that basis,Brown proposed that the complex

motor output required for locomotion is a property of the

spontaneous activity of the neuronal circuits in the spinal cord

and brainstem. Similarly, Llinas et al. (1998) suggested that

consciousness might be the result of the intrinsic activity of

brain circuits. As such, consciousness can be thought of as an

oneiric-like internal functional state modulated, rather than

generated, by the senses. This proposal is in line with the classi-

cal view that ‘perception is a model in the brain’ (Blakemore,

1976) and such a model is built up with inborn circuits and

hence is present at birth, and is “fine-tuned” later on during

normal maturation (see also Agnati et al., 2007c). In other

words, the CNS is a “reality”-emulating system in which only

some parameters of such “reality” are delineated by the senses.

Such a view of the brain as a closed system capable of an

autonomous creation of reality even in the absence of sensory

inputs, resembles the more recent proposal by Hobson (2009)

that during rapid eye movement (REM) sleep (i.e., in theabsence of sensory inputs) the brain may create a virtual reality

model of the world. Such a model could be of functional use in

the development and maintenance of waking consciousness.

Available experimental data comparing awake and REM sleep

state (Llinas and Paré, 1991) provide support to this idea. They

suggest that we do not perceive the external world during REM

sleep because the intrinsic activity of the corticothalamic

systems doesnot place sensory input in thecontext of thefunc-

tional state being generated by the brain. In other words, the

dreaming condition appears as a state of hyperattentiveness

to intrinsic activity in which sensory input cannot access the

machinery generating conscious experience.

In agreement with the crucial role played by corticothalamic

interconnections in consciousness formation are also the

neuropathological data on familial fatal insomnia (FFI)

(Montagna et al., 2003). Autopsy verification in FFI patients

disclosed atrophy of the mediodorsal and anterior ventral

thalamic nuclei. In these patients worsening of sleep and auto-

nomic disturbances are associated with the onset of peculiar

oneiric behaviors whereby patients, especially if left to them-

selves, fall into a hallucinatory state displaying motor gestures

related to the content of their dreams.

5.2.2. Thecortical and subcortical projections from thebrainstem

Moruzzi and Magoun (1949) obtained evidence of how distinct

nerve cell populations in the midbrain and pons could

produce a global activation of the cerebral cortex. Lesions to

these so-called reticular activating systems resulted in a

sleep-like state. The discovery of monosynaptic DA, NA and

5-HT nerve cell projections from the pons and midbrain to

the cerebral cortex and subcortical regions provided the

structural and neurochemical correlate to these pioneering

physiological observations (Andén et al., 1964, 1966; Chalmers,

2000; Dahlström and Fuxe, 1964; Fuxe, 1965; Fuxe et al., 2007b,

2010; Thierry et al., 1973).

In particular, it has been shown that the locus coeruleus

ascending NA projections from the pons to the cerebral cortex

play a significant role in tonic arousal ( Jouvet, 1972; Lidbrink

and Fuxe, 1973). Furthermore, the ascending 5-HT projections

from the mesencephalicraphenucleito corticaland subcortical

regions play a role, among others, in the maintenance of slow-

wave sleep and in preventing melancholy (Fuxe et al., 2007b;

Jouvet, 1972; Kiianmaa and Fuxe, 1977). The meso-limbic-

cortical DA neurons from the ventral tegmental area (Andén et

al., 1966; Dahlström and Fuxe, 1964; Thierry et al., 1973) inner-

vate the subcortical limbic forebrain, especially the nucleus

accumbens core and shell, and many cortical regions namely

the limbic cortex and prefrontal cortex. They play a major role

in reward and reward prediction, attention, working memory

and modulating the transfer of emotional information from

thesubcortical limbic forebrain to thecerebral cortex, especially

the prefrontal cortex (Fuxe et al., 2007b).

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The impact of these subcortical and cortical monoamine

projections for the performance of the FMs in the cerebral

cortex and, hence, for higher consciousness also becomes

clear from the fact that disturbances in these ascending

monoamine systems contribute to the development of schizo-

phrenia, attention deficit and hyperactivity disorders (Fuxe et

al., 2007b). Furthermore, hallucinogens of the indolalkylamine

type like d-LSD produce their hallucinations by activating distinct subtypes of 5-HT receptors, the 5-HT2A subtype located

in the cerebral cortex (Fuxe et al., 2009). These ascending mono-

synaptic monoamine projections from the pons and midbrain

innervating the cerebral cortex and subcortical regions serve

as important examples of the substantial impact the lower

brainstem afferents exert on the function of the cerebral cortex

directly or indirectly via innervations of subcortical regions like

the striatum, and thus on consciousness.

Summing up these data on the functional meaning of the

monoamine ascending systems, it can be stated that the

integration of the various functional cortical modules can no

longer develop well-tuned high brain function without their

global modulation and fine-tuning by cortical and subcortical

DA, NA and 5-HT nerve terminal networks acting mainly via

VT (see below and Agnati et al., 2007b; Fuxe et al., 2010).

The cortical cholinergic nerve terminal systems arising

from the basal forebrain probably have a similar role in con-

sciousness and can operate via both VT and WT (Descarries,

1998; Perry et al., 1999). Thus, while it is clear that the evolu-

tionary recent six-layered cerebral cortex plays a fundamental

role in the higher level consciousness, this evolutionarily

recent structure remains under the strong control of phyloge-

netically ancient brainstem systems that are, in fact, essential

for higher consciousness. As an intriguing example of such, it

has been proposed that a primary consciousness may exist in

children born without a cerebral cortex. Also, goal-directed

behavior has been observed in mammals after experimental

decortication (Merker, 2007).

5.2.3. The claustrum

As discussed above, it is widely accepted that there is no

single cortical area ‘where it all comes together ’ to produce

the conscious content. The elements of a coalition implicated

in the NCCs are widely distributed over both the back and the

front of the brain. Thus, effectively, they bind by interacting in

a widespread manner. However, claustrum, that according to

many authors should be considered the seventh layer of the

cortex in the insular region (Tanne-Gariepy et al., 2002), has

been proposed to play a special integrative role in view of its

vast interconnectivity with most allocortical and neocortical

regions (Crick and Koch, 2005). Important claustrum intercon-

nections have been described with the frontal lobe including

the cingulated cortex, andthe temporal,parietaland entorhinal

cortex. As mentioned by Crick and Koch (2005), the claustrum

also projects to thehippocampus, amygdala and caudate nucle-

us. It follows that it could have the possibility to bind disparate

events into a single percept experienced at one point in time

(Crick and Koch, 2005). Based on these data, Crick and Koch

(2005) suggested that it might be important to investigate the

functional role of the claustrum, namely whether it contains

specialized mechanisms capable of integrating the information

that travels widely within its anterior –posterior and ventral–

dorsal extent, thereby synchronizing different perceptual,

cognitive and motor modalities. Furthermore, they pointed out

that this postulated intra-claustrum integrative action differs

fromthatof thethalamus, which also haswidespread reciprocal

relations with most cortical regions but does not possess any

obvious mechanism to directly link its various constitutive

nuclei.

6. From NCCs to conscious episodes: the needfor metaphors

It is not yet possible to move from the NCCs to conscious

episodes introspectively obtained and some philosophers

even claim that some aspects of consciousness, such as

subjectivity, might be inherently inexplicable. As pointed out

by Baars (1998), however, we cannot know today whether or

not we will eventually understand problems like that,

although they might become clearer as more plausible

hypotheses are tested. In this respect, a useful thinking tool

is to suggest metaphors giving hints of some aspects of theNCCs-to-consciousness journey. A metaphor can be defined

as “the application of a word or phrase to an object or concept it

does not literally denote, suggesting comparison to that object or

concept” (Webster's College Dictionary, 1995).

How farcan wego along this journey by means of metaphors?

It is worth mentioning Werner's (2007) advice on the use of

metaphors in neuroscience of cognition and consciousness.

Werner discusses the strict limits within which the use of

metaphors can illuminate a target domain in cognitive neuro-

science. Thus, Werner delineates the risk of metaphors since

“they tend to carry with them the style of reasoning of the source

domain which may be (and often is) quite inappropriate for the target;

thus entailing the risk of tacitly contaminating the target with errone-

ous styles of reasoning” (Werner, 2007). Criteria for productive

metaphors, however, have been defined by Baars (1998), who

states: productive metaphors should help organize existing evidence,

yield testable hypotheses and suggest conceptual clarifications

(Baars, 1998). Any cognitive metaphor should, therefore, be

considered from Werner's and Baar's points of view. Thus,

metaphors should be used as instruments to grasp some

aspects of the still obscure physical processes relating NCCs to

consciousness, andnot as a ‘scientific’ descriptionof conscious-

ness itself. This is the case, thus far, to give any account of

internal, conscious experiences such as the so-called ‘qualia’.

No scientific description can be given. However, the way in

which the neurobiological pre-conscient issues are integrated

reaching subjective experiences of the ‘self ’ can benefit from a

metaphoric approach.

Many metaphors have been proposed to illustrate certain

features of ‘consciousness’. They basically reflect a common

theme that can be labeled the ‘theater metaphor ’ (Baars,

1988, 1997; Crick, 1984; Dennett and Kinsbourne, 1992) and

imply both convergence of input and divergent dissemination

of the integrated content. We would like to introduce a new

one, the “Hall of Mirrors”, to explain reverberating activity

between and within the FMs.

Our metaphor suggests that the mosaic of FMs, i.e., the

NCCs, can be viewed as a transient assembled Hall of Mirrors

(Fig. 5) where each mirror reflects the images of other mirrors.

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A temptative clarification of the term “mirror ” is given in

Section 6.1 for the moment let us discuss their fundamental

feature, namely the reflection process.

Thereflection process of a mirror is notachieved passively,

but by filtering and enriching the images with the memories

that it may store, and according to the peculiar integrative

capabilities with which the reflection is endowed. The final

result of these multiple reciprocal reflections among mirrors

is the creation of a ‘virtual space’ (the set of the internal

theater)and of a ‘virtual personage’ (the ‘self ’) who lives within

this theater. These are dynamic operations that allow the

stage of the theater and the attitudes and feelings of the

personage to be continuously rebuilt.

Of particular interest can be the discussion of the sugges-

tions proposed by the metaphor from the standpoint of the

abovementioned criteria indicated by Baars (1998).

6.1. ‘ Hall of Mirrors’ : existing evidence

The proposed metaphor shares with all the metaphors

illustrating the integrated brain activity as an ‘internal

theater ’ the view that the overall function of consciousness

is to provide very widespread access to unconscious brain

regions (the “audience” of the theater). As demonstrated by a

number of neuropsychological studies (Buchwald, 1974;

Kosslyn, 1994; Shiffrin et al., 1981) such access is needed for

coordination and control (see Baars, 1998 for a thoughtful

discussion). According to our proposal in a top-down

summing up, a rather stable organization of a fundamental

set of mirrors (leading to the “self ”) variably interconnected

with a plastic set of mirrors (building up a changeable ‘Hall

of Mirrors’, i.e. the stage of the internal theater) provides the

“tools” for such a coordination. Consciousness, therefore,

appears to emerge from this dynamic mirror effect, as well

as from the integrative actions inside of the FMs involved.

Thus, the present metaphor suggests that specific

morphofunctional features of cerebral cortex structures can

integrate, display, disseminate (‘reflect’) contents to other

brain structures and receive feedback from them.

Some hints to give a morpho-functional correlate to the

Mirror expression and hence to the Hall of Mirrors metaphor

could be deduced from recent studies on the parcellation of

the cortex, aimed to characterize its functional–anatomical

organization (Knösche and Tittgemeyer, 2011).

Parcellation leads to the subdivision of the cortical surface

into compact areas, which are internally relatively homoge-

neous and distinct from one another, with respect to the

considered structural and/or functional criteria. It could be

surmised that sometimes a Mirror is a mosaic of FMs within

one of these relatively homogenous and compact areas. As a

matter of fact, the importance of the cortex parcellation has

been proved also very useful for studying the organizational

principles of the brain and its ontogenetic and phylogenetic

development (Bystron et al., 2008; Rakic, 2009).

Given that brain regions frequently maintain characteristic

connectivity profiles and the functional repertoire of a cortical

area is closely related to its anatomical connections, long-

range connectivity may be used not only to define segregated

cortical areas (Knösche and Tittgemeyer, 2011) but also the

Hall of Mirrors associated to a certain function. This aspect

could be also discussed in the frame of Mesulam's proposal

(Mesulam, 2005) that many neurological and psychiatric

disorders are likely to be associated with altered anatomical

connectivity. Thus, it could be possible to investigate neuro-

logical and psychiatric disorders at least at three different

integrative levels: Functional Module, Mirror and Hall of Mirrors.

As discussedin the previous sections, this view is consistent

with existing experimental evidence of peculiar columnar map-

pings of the sensory receptive fields onto the somatosensory

(Mountcastle et al., 1957; Rakic, 2008; Woolsey and Van der

Loos, 1970), visual (Hubel and Wiesel, 1977), auditory

(Hromàdka and Zador, 2009), piriform (Gottfried, 2010) and

primary taste (Chen et al., 2011) brain cortex. Similar forms of

morphofunctional organization also exist outside the cortical

areas, such as in the brainstem (Erzurumlu et al., 2010), the

superior colliculus and the cerebellum (Arenz et al., 2009). As

proposed by Llinas et al. (1998) the activity involving resonant

columns could be the basis for cognitive events. According to

Fig. 5 – Consciousness as a virtual space and a virtual personage created by the existence of multiple interacting “mirrors”. The

metaphor of mirrors is simply a heuristic hypothesis to depict the metaphor of the internal theater in neurobiological terms.

14 B R A I N R E S E A R C H 1 4 7 6 ( 2 0 1 2 ) 3 – 2 1



our model, these resonant columns are made up of FMs at

cortical level. FMs are microcircuits organized as nested

mosaics of different miniaturization (see Fig. 4). The columns

(the Mirrors) dynamically assemble to form a higher-order

mosaic where reverberating activity occurs along some of the

available wiring interconnections (such as the cortico-

thalamic pathways), leading to the formation of a NCC (Hall of

Mirrors). This view is in agreement with Edelman and Tononi's(2000) proposal on the existence of a ‘dynamical core’ formed

by shifting assemblies of spiking neurons throughout the

forebrain that are stabilized using massive re-entrant feed-

back connections (Edelman and Tononi, 2000). As also pointed

out by Crick and Koch (2003), competitions among rival cell

assemblies, i.e., potentially differently formed mosaics, occur as

a dynamic process (Crick and Koch, 2003). The winning coalition

is the one that makes the largest contribution to what we are

conscious of.

An interesting approach to investigate our hypothesis

could be based on the following question: what is it that

makes the human Hall of Mirrors (i.e., the mosaics of FMs)

so peculiar when compared to other mammalian species,

despite quite similar types of macro-anatomical cortical

regions? As mentioned in Section 2, the human brain

possesses not only special types of neurons (VEN) and astro-

cytes (varicose projection astrocytes) but also a higher density

of synaptic contacts per neuron and a higher astrocyte/neuron

ratio. Thus, data on neurons suggest more reverberating

circuits, while the data on astrocytes seem to indicate more

extended astrocyte networks and hence more complex

neuron–astroglial interactions. Altogether they open the possi-

bility for the formation of more complex FMs. Furthermore, it

may also be surmised that the hierarchical dimension of the

integrative processes occurring within human FMs could be

more complex. In this respect it would be of particular interest

to investigate whether the human brain has special protein

mosaics, e.g., special receptor mosaics (Agnati et al., 2005b,

2007d).

6.2. ‘ Hall of Mirrors’ : testable hypotheses

The ‘Hall of Mirrors’ metaphor yield testable hypotheses that

will be the focus of the present Section.

A common view in the cognitive neuroscience is that brain

areas are highlyselectiveandexhibit considerable specialization,

each responding to a set of inputs and contributing primarily to a

single cognitive domain. The here proposed metaphor would

suggest a different view in which the same basic modules (the

FMs) can be variably associated to realize a large spectrum of

NCCs, leading to the testable hypothesis that single brain regions

(even fairly small regions) could contribute to multiple cognitive-

emotional tasks.It is noteworthy that overthepast years increas-

ing evidence emerged pointing to this direction. Examples are

provided by studies on the Broca's area (see Poldrack, 2006),

showing that current evidence for the notion that Broca's area is

a “language” region is fairly weak, since it was more frequently

activated by non-language tasks than by language-related ones.

Similarly, a meta-analysis by Anderson et al. (2010)demonstrated

that most regions of the brain appear to be activated by multiple

tasks across diverse task categories. The results reported in that

study suggested that the brain achieves its variety of functions

by putting the same regions together in different patterns of

functional cooperation.

In this context, a cognitive task of particular interest is the

so-called ‘mirror ’ neuronal episodes. According to current

neurobiological research, a mirror neuron is a neuron that

fires both when an animal acts and when the animal observes

the same action performed by another subject (Rizzolatti and

Craighero, 2004). Thus, the neuron “mirrors” the behavior of the other, as though the observer were acting directly. Brain

activity consistent with that of mirror neurons has been

found in the premotor cortex and the inferior parietal cortex

in humans (Ferrari et al., 2006, 2009; Rizzolatti et al., 2009).

Such neurons have been observed in primates, and are

believed to occur in other species including birds. Functional

magnetic resonance imaging (fMRI) studies in humans

suggest that a much wider networkof brain areas shows mirror

properties in humans than was previously thought. These

additional areas include the somato-sensory cortex and are

thought to make the observer feel what it feels like to move in

the observed way (Gazzola and Keysers, 2009). fMRI experi-

ments suggest that rather than mirror neurons the human

brain areas have mirror neuron systems (Iacoboni et al., 1999).

Based on the ‘Hall of Mirrors’ metaphor, we suggest the

testable hypothesis thatmirror systems are an epiphenomenon

of a more fundamental feature of the functional organization of

the brain, i.e., the existence of computational units (mosaics of

FMs) acting like ‘mirrors’. These mosaics mirror a suitable

input, processing it according to their intrinsic functional char-

acteristics, namely connectivity and more generally to memory

stores, hence their ‘history’. The first set of mirrors is the FM

mosaics reflecting the relevant cues of the environment in an

‘analogic code’ that is the most useful code for the task the

brain should tackle in that instance—a motor code in the case

of a movement, an emotional code in the case of a feeling.

This assumption is not only in agreement with the data on

‘mirrorsystems’ but also with theimagery processes: to produce

an imagery movement the brain activates, at least in part,

networks in the motor area in order to produce an imagery

movement. Motor Imagery (MI) has been shown to involve the

conscious internal representation of movement, without overt

motor performance (Decety and Grezes, 1999; Fleming et al.,

2010). Similarities in brain activation between MI and actual

movement have also been demonstrated by fMRI (Gerardin et

al., 2000). In particular, fMRI studies have shown that during

imagined and executed finger movements, common areas of

brain activation can be observed in the premotor cortex, supple-

mentary motor area and parietal cortex, with activation peaks

slightly more rostral in frontal areas and slightly more superior

and caudal in parietal areas during MI compared with move-

ment execution (Gerardin et al., 2000). Both the right and left

parietal cortices show greater blood oxygen level-dependent

signals during imagery than during motor execution. In addi-

tion, the greater activation of the superior parietal cortex during

imagery than during preparation for movement, indicates that

MI is more than simply readiness to move (Stephan et al.,

1995). The ‘mirror ’ episodes stress the importance of reverberat-

ing phenomena in the brain. However, emphasis should be

placed on the difference between the ‘passive’ process of reflec-

tion of a beam of light by a mirror and the reverberation of

neuronal activity between two FM mosaics, which transform

15B R A I N R E S E A R C H 1 4 7 6 ( 2 0 1 2 ) 3 – 2 1



the incoming information not only according to their structural

organization but also according to their ‘history’.

The ‘hall of mirror metaphor ’ also suggests that the same

logic can be at the basis of a particularly important task such

as self-awareness. In other words, the continuous building of

a ‘virtual personage’ (the ‘self ’) living in the internal theater

would be the result of the mirror effect within some set of

FMs. An interesting possibility to test such an hypothesismay come from the fundamental study by Craig (2009)

where he proposes that the anterior insular cortex contains

interoreceptive representations of all subjective feelings

from the body and likely also emotional awareness, therefore

being able to play a fundamental role for self-awareness.

Thus, FMs that are key for high-level sentience may be located

in the insula and anterior cingulate cortex. Experiments on

self-recognition seemed to confirm the important role of

these regions in the generation of an abstract representation

of oneself. In other words, these regions appear to be deeply

involved in the creation of the ‘virtual sentient personage’

within the internal theater. As mentioned above, it is note-

worthy that these two regions exhibit an extraordinary

concentration of VENs, which are present only in few species

(namely those capable of passing the mirror test). These

neurons could be part of the circuitry supporting human

social networks. In particular, Allman et al. (2005) proposed

that the VENs relay an output from the fronto-insular and

anterior cingulatecortex to theparts of the frontaland temporal

cortex associated with theory-of-mind, where fast intuitions

are merged with slower, deliberative judgments (Allman et al.,

2005).

In agreement with such a view, it has been shown that the

loss of emotional awareness and self-consciousness in

patients with fronto-temporal dementia correlates with the

degeneration of VENs (Seeley et al., 2006).

6.3. ‘ Hall of Mirrors’ : suggested conceptual issues

As described in theforegoing Sections, thebasicidea concerning

the morphofunctional organization of the brain suggested by

the ‘Hall of Mirrors’ metaphor is a view of the cerebral cortex

as composed of FMs, i.e. microcircuits structured as a hierarchi-

cal series of networks (computational mosaics) of different

miniaturization. These basic units are able to perform a first-level integrative function by allowing the conversion of incom-

ing fragments of sensation into particular fragments of percep-

tion. They, in turn, can be dynamically linked to form mosaics

of increasing order, leading to the NCCs. A block diagram (see

Fig. 6) could indicate aspects of the main system components

involved in the present view A piano keyboard could also serve

as a simple analogy to illustrate the FM articulation in the

cerebral cortex. In fact, FMs can be represented by the keys of

the piano activated by interoceptive and/or external stimuli

but also by imagery. The complex mechanism behind a piano

key can be thought as the complex hierarchical articulation of

a FM. With the given set of piano keys a great many different

assemblies of sounds can be produced, since the keys can be

touched according to different spatial and temporal patterns.

Each specific melody, in other words, depends on the set of

keys used (spatial pattern) and the temporal sequence in

which these keys are activated (temporal pattern). Similarly,

the cognitive value of the mosaic of FMs depends on the selec-

tion of the activated FMs, and hence on their spatial and

temporal pattern, and on the possibility that the partial and

separated cognitive elements are properly integrated.

It follows that, according to the proposed ‘Hall of Mirrors’

metaphor, a key concept in the formation of the internal

theater is that of ‘reuse’ of the same basic circuits to build

the many different patterns of activity that lead to conscious

episodes. In this respect, the present neurobiological view

Fig. 6 – Possible merging of different available hypotheses in a unique schematic integrated view: (1) Coalitions of shifting

assemblies of brain cells stabilized by re-entrant feed-backs ( Edelman and Tononi, 2000 ) represent the NCCs. According to the

hypothesis here presentedthe basic element (tessera)of theassembly(mosaic) is a FM characterizedby a Russian doll structure;

(2) Special FMs could be found at the level of the insula and the anterior cingulate cortex ( Craig, 2009 ) giving the body an

emotional awareness; (3) as proposed by Llinas ( Llinas et al., 1998 ) thalamo-cortical interconnections should represent the main

system selecting and binding the FMs to form the NCCs; (4) the claustrum could contribute to the process by acting as a

‘conductor ’ giving the proper emphasis to each FM ( Crick and Koch, 2003 ).

16 B R A I N R E S E A R C H 1 4 7 6 ( 2 0 1 2 ) 3 – 2 1



shows consistency with some general cognitive theories that

appeared in the last 5 years (Anderson, 2010; Dehaene, 2009;

Gallese, 2008; Hurley, 2008) suggesting that low-level neural

circuits are used and reused for various purposes in different

cognitive and task domains. The ‘massive redeployment

hypothesis’ (Anderson, 2007a, 2007b), for instance, explains

the observed patterns of scattered regions corresponding to

different cognitive tasks (such as language, visual perception,attention) with the suggestion that local circuits may have

low-level computational “workings” that can be put to many

different higher-level cognitive uses.

As pointed out by Anderson (2010) this represents a novel

concept, something about the brain that we are just now

beginning to notice. It offers a distinct perspective on several

general topics (such as the evolution and development of the

brain, the degree of modularity in brain organization and the

degree of localization of cognitive functions) and could also

have some practical implications in terms of rehabilitative

medicine.

7. Final comments

A basic assumption of the present paper is the building up of

mosaic networks made of elements (the FMs) that are

themselves hierarchically organized (like a Russian doll), i.e.

encasing mosaic networks each made of other mosaic

networks of a higher miniaturization. The relevance of this

‘vertical’ morphofunctional organization for the integrative

actions of the brain can be better appreciated when observing

that such an arrangement allows an enormous number of

possible configurations for each FM, providing it with an

extraordinary potential capability to process and store infor-

mation. The integrative power of the brain is further

enhanced if the above discussed mechanism of ‘neural

reuse’ (Anderson, 2010) is in operation. In fact, starting from

a given set of FMs, it allows the realization of a wide spectrum

of different assemblies, leading to the emergence of NCCs. As

mentioned above, parcellation leads to the subdivision of the

cortical surface into compact areas, which internally contain

relatively similar FMs. It is suggested that these FMs can

independently participate in the formation of different

mosaics. Thus, it can also be surmised that, by involving

different mosaics of FMs, thesame area canbe simultaneously

redeploymented for different tasks.

As pointed out in Section 5, the formation of these

conscious episodes could result from the interplay of two

basic components of the cerebral activity: the first one inter-

nal and withdrawn, the second one, being responsible for

sensorimotor actions, open to the external world. As

suggested by Llinas, “in principle one can see how the intrinsic

activity of neurons, which reflect a closed reference system, may be

the stage on which our image of the external world is ultimately

generated” (Llinas, 1988).

In conclusion, everyone lives in his own internal theater as

assessed by Chamfort: C'est là proprement l'homme; là se borne

son empire. Tout le reste lui est étranger (see Auguis, 1824–1825).

The internal theater, however, cannot be compared to a

prison since, as stated by Pessoa, there is an extraordinary

opening in its thick walls: “our imagination which allows us not

only to imagine skies above us but even non-existing skies”

(Pessoa, 1982).

As a final remark, the provided considerations clearly

delineate the restricted use of the ‘Hall of Mirrors’ metaphor

here proposed. It is suggested only as a pictorial or literary

image of the mechanisms building the set of our internal

theater. In the meantime,we believe that the ‘negative analogy’

of such a metaphor can be thought of as a useful way of illus-trating the complexity of the neurobiological problems involved

and the neurobiological investigations that should be carried

out, namely regarding:

• The rules for recruitment of the mosaics of different minia-

turization forming single FMs and those underlying the

logical operations carried out at each level.

• Theprocesses leading to therecruitmentof theFMs forming

the higher-order mosaics and the NCCs.

• The functional organization of the FMs: boundaries and

communication processes inside each FM and among FMs.

In particular, the different functional meaning of the back-

ground tone versus the binding phenomenon.

Acknowledgments

This workwas supported by grants fromIRCCS SanCamillo, Italy.

In addition, C. Cela-Conde's contribution was made

possible by project research grant HUM2007-64086/FISO

awarded by the Dirección General de Investigación del Ministerio

de Educación y Ciencia (Spain).

R E F E R E N C E S

Agnati, L.F., Fuxe, K., 1984. New concepts on the structure of theneuronal networks: the miniaturization and hierarchicalorganization of the central nervous system. Biosci. Rep. 4,93–98.

Agnati, L.F., Fuxe, K., 2000. Volume Transmission as a key featureof information handling in the central nervous systempossible new interpretative value of the Turing's B-typemachine. Prog. Brain Res. 125, 3–19.

Agnati, L.F., Fuxe, K., Zoli, M., Rondanini, C., Ogren, S.O., 1982. Newvistas on synaptic plasticity: the receptor mosaic hypothesis of the engram. Med. Biol. 60, 183–190.

Agnati, L.F., Zoli, M., Merlo Pich, E., Benfenati, F., Fuxe, K., 1990.Aspects of neural plasticity in the central nervous system. VII.Theoretical aspects of brain communication and computation.Neurochem. Int. 16, 479–500.

Agnati, L.F., Cortelli, P., Pettersson, R., Fuxe, K., 1995. The conceptof trophic units in the central nervous system. Prog. Neurobiol.46, 561–574.

Agnati, L.F., Fuxe, K., Ferré, S., 2005a. How receptor mosaicsdecode transmitter signals. Possible relevance of cooperativity.Trends Biochem. Sci. 30, 88–193.

Agnati, L.F., Genedani, S., Lenzi, P.L., Leo, G., Mora, F., Ferré, S., Fuxe,K., 2005b. Energy gradients for the homeostatic control of brainECF compositionand for VT signal migration: introduction of thetide hypothesis. J. Neural Transm. 112, 45–63.

Agnati, L.F., Zunarelli, E., Genedani, S., Fuxe, K., 2006. On theexistence of a global molecular network enmeshing the wholecentral nervous system: physiological and pathologicalimplications. Curr. Protein Pept. Sci. 7, 3–15.

17B R A I N R E S E A R C H 1 4 7 6 ( 2 0 1 2 ) 3 – 2 1



Agnati, L.F., Agnati, A., Mora, F., Fuxe, K., 2007a. Does the humanbrain have unique genetically determined networks coding logical and ethical principles and aesthetics? From Plato tonovel mirror networks. Brain Res. Rev. 55, 68–77.

Agnati, L.F., Genedani, S., Leo, G., Rivera, A., Guidolin, D., Fuxe, K.,2007b. One century of progress in neuroscience founded onGolgi and Cajal's outstanding experimental and theoreticalcontributions. Brain Res. Rev. 55, 167–189.

Agnati, L.F., Guidolin, D., Fuxe, K., 2007c. The brain as a system of nested but partially overlapping networks. Heuristic relevanceof the model for brain physiology and pathology. J. NeuralTransm. 114, 3–19.

Agnati, L.F., Guidolin, D., Leo, G., Fuxe, K., 2007d. A booleannetwork modelling of receptor mosaics relevance of topologyand cooperativity. J. Neural Transm. 114, 77–92.

Agnati, L.F., Guidolin, D., Carone, C., Dam, M., Genedani, S., Fuxe,K., 2008. Understanding neuronal molecular networks buildson neuronal cellular network architecture. Brain Res. Rev. 58,379–399.

Agnati, L.F., Baluška, F., Barlow, P.W., Guidolin, D., 2009a. Mosaic,self-similarity logic, and biological attraction principles: threeexplanatory instruments in biology. Commun. Integr. Biol. 2,552–563.

Agnati, L.F., Fuxe, K., Baluska, F., Guidolin, D., 2009b. Implicationsof the ‘Energide’ concept for communication and informationhandling in the central nervous system. J. Neural Transm. 116,1037–1052.

Agnati, L.F., Guidolin, D., Guescini, M., Genedani, S., Fuxe, K.,2010a. Understanding wiring and Volume Transmission. BrainRes. Rev. 64, 137–159.

Agnati, L.F., Guidolin, D., Leo, G., Carone, C., Genedani, S., Fuxe, K.,2010b. Receptor-receptor interactions: a novel concept in brainintegration. Prog. Neurobiol. 90, 157–175.

Allman, J.M., Watson, K.K., Tetreault, N.A., Hakeem, A.Y., 2005.Intuition and autism: a possible role for von economo neurons.Trends Cogn. Sci. 9, 367–373.

Alonso-Nanclares, L., Gonzalez-Soriano, J., Rodriguez, J.R.,DeFelipe, J., 2008. Gender differences in human cortical

synaptic density. Proc. Natl. Acad. Sci. U. S. A. 105,14615–14619.

Andén, N.E., Carlsson, A., Dahlström, A., Fuxe, K., Hillarp, N.A.,Larsson, K., 1964. Demonstration and mapping out of nigro-neostriatal dopamine neurons. Life Sci. 3, 523–530.

Andén, N.E., Dahlström, A., Fuxe, K., Larsson, K., Olson, L.,Ungerstedt, U., 1966. Ascending monoamine neurons to thetelencephalon and diencephalon. Acta Physiol. Scand. 67,313–326.

Anderson, M.L., 2007a. Evolution of cognitive function viaredeployment of brain areas. Neuroscientist 13, 13–21.

Anderson, M.L., 2007b. Massive redeployment, exaptation, and thefunctional integration of cognitive operations. Synthese 159,329–345.

Anderson, M.L., 2010. Neural reuse: a fundamental organizationalprinciple of the brain. Behav. Brain Sci. 33, 245–313.

Anderson, M.L., Brumbaugh, J., Suben, A., 2010. Investigating functional cooperation in the human brain using simplegraph-theoretic methods. In: Chaovalitwongse, A., P.M.Pardalos,V., Xanthopoulos, P. (Eds.), ComputationalNeuroscience. Springer,New York, pp. 31–42.

Aoki, C., Venkatesan, C., Go, C.-G., Forman, R., Kurose, H., 1998.Cellular and subcellular sites for noradrenergic action in themonkey dorsolateral prefrontal cortex as revealed by theimmunocytochemical localization of noradrenergic receptorsand axons. Cereb. Cortex 8, 269–277.

Arenz, A., Bracey, E.F., Margrie, T.W., 2009. Sensoryrepresentations in cerebellar granule cells. Curr. Opin.Neurobiol. 19, 445–451.

Auguis, P.R., 1824–1825. Chamfort, Oeuvres complètes, tome II.Chamerot, Paris.

Baars, B.J., 1988. A Cognitive Theory of Consciousness. CambridgeUniversity Press, Cambridge.

Baars, B.J., 1997. In the Theater of Consciousness. The Workspaceof the Mind. Oxford University Press, Oxford.

Baars, B.J., 1998. Metaphors of consciousness and attention in thebrain. Trends Neurosci. 21, 58–62.

Baars, B.J., Ramsoy, T.Z., Laureys, S., 2003. Brain, consciousexperience and the observing self. Trends Neurosci. 26, 671–675.

Badlangana, N.L., Bhagwandin, A., Fuxe, K., Manger, P.R., 2007.Observations on the giraffe central nervous system related tothe corticospinal tract, motor cortex and spinal cord: whatdifference does a long neck make? Neuroscience 148, 522–534.

Baluška, F., Volkmann, D., Barlow, P.W., 2006. Cell–cell channelsand their implication for cell theory. In: Baluška, F., Volkmann,D., Barlow, P.W. (Eds.), Cell–Cell Channels. Landes Bioscience,Georgetown, pp. 1–18.

Benavides-Piccione, R., Ballesteros-Yáñez, I., DeFelipe, J., Yuste, R.,2002. Cortical area and species differences in dendritic spinemorphology. J. Neurocytol. 31, 337–346.

Blakemore, C., 1976. Mechanics of the Mind. Cambridge UniversityPress, Cambridge.

Brown, G., 1914. The intrinsic factors in the act of progression inthe mammal. Proc. R. Soc. Lond. 84, 308–319.

Buchwald, J.S., 1974. Operant conditioning of brain activity — anoverview. In: Chase, M.H. (Ed.), Operant Conditioning of BrainActivity. University of California Press, Los Angeles, pp. 12–43.

Butti, C., Sherwood, C.C., Hakeem, A.Y., Allman, J.M., Hof, P.R.,2009. Total number and volume of Von Economo neurons inthe cerebral cortex of cetaceans. J. Comp. Neurol. 515, 243–249.

Buxhoeveden, D.P., Casanova, M.F., 2002. The minicolumnhypothesis in neuroscience. Brain 125, 935–951.

Buzsáki, G., 2007. The structure of consciousness. Nature 446, 267.

Buzsáki, G., 2010. Neural syntax: cell assemblies, synapsembles,and readers. Neuron 68, 362–385.

Bystron, I., Blakemore, C., Rakic, P., 2008. Development of thehuman cerebral cortex: Boulder Committee revisited. Nat. Rev.Neurosci. 9, 110–122.

Canales, A.F., Gómez, D.M., Maffe, C.R., 2007. A critical assessment

of the consciousness by synchrony hypothesis. Biol. Res. 40,517–519.

Carreira-Perpiñán, M.A., Goodhill, G.J., 2002. Are visual cortexmaps optimized for coverage? Neural Comput. 14, 1545–1560.

Chalmers, D.J., 2000. What is a neural correlate of consciousness?In: Metzinger, T. (Ed.), Neural Correlates of Consciousness:Empirical and Conceptual Questions. MIT Press, Cambridge,MA, pp. 17–40.

Chen, X., Gabitto, M., Peng, Y., Ryba, N.J.P., Zuker, C.S., 2011. Agustotopic map of taste qualities in the mammalian brain.Science 333, 1262–1266.

Cook, N.D., 2008. The neuron-level phenomena underlying cognition and consciousness: synaptic activity and the actionpotential. Neuroscience 153, 556–570.

Coull, J.T., 1998. Neural correlates of attention and arousal:insights from electrophysiology, functional neuroimaging andpsychopharmacology. Prog. Neurobiol. 55, 343–361.

Craig, A.D., 2009. How do you feel now? The anterior insula andhuman awareness. Nat. Rev. Neurosci. 10, 59–70.

Crick, F., 1984. Function of the thalamic reticular complex: thesearchlight hypothesis. Proc. Natl. Acad. Sci. U. S. A. 81,4586–4590.

Crick, F., Koch, C., 2003. A framework for consciousness. Nat.Neurosci. 6, 119–126.

Crick, F., Koch, C., 2005. What is the function of the claustrum?Philos. Trans. R. Soc. Lond. B Biol. Sci. 360, 1271–1279.

Cutsuridis, V., Wennekers, T., Graham, B.P., Vida, I., Taylor, J.G.,2009. Microcircuits: their structure, dynamics and role for brainfunction. Neural Netw. 22, 1037–1038.

da Costa, N.M., Martin, K.A., 2010. Whose cortical column wouldthat be? Front. Neuroanat. 4, 1–10.

18 B R A I N R E S E A R C H 1 4 7 6 ( 2 0 1 2 ) 3 – 2 1



Dahlström, A., Fuxe, K., 1964. Evidence for the existence of monoamine-containing neurons in the central nervoussystem. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol. Scand. Suppl. 232, 1–55.

de Veer, M.W., Gallup Jr., G.G., Theall, L.A., van den Bos, R.,Povinelli, D.J., 2003. An 8-year longitudinal study of mirror self-recognition in chimpanzees (Pan troglodytes).Neuropsychologia 41, 229–234.

Decety, J., Grezes, J., 1999. Neural mechanisms subserving theperception of human actions. Trends Cogn. Sci. 3, 172–178.

Deco, D., Jirsa, V., McIntosh, A.R., Sporns, O., Kötter, R., 2009. Keyrole of coupling, delay, and noise in resting brain fluctuations.Proc. Natl. Acad. Sci. U. S. A. 106, 10302–10307.

DeFelipe, J., Alonso-Nanclares, L., Arellano, J.I., 2002.Microstructure of the neocortex: comparative aspects.

J. Neurocytol. 31, 299–316.

Dehaene, S., 2009. Reading in the Brain. Viking, New York.Dennett, D.C., Kinsbourne, M.J., 1992. Time and the observer: the

where and when of consciousness in the brain. Behav. BrainSci. 15, 183–247.

Descarries, L., 1998. The hypothesis of an ambient level of acetylcholine in the central nervous system. J. Physiol. 92,215–220.

Douglas, R.J., Koch, C., Mahowald, M., Martin, K.A., Suarez, H.H.,1995. Recurrent excitation in neocortical circuits. Science 269,981–985.

Edelman, G.M., Tononi, G., 2000. A Universe of Consciousness.Basic Books, New York.

Erzurumlu, R.S., Murakami, Y., Rijli, F.M., 2010. Mapping the facein the somatosensory brainstem. Nat. Rev. Neurosci. 11,252–263.

Fajardo, C., Escobar, M.I., Buriticá, E., Arteaga, G., Umbarila, J.,Casanova, M.F., Pimienta, H., 2008. Von Economo neurons arepresent in the dorsolateral (dysgranular) prefrontal cortex of humans. Neurosci. Lett. 435, 215–218.

Ferrari, P.F., Visalberghi, E., Paukner, A., Fogassi, L., Ruggiero, A.,Suomi, S.J., 2006. Neonatal imitation in rhesus macaques. PLoSBiol. 4, 1501–1508.

Ferrari, P.F., Bonini, L., Fogassi, L., 2009. From monkey mirror neurons to primate behaviours: possible ‘direct’ and ‘indirect’pathways. Philos. Trans. R. Soc. Lond. B Biol. Sci. 364,2311–2323.

Fleming, M.K., Stinear, C.M., Byblow, W.D., 2010. Bilateral parietalcortex function during motor imagery. Exp. Brain Res. 201,499–508.

Freeman, W.J., 1997. Three centuries of category errors in studiesof the neural basis of consciousness and intentionality. NeuralNetw. 7, 1175–1183.

Fuxe, K., 1965. Evidence for the existence of monoamine neuronsin the central nervous system. IV. Distribution of monoaminenerve terminals in the central nervous system. Acta Physiol.Scand. Suppl. 64 (Suppl. 247), 39–85.

Fuxe, K., Canals, M., Torvinen, M., Marcellino, D., Terasmaa, A.,Genedani, S., Leo, G., Guidolin, D., Diaz-Cabiale, Z., Rivera, A.,Lundstrom, L., Langel, U., Narvaez, J., Tanganelli, S., Lluis, C.,Ferre, S., Woods, A., Franco, R., Agnati, L.F., 2007a.Intramembrane receptor –receptor interactions: a novelprinciple in molecular medicine. J. Neural Transm. 114, 49–75.

Fuxe, K., Dahlstrom, A., Hoistad, M., Marcellino, D., Jansson, A.,Rivera, A., Diaz-Cabiale, Z., Jacobsen, K., Tinner-Staines, B.,Hagman, B., Leo, G., Staines, W., Guidolin, D., Kehr, J.,Genedani, S., Belluardo, N., Agnati, L.F., 2007b. From thegolgi–cajal mapping to the transmitter-based characterizationof the neuronal networks leading to two modes of braincommunication: Wiring and Volume Transmission. Brain Res.Rev. 55, 17–54.

Fuxe, K., Marcellino, D., Woods, A.S., Leo, G., Antonelli, T., Ferraro,L., Tanganelli, S., Agnati, L.F., 2009. Integrated signaling inheterodimers and receptor mosaics of different types of GPCRs

of the forebrain: relevance for schizophrenia. J. Neural Transm.116, 923–939.

Fuxe, K., Dahlström, A.B., Jonsson, G., Marcellino, D., Guescini, M.,Dam, M., Manger, P., Agnati, L.F., 2010. The discovery of centralmonoamine neurons gave Volume Transmission to the wiredbrain. Prog. Neurobiol. 90, 82–100.

Gallese, V., 2008. Mirror neurons and the social nature of language: the neural exploitation hypothesis. Soc. Neurosci. 3,

317–333.Gallup Jr., G.G., 1970. Chimpanzees: self-recognition. Science 167,

86–87.

Gazzola, V., Keysers, C., 2009. The observation and execution of actions share motor and somato-sensory voxels in all testedsubjects: single-subject analyses of unsmoothed fMRI data.Cereb. Cortex 19, 1239–1255.

Gerardin, E., Sirigu, A., Lehericy, S., Poline, J.B., Gaymard, B.,Marsault, C., Agid, Y., Le Bihan, D., 2000. Partially overlapping neural networks for real and imagined hand movements.Cereb. Cortex 10, 1093–1104.

Ghosh, A., Rho, Y., McIntosh, A.R., Kötter, R., Jirsa, V.K., 2008. Noiseduring rest enables the exploration of the brain's dynamicrepertoire. PLoS Comput. Biol. 4, e1000196.

Giaume, C., Koulakoff, A., Roux, L., Holcman, D., Rouach, N., 2010.

Astroglial networks: a step further in neuroglial andgliovascular interactions. Nat. Rev. Neurosci. 11, 87–99.

Golding, N.L., Staff, N.P., Spruston, N., 2002. Dendritic spikes as amechanism for cooperative long-term potentiation. Nature418, 326–331.

Goldman-Rakic, P.S., 1995. Cellular basis of working memory.Neuron 14, 477–485.

Gottfried, J.A., 2010. Central mechanisms of odour objectperception. Nat. Rev. Neurosci. 11, 628–641.

Gray, C.M., Engel, A.K., König, P., Singer, W., 1989a.Stimulus-dependent neuronal oscillations in cat visualcortex. Receptive field properties and featuredependence. Eur. J. Neurosci. 2, 607–619 .

Gray, C.M., König, P., Engel, A.K., Singer, W., 1989b. Oscillatoryresponses in cat visual cortex exhibit inter-columnar

synchronization which reflects global stimulus properties.Nature 338, 334–337.

Graybiel, A.M., Grillner, S., 2006. Microcircuits: The Interfacebetween Neurons and the Global Brain Function. MIT Press,Boston.

Guidolin, D., Albertin, G., Guescini, M., Fuxe, K., Agnati, L.F., 2011.Central nervous systemand computation. Q. Rev. Biol. 86,265–285.

Hakeem, A.Y., Sherwood, C.C., Bonar, C.J., Butti, C., Hof, P.R.,Allman, J.M., 2009. Von Economo neurons in the elephantbrain. Anat. Rec. (Hoboken) 292, 242–248.

Hameroff, S., 2010. The “conscious pilot”- dendritic synchronymoves through the brain to mediate consciousness. J. Biol.Phys. 36, 71–93.

Harvey, C.D., Svoboda, K., 2007. Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature 450, 1195–1200.

Hebb, D.O., 1949. The Organization of Behavior. Wiley, New York.Hobson, J.A., 2009. Rem sleep and dreaming: towards a theory of

protoconsciousness. Nat. Rev. Neurosci. 10, 803–813.

Holtmaat, A.J., Trachtenberg, J.T., Wilbrecht, L., Shepherd, G.M.,Zhang, X.,Knott, G.W., Svoboda, K.,2005. Transientand persistentdendritic spines in the neocortex in vivo. Neuron 45, 279–291.

Hromàdka, T., Zador, A.M., 2009. Representations in auditorycortex. Curr. Opin. Neurobiol. 19, 430–433.

Hubel, D.H., Wiesel, T.N., 1977. Functional architecture of macaque monkey visual cortex. Proc. R. Soc. Lond. B 198, 1–59.

Hurley, S.L., 2008. The shared circuits model (SCM): how control,mirroring, and simulation can enable imitation, deliberation,and mindreading. Behav. Brain Sci. 31, 1–58.

Iacoboni, M., Woods, R.P., Brass, M., Bekkering, H., Mazziotta, J.C.,Rizzolatti, G., 1999. Cortical mechanisms of human imitation.Science 286, 2526–2528.

19B R A I N R E S E A R C H 1 4 7 6 ( 2 0 1 2 ) 3 – 2 1



Jacob, F., 1977. Evolution and tinkering. Science 196, 1161–1166.

John, E.R., 2002. The neurophysics of consciousness. Brain Res.Rev. 39, 1–28.

Jouvet, M., 1972. The role of monoamines and acetylcholine-containing neurons in the regulation of the sleep–waking cycle. Ergeb. Physiol. 64, 166–307.

Kenakin, T., Agnati, L.F., Caron, M., Fredholm, B., Guidolin, D.,Kobilka, B., Lefkowitz, R.W., Lohse, M., Woods, A., Fuxe, K.,

2010. International Workshop at the Nobel Forum, KarolinskaInstitutet on G protein-coupled receptors: finding the words todescribe monomers, oligomers, and their molecular mechanisms and defining their meaning. Can a consensus bereached ? J. Recept. Signal Transduct. Res. 30, 284–286.

Kiianmaa, K., Fuxe, K., 1977. The effects of 5,7-dihydroxytryptamine-induced lesions of the ascending 5-hydroxytryptamine pathways on the sleep wakefulnesscycle. Brain Res. 131, 287–301.

Knight, R.T., 1997. Distributed cortical network for visualattention. J. Cogn. Neurosci. 9, 75–91.

Knösche, T.R., Tittgemeyer, M., 2011. The role of long-rangeconnectivityfor the characterization of the functional–anatomicalorganization of the cortex Front. Syst. Neurosci. 5, 1–13.

Koblauch, A., Palm, G., Sommer, F.T., 2010. Memory capacities for

synaptic and structural plasticity. Neural Comput. 22, 289–341.

Kosslyn, S.M., 1994. Image and Mind. Harvard University Press,Harvard.

Laureys, S., 2005. The neural correlate of (un)awareness: lessonsfrom the vegetative state. Trends Cogn. Sci. 9, 556–559.

Lidbrink, P., Fuxe, K., 1973. Effects of intracerebral injections of 6-hydroxydopamine on sleep and waking in the rat. J. Pharm.Pharmacol. 25, 84–87.

Llinas, R., 1988. The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous systemfunction. Science 242, 1654–1664.

Llinas, R., Paré, D., 1991. Of dreaming and wakefulness.Neuroscience 44, 521–535.

Llinas, R., Ribary, U., 2001. Consciousness and the brain. Thethalamocortical dialogue in health and disease. Ann. N Y Acad.

Sci. 929, 166–178.

Llinas, R., Ribary, U., Contreras, D., Pedroarena, C., 1998. Theneuronal basis for consciousness. Philos. Trans. R. Soc. Lond. BBiol. Sci. 353, 1841–1849.

Lorente de Nò, R., 1938. Architectonics and structure of thecerebral cortex. In: Fulton, J.F. (Ed.), Physiology of the NervousSystem. Oxford University Press, New York, pp. 291–330.

McCulloch, W.S., Pitts, W.H., 1943. A logical calculus of the ideasimmanent in nervous activity. Bull. Math. Biophys. 5, 115–133.

McFadden, J., 2002. Hebbian reverberations in emotional memoryelectromagnetic field: evidence for an electromagnetic theoryof consciousness. J. Conscious. Stud. 9, 23–50.

Merker, B., 2007. Consciousness without a cerebral cortex: achallenge for neuroscience and medicine. Behav. Brain Sci. 30,63–134.

Mesulam, M., 2005. Imaging connectivity in the human cerebralcortex: the next frontier? Ann. Neurol. 57, 5–7.

Miyawaki, Y., Uchida, H., Yamashita, O., Sato, M.A., Morito, Y.,Tanabe, H.C., Sadato, N., Kamitani, Y., 2008. Visual imagereconstruction from human brain activity using acombination of multiscale local image decoders. Neuron 60,915–929.

Montagna, P., Gambetti, P., Cortelli, P., Lugaresi, E., 2003. Familialand sporadic fatal insomnia. Lancet Neurol. 2, 167–176.

Monti, M.M., Vanhaudenhuyse, A., Coleman, M.R., Boly, M.,Pickard, J.D., Tshibanda, L., Owen, A.M., Laureys, S., 2010.Willful modulation of brain activity in disorders of consciousness. N. Engl. J. Med. 362, 579–589.

Moruzzi, G., Magoun, H.W., 1949. Brain stem reticular formationand activation of the EEG. Electroencephalogr. Clin.Neurophysiol. 1, 455–473.

Mountcastle, V.B., Davies, P.W., Berman, A.L., 1957. Responseproperties of neurons of cats somatic sensory cortex toperipheral stimuli. J. Neurophysiol. 20, 374–407.

Murphy, S.T., Zajonc, R.B., 1993. Affect, cognition, and awareness:affective priming with optimal and suboptimal stimulusexposures. J. Pers. Soc. Psychol. 64, 723–739.

Oberheim, N.A., Wang, X., Goldman, S., Nedergaard, M., 2006.Astrocytic complexity distinguishes the human brain. Trends

Neurosci. 29, 547–553.Oberheim, N.A., Takano, T., Han, X., He, W., Lin, J.H., Wang, F.,

Xu, Q., Wyatt, J.D., Pilcher, W., Ojemann, J.G., Ransom, B.R.,Goldman, S.A., Nedergaard, J., 2009. Uniquely hominid featuresof adult human astrocytes. Neuroscience 29, 3276–3287.

Ostrow, L.W., Sachs, F., 2005. Mechanosensation and endothelinin astrocytes—hypothetical roles in CNS pathophysiology.Brain Res. Rev. 48, 488–508.

Parpura, V., Scemes, E., Spray, D.C., 2004. Mechanisms of glutamate release from astrocytes: gap junction“hemichannels”, purinergic receptors and exocytotic release.Neurochem. Int. 45, 259–264.

Penrose, R., Gardner, M., 1999. The Emperor's New Mind:Concerning Computers, Minds and the Laws of Physics. OxfordUniversity Press, Oxford.

Pereira, A., Furlan, F.A., 2009. On the role of synchrony for neuron–astrocyte interactions and perceptual consciousprocessing. J. Biol. Phys. 35, 465–480.

Pereira, A., Furlan, F.A., 2010. Astrocytes and human cognition:modeling information integration and modulation of neuronalactivity. Prog. Neurobiol. 92, 405–420.

Perry, E.K., Walker, M., Grace, J., Perry, R., 1999. Acetylcholine inmind: a neurotransmitter correlate of consciousness? TrendsNeurosci. 22, 273–280.

Pessoa, F., 1982. Livro de desassossego por Bernardo Soares. Atica,Lisboa.

Peters, A., Sethares, C., 1996. Myelinated axons and the pyramidalcell modules in monkey primary visual cortex. J. Comp. Neurol.365, 232–255.

Plotnik, J.M., de Waal, F.B., Reiss, D., 2006. Self-recognition in an

Asian elephant. Proc. Natl. Acad. Sci. U. S. A. 103,17053–17057.

Pockett, S., 2000. The Nature of Consciousness: A Hypothesis.Writers Club Press, Lincoln.

Poldrack, R.A., 2006. Can cognitive processes be inferred fromneuroimaging data? Trends Cogn. Sci. 10, 59–63.

Pöppel, E., 1994. Temporal mechanisms in perception. Int. Rev.Neurobiol. 37, 185–202.

Pöppel, E., Logothetis, N., 1986. Neuronal oscillations in thehuman brain. Discontinuous initiations of pursuit eyemovements indicate a 30-Hz temporal framework for visualinformation processing. Naturwissenschaften 73, 267–268.

Premack, D., 2007. Human and animal cognition: continuityand discontinuity. Proc. Natl. Acad. Sci. U. S. A. 104,13861–13867.

Rakic, P., 2008. Confusing cortical columns. Proc. Natl. Acad. Sci.U. S. A. 105, 12099–12100.

Rakic, P., 2009. Evolution of the neo-cortex: a perspective fromdevelop-mental biology. Nat. Rev. Neurosci. 10, 724–735.

Riad, M., Garcia, S., Watkins, K.C., Jodoin, N., Doucet, E., Langlois,X., El Mestikawy, S., Hamon, M., Descarries, L., 2000.Somatodendritic localization of 5-HT1A and preterminalaxonal localization of 5-HT1B serotonin receptors in adult ratbrain. J. Comp. Neurol. 417, 181–194.

Rinkus, G.Y., 2010. A cortical sparse distributed coding modellinking mini- and macrocolumn-scale functionality. Front.Neuroanat. 4, 1–13.

Rizzolatti, G., Craighero, L., 2004. The mirror-neuron system.Annu. Rev. Neurosci. 27, 169–192.

Rizzolatti, G., Fabbri-Destro, M., Cattaneo, L., 2009. Mirror neuronsand their clinical relevance. Nat. Clin. Pract. Neurol. 5, 24–34.

20 B R A I N R E S E A R C H 1 4 7 6 ( 2 0 1 2 ) 3 – 2 1



Robertson, J.M., 2002. The astrocentric hypothesis: proposed roleof astrocytes in consciousness and memory formation.

J. Physiol. Paris 96, 251–255.

Rockland, K.S., 2010. Five points on columns. Front. Neuroanat. 4,1–10.

Romo, R., Brody, C.D., Hernández, A., Lemus, L., 1999. Neuronalcorrelates of parametric working memory in the prefrontalcortex. Nature 399, 470–473.

Rouach, N., Koulakoff, A., Abudara, V., Willecke, K., Giaume,C., 2008. Astroglial metabolic networks sustainhippocampal synaptic transmission. Science 322,1551–1555.

Seeley, W.W., Carlin, D.A., Allman, J.M., Macedo, M.N., Bush, C.,Miller, B.L., Dearmond, S.J., 2006. Early frontotemporaldementia targets neurons unique to apes and humans. Ann.Neurol. 60, 660–667.

Semyanov, A., Kullmann, D.M., 2002. Kainate receptor-dependentaxonal depolarization and action potential initiation ininterneurons. Nat. Neurosci. 4, 718–723.

Sevush, S., 2006. Single-neuron theory of consciousness. J. Theor.Biol. 238, 704–725.

Shepherd, G.M., 1979. The Synaptic Organization of the Brain.Oxford University Press, New York.

Shepherd, G.M., 2011. The microcircuit concept applied to corticalevolution: from three-layer to six-layercortex. Front. Neuroanat.5, 30.

Shiffrin, R.M., Dumais, S.T., Schneider, W., 1981. Characteristics of automatism. In: Long, J., Baddeley, A. (Eds.), Attention andPerformance IX. Erlbaum, Hillsdale (NJ), pp. 223–240.

Shmuel, A., Leopold, D.A., 2008. Neuronal correlates of spontaneous fluctuations in fMRI signals in monkey visualcortex: implications for functional connectivity at rest. Hum.Brain Mapp. 29, 751–761.

Stephan, K.M., Fink, G.R., Passingham, R.E., Silbersweig, D.,Ceballos-Baumann, A.O., Frith, C.D., Frackowiak, R.S., 1995.Functional anatomy of the mental representation of upper extremity movements in healthy subjects. J. Neurophysiol. 73,

373–386.Tanne-Gariepy, J., Boussaoud, D., Rouiller, E.M., 2002. Projections of

the claustrum to the primary motor, premotor, and prefrontalcortices in the macaque monkey. J. Comp. Neurol. 454, 140–157.

Thierry, A.M., Stinus, L., Blanc, G., Glowinski, J., 1973. Someevidence for the existence of dopaminergic neurons in the ratcortex. Brain Res. Rev. 50, 230–234.

Wang, X.-J., 2001. Synaptic reverberation underlying mnemonicpersistent activity. Trends Neurosci. 24, 455–463.

Webster's College Dictionary, 1995. Random House.Welzel, O., Tischbirek, C.H., Jung, J., Kohler, E.M., Svetlitchny, A., et

al., 2010. Synapse clusters are preferentially formed bysynapses with large recycling pool sizes. PLoS One 5, e13514.

Werner, G., 2007. Perspectives on the neuroscience of cognitionand consciousness. Biosystems 87, 82–95.

Woolsey, T.A., van der Loos, H., 1970. The structural organizationof layer IV in the somatosensory region (SI) of mouse cerebralcortex. Brain Res. 17, 205–242.

Zurborg, S., Yurgionas, B., Jira, J.A., Caspani, O., Heppenstall, P.A.,2007. Direct activation of the ion channel TRPA1 by Ca2+. Nat.Neurosci. 10, 277–279.

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