Opinion

Redefining the Role of Limbic

Areas in Cortical Processing
Lorena Chanes1,2 and Lisa Feldman Barrett1,2,*
There is increasing evidence that the brain actively constructs action and
Trends
perception using past experience. In this paper, we propose that the direction
The brain functions as a generative
of information flow along gradients of laminar differentiation provides important model of the world that, following the
insight on the role of limbic cortices in cortical processing. Cortical limbic areas, principles of Bayesian probability,
explains sensory input based on past
with a simple laminar structure (e.g., no or rudimentary layer IV), send ‘feedback’ experience.
projections to lower level better laminated areas. We propose that this ‘feed-
back’ functions as predictions that drive processing throughout the cerebral The structural model of corticocortical
connections allows us to hypothesize
cortex. This hypothesis has the potential to provide a unifying framework for an that predictions flow from less to better
increasing number of proposals that use predictive coding to explain a myriad of laminated areas and prediction errors
flow in opposite direction.
neural processes and disorders, and has important implications for hypotheses
about consciousness. Limbic cortices, with their simple laminar
structure, issue predictions from the top
of the hierarchy within every sensory
A General Organizational Framework for Predictive Coding in the Cerebral system. The lowest levels correspond
Cortex to primary sensory cortices, with a
well-developed laminar structure.
Research and theory are converging on the idea that the brain actively constructs how we
experience and act on the world. According to the principles of active inference and Owing to their position in cortical hier-
predictive coding, the brain functions as a hierarchical generative model of the world that archies and their connectivity, limbic
follows the principles of Bayesian probability to explain sensory input based on past cortices are well suited to integrate a
neural ‘workspace’ for a unified con-
experience [1–3] (for an early proposal, see [4]). Signals based on this generative model,
scious experience.
called ‘predictions’, are sent from higher areas in the processing hierarchy to lower areas;
this corresponds to ‘feedback’ or descending projections [5–9]. Predictions modulate the This model motivates novel hypoth-
firing of sensory neurons in advance of sensory signals arriving from peripheral receptors and eses about the organization of intrinsic
networks and has the potential to inte-
are compared with incoming sensory input. The difference between predictions and sensory
grate a range of neural processes and
input (called ‘prediction error’) is sent back up the hierarchy; this corresponds to ‘feedfor- disorders.
ward’ or ascending projections. The reliability of the prediction error signal is also taken into
account so that the impact of prediction error in updating the model is not fixed but weighted
based on its reliability (or inverse of its variance, called ‘precision’) (see [2] for a review).
Together, perceptions and actions are thought to derive from the brain's best guess about
the causes of sensory events, with incoming sensory input keeping those guesses in check.
In a recent paper [10], we considered the notion of systematic variation of laminar structure
of the cortex and integrated a structural theory of corticocortical connections ([11,12]; see
[13] for a recent review) with the principles of predictive coding to propose an interoceptive
system in the brain. In this paper, we extend this logic to the entire cerebral cortex. This 1
Northeastern University, Department
redefines the role of cortical limbic areas in cortical processing. of Psychology, Boston, MA, USA
2
Massachusetts General Hospital,
Department of Psychiatry and the
Implementing predictive coding principles within the structural model of corticocortical con- Athinoula A. Martinos Center for
nections reveals that the direction of predictions and prediction errors between two cortical Biomedical Imaging, Charlestown, MA,
areas is determined by the laminar structure of those areas, such that predictions flow from less USA

to more laminated cortices and prediction errors flow in opposite direction (as discussed in [10]).
Cortical limbic areas (cingulate cortex, ventral anterior insula, posterior orbitofrontal cortex, *Correspondence: [email protected]
parahippocampal gyrus, and temporal pole) have the simplest laminar structure in the (L.F. Barrett).

96 Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2 http://dx.doi.org/10.1016/j.tics.2015.11.005

© 2015 Elsevier Ltd. All rights reserved.
 Figure 1. Limbic Cortices in the Glossary
Human Brain. Cortical limbic areas (in
Agranular cortex: part of the
blue) form a ring around the corpus cal-
neocortex that lacks a layer IV.
losum on the medial wall of each hemi-
Allocortex: part of the cerebral
sphere, continuing along the temporal
cortex with the simplest structure
cortex and the base of the brain [13]. They
(two or three layers). It comprises the
are neocortical areas that either lack or
primary olfactory cortex (part of the
have a rudimentary layer IV (i.e., are agra-
cerebral cortex that receives the
nular or dysgranular, respectively). They
projection from the olfactory bulb)
are located between the simpler allocortex
and the hippocampus.
and the better laminated eulaminate cor-
Allostasis: process of activating
tex. Limbic cortices include the cingulate
physiological systems (such as
cortex (subgenual anterior cingulate cor-
TP tex, sgACC; pregenual anterior cingulate
hormonal, autonomic, or immune
systems) with the aim of returning the
cortex, pgACC; dorsal anterior cingulate
body to homeostasis.
cortex, dACC; mid-cingulate cortex,
vAl Dysgranular cortex: part of the
POFC MCC; posterior cingulate cortex, PCC),
neocortex with a rudimentary layer IV.
the ventral anterior insula (vAI), the poster-
TP ior orbitofrontal cortex (POFC), the para-
Eulaminate cortices: part of the
neocortex with a well-developed layer
hippocampal gyrus (PHG), and the
IV. Eulaminate II areas have a better
MCC temporal pole (TP). Modified from [110].
dACC developed layer IV than eulaminate I
pgACC areas. Also called granular cortex.
PCC
Interoception: the perception and
sgACC integration of autonomic, hormonal,
visceral, and immunological
POFC PHG homeostatic signals that collectively
describe the physiological state of the
TP body.
Koniocortices: the eulaminate
cortices with the most well-developed
layer IV.
Limbic cortices or cortical limbic
areas: part of the neocortex with
agranular or dysgranular structure.
They are sometimes referred to as
periallocortex (agranular) and
neocortex (see Glossary) (Figure 1; Box 1). As a result, we hypothesize that they are at the top of proisocortex (dysgranular) cortex.
Neocortex: part of the cerebral
the predictive hierarchy in all cortical systems, sending predictions, while the most laminated
cortex with three or more layers and
areas (e.g., primary sensory cortices) are at the lowest levels, receiving predictions. We further columnar organization. Sometimes
propose that owing to (i) their anatomical location abutting every sensory system [13], (ii) their referred to as ‘isocortex’.
position at the top of predictive hierarchies, and (iii) their strong connectivity to each other [14– Visceromotor limbic cortices:
limbic (agranular and dysgranular)
19], as well as to subcortical structures such as the amygdala, the ventral striatum, and the
cortices that modulate the regulation
hypothalamus [20–27], limbic cortices create a highly connected, dynamic functional ensem- of the autonomic nervous system, as
ble for information integration and accessibility in the brain. We then hypothesize that limbic well as of the hormonal and immune
cortices, by virtue of their structural and functional properties, contribute to creating a unified systems.

conscious experience. We further suggest that our hypotheses provide novel insights about the
flow of information within intrinsic brain networks. Finally, we discuss how our approach may
offer a unifying framework for the growing number of predictive coding models of neural
processes and disorders.

Box 1. Systematic Variation of Laminar Structure in the Cerebral Cortex and Cortical Limbic Areas
The cerebral cortex varies systematically in its degree of laminar differentiation [29,30]. Laminar differentiation increases
progressively, from agranular cortices (which lack a layer IV) to dysgranular areas (with a rudimentary layer IV), then to
eulaminate areas (with six layers including a well-developed layer IV), and finally koniocortices (with six layers including the
most developed layer IV). For the purpose of the present paper, we operationally define cortical limbic areas or limbic
cortices cytoarchitecturally, rather than by location or function (following [13]). Limbic cortices are those neocortical areas
that either lack a layer IV (i.e., are agranular) or have a rudimentary layer IV (i.e., are dysgranular). Limbic cortices are
located between the simpler allocortex and the better laminated eulaminate cortices [29,30]. They are also sometimes
referred to as periallocortex (agranular parts) and proisocortex (dysgranular parts).

Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2 97

Predictive Coding within the Laminar Architecture of Corticocortical
Connections
Predictive coding and active inference approaches to cortical processing have been imple-
mented anatomically within the laminar architecture of the cortex. There are several models of
corticocortical processing to choose from. The first papers (e.g., [6–9]) used the Felleman and
Van Essen model of connections [28]. More recently, we implemented predictive coding
hypotheses using the structural model of corticocortical connections [11,12] (Box 2) to propose
the Embodied Predictive Interoception Coding (EPIC) model [10]. The Felleman and van Essen
model identified laminar patterns for feedback and feedforward projections. The structural
model went one step further to show that those patterns are predicted by the degree of laminar
differentiation of the connected areas. This, together with the systematic variation in cortical
structure across the cerebral cortex [29,30], has important implications for information flow.
Moreover, the structural model generalizes to the entire cerebral cortex; it has successfully
predicted the flow of information in frontal, temporal, parietal, and occipital cortices in experi-
ments with macaques and cats, using both experimental and computational techniques (Box 2).
Other models (e.g., using the distance rule [31,32]) have proven powerful and valid for some

Box 2. The Structural Model of Corticocortical Connections

In 1997, Barbas and Rempel-Clower introduced a structural model of corticocortical connections by analyzing projection
patterns within prefrontal cortices and their laminar structure in the monkey [12]. Using anterograde and retrograde
tracers, they showed that there is a relationship between laminar structure in cortical columns and the distribution of
projection neurons that connect those columns (for a recent review, see [13]). Feedback projections originate in less
differentiated cortical areas (such as agranular cortex with undifferentiated layers II and III and without a layer IV)
primarily in the deep layers (layers V and VI) and terminate in superficial layers of areas with a more developed laminar
structure (such as eulaminate cortices) (e.g., the blue neuron in Figure I). Feedforward projections originate in areas with
higher degree of laminar differentiation (e.g., eulaminate cortices with a fully expressed layer IV) primarily in the superficial
layers (II–III) and terminate in middle deep layers (IV–VI) of areas with less differentiated laminar architecture (e.g.,
dysgranular cortex) (e.g., the red neuron in Figure I). The structural model successfully predicts the flow of information in
frontal, temporal, and parietal cortices in experiments with monkeys and cats (see [13] for a review) and outperforms
other models of corticocortical connections [111].

Agranular Dysgranular Eulaminate I Eulaminate II

I
II
III

IV

VI

WM

Figure I. Structural Model of Corticocortical Connections. Feedback connections originate in deep layers of less
laminated areas and terminate in superficial layers of more laminated areas (blue neuron). Feedforward connections
originate in superficial layers of more laminated areas and terminate in deep layers of less laminated areas (red neuron).

98 Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2

systems (e.g., visual areas), but are known to be less suitable for predicting information flow
within other systems (e.g., prefrontal areas; specifically, see Figure 6 legend in [32]).

A direct consequence of using the structural model to implement predictive coding is that the
direction of predictions (‘feedback’ connections) and prediction errors (‘feedforward’ connec-
tions) is determined by the relative degree of laminar differentiation of the cortical areas involved
[10]. Predictions originate primarily in the deep layers of cortical areas with less laminar
differentiation and terminate primarily in the superficial layers of more differentiated areas. By
contrast, prediction errors originate primarily in the superficial layers of cortical areas with more
laminar differentiation and terminate in the deep layers of less differentiated areas. When two
areas have a comparable laminar structure, their projections originate and terminate both in
superficial and deep layers (they are ‘lateral’). This implies that some cortical areas, such as
limbic cortices (which have the least differentiated laminar structure in the entire neocortex)
primarily send predictions to better laminated cortical areas and primarily receive prediction
error. Moreover, primary sensory cortices (with the most differentiated laminar structure) receive
predictions from less laminated cortical areas and send prediction error. Other cortical areas
(with intermediate degrees of laminar differentiation) send both predictions and prediction error
depending on the relative laminar differentiation of the receiving cortices.

In the EPIC model [10], we used evidence from tract tracing studies in monkeys, as well as
functional imaging evidence in humans, to propose that visceromotor limbic cortices (notably
the anterior and mid-cingulate cortices and the ventral anterior insula) send predictions to the
primary interoceptive cortex in the mid-to-posterior insula (I1), which is eulaminate in structure
(extending the logic in [6–9]). Visceromotor cortical limbic areas also send predictions to
subcortical structures that control the autonomic, hormonal, metabolic, and immunological
systems (e.g., the amygdala and the hypothalamus). In this paper, we further extend our
implementation of predictive coding within the structural model of corticocortical connections
to hypothesize that limbic cortices are at the top of each cortical sensory system. We call this the
limbic workspace model.

Limbic Cortices in Sensory Systems

One hypothesis of the limbic workspace model is that all cortical sensory systems are structured
similarly to the interoceptive system. This hypothesis builds on evidence from tract tracing
studies in monkeys, indicating that limbic cortices can be identified in visual (e.g., [33–36]),
auditory (e.g., [37–39]), and somatosensory (e.g., [36,40]) systems (also see [41,42]). The
anatomical pathways in the description of the different sensory systems that follows are, as
in [10], inferred in humans based on tract tracing studies performed in monkeys, unless
otherwise noted; this is similar to what has been done elsewhere [42], as inferences about
the human brain are commonly made studying other species such as the macaque monkey. We
acknowledge, of course, that different species have some important differences in brain
structure and function.

It is well established that visual and auditory systems work via predictive coding (e.g., [5], [43–45]
in humans, for a review on visual processing see [46]), and there is increasing evidence that the
olfactory and gustatory sensory systems work via predictive coding as well ([47–49] in rodents,
[50,51] in humans), along with a proposal that somatomotor system works similarly [6–9]. We
propose that limbic cortices are at the top of each hierarchical cortical system and send
predictions to better laminated areas. Primary sensory cortices are at the bottom and send
prediction error back to areas with simpler laminar structure. Evidence in support of our
hypothesis can be most clearly seen in the visual, auditory, and somatosensory systems
(Figure 2, blue, green, and red respectively), where predictions flow from cortical limbic areas
(agranular and dysgranular cortex) to multimodal association areas (e.g., lateral temporal

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 A1 S1

Unimodal associaon areas

V1
Mulmodal associaon areas

G1

Predicons
Predicons
I1
O1
Limbic
Predicon error Predicon error Allocortex corces Eulaminate I Eulaminate II Koniocortex

Figure 2. Schematic Representation of Exteroceptive and Interoceptive Cortical Sensory Systems. This figure
is not meant to be exhaustive but representative. Each ring represents a different type of cortex, from greater (exterior
circles) to less (interior circles) laminar differentiation. Primary sensory cortices (lower level of each sensory system) are
indicated: A1, primary auditory cortex; G1, primary gustatory cortex; I1, primary interoceptive cortex; O1, primary olfactory
cortex; S1, primary somatosensory cortex; V1, primary visual cortex. Unimodal association areas include extrastriate areas
(V2, V3, V4, MT/V5) for the visual system, superior temporal areas surrounding A1 for the auditory system, and the superior
parietal lobule for the somatosensory system. Multimodal association areas include the dorsolateral prefrontal cortex, lateral
temporal cortex, and posterior parietal cortex. Predictions flow from cortical areas with less laminar differentiation to areas
with greater laminar differentiation. Prediction error flows in opposite direction. The number of cortical steps (hierarchical
levels) is less in interoceptive, gustatory, and olfactory systems than in exteroceptive visual, auditory, and somatosensory
systems.

cortex and posterior parietal cortex) (e.g., [14–17] and based on intrinsic connectivity analyses in
humans [52]). These multimodal areas are eulaminate in structure (i.e., they have a well-defined
layer IV) and are shared across the three systems. From there, predictions are sent to unimodal
association areas (extrastriate areas for the visual system, superior temporal areas surrounding
primary auditory cortex for the auditory system, and the superior parietal lobule for the somato-
sensory system) (e.g., [36,41,53]). Unimodal association areas are eulaminate cortices with a
better developed layer IV. From these areas, predictions flow to primary sensory cortices
{primary visual cortex or V1 (e.g., [33,54–56]), primary auditory cortex or A1 (e.g., [37,57])
and primary somatosensory cortex or S1 (e.g., [36,40])}, which are koniocortices in structure (i.
e., they contain the most well-developed layer IV).

Sensory input from the periphery (visual, auditory, and somatosensory input via the thalamus)
arrives at the cortex at primary sensory areas (V1, A1, and S1). In those areas, sensory
information is represented in great detail (see, for example, the early experiments for primary
visual cortex [58]) and prediction error is computed. From there, prediction error (the sensory
evidence that did not match the prediction) flows through the gradients of laminar differentiation
to progressively less well laminated areas (unimodal association areas to multimodal association
areas and finally to limbic cortices). Note that even though predictions and prediction errors flow
hierarchically, areas within each system are not necessarily physically placed in a strictly linear
manner (for a discussion see [42]). Moreover, these systems likely influence each other at every
level of the hierarchy through lateral connections.

At higher levels of the predictive hierarchy (in areas with relatively less laminar differentiation),
information becomes more integrated. This integration across sensory domains comes with
progressive dimensionality reduction (meaning sensory detail is summarized and compressed).
For example, multimodal association areas are shared across visual, auditory, and

100 Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2

somatosensory systems (e.g., [41]; see [42,59] for reviews; for evidence of a multimodal
integration network in humans, see [52]).

Moreover, there are differences across systems in the amount of cortical processing. Compared
with interoception (Figure 2, yellow), information from visual, auditory, and somatosensory
modalities is processed more extensively in the cerebral cortex. In these exteroceptive systems,
predictions and prediction errors are computed across several levels of cortical processing (i.e.,
there are several synaptic connections between primary sensory cortices in which representa-
tions are more specialized and cortical limbic areas in which they are more integrated), whereas
there are fewer steps in the interoception system. Accordingly, primary interoceptive cortices in
mid- and posterior insula (I1) are eulaminate in structure (i.e., they have a less developed layer IV
than koniocortices of primary visual, auditory, and somatosensory cortices) (see [10]). This
difference in degree of laminar differentiation along which predictive signals are coded [smaller in
the interoceptive system (eulaminate to limbic) versus larger in the visual, auditory, and somato-
sensory systems (koniocortex to limbic)] may be one reason why interoceptive perception is less
differentiated and lower in dimensionality when compared with exteroceptive perception (for a
description of other reasons, such as the anatomy of the ascending interoceptive circuitry, see
[60]).

The gustatory system (Figure 2, pink) is structurally similar to the interoceptive system. It has few
steps between limbic and primary gustatory cortex (G1) (see, e.g., [14,15,17]), as G1 is
eulaminate in structure (i.e., not as well laminated as koniocortices) (for a review in humans,
see [61]).

The olfactory system (Figure 2, purple) is structured in a way that likely reflects its ancient
evolutionary origin: the primary olfactory cortex (O1) is three-layered allocortex. It abuts the
anterior insula and receives olfactory input directly from the olfactory bulb without a thalamic
relay (see [62] for a review in humans). Because O1 is allocortical (rather than neocortical), the
neurons are not structured in columns [63,64] and, therefore, strictly speaking, it is not known
whether the structural model of corticocortical connections holds. Furthermore, axons leaving
O1 to ipsilateral limbic cortices travel through the superficial layer I to the targeted areas [65] rather
than through white matter tracts. Thus, they will reach target areas via superficial cortical layers.
We can speculate, however, that predictions flow similarly from limbic cortices to O1, as odor
expectations alone, even in the absence of olfactory input, are associated with activity in the
main olfactory bulb ([66] in rodents; for a review of ‘top-down’ influences on olfaction, see [49]).

Taken together, these findings are consistent with the hypothesis that predictions issued in
limbic cortices involve more integrated, lower dimensional (multimodal) information, and these
predictions become higher in dimensionality (as predictions issued at lower hierarchical levels
within each sensory system are more specialized) until they reach primary sensory cortices,
where the most specialized cortical processing occurs. As prediction error is sent from primary
sensory to limbic cortices, it is compressed and summarized (for evidence consistent with this
hypothesis, see [52,67–69]; for a discussion of the energy efficiency of this arrangement, see
[70]). Therefore, the limbic workspace model proposes a general role of limbic cortices in cortical
processing, which is compatible with more specific functions of these areas and the existence
of differences across them; different cortical limbic areas may be more heavily associated with
specific systems.

In a predictive coding framework, perception and action are tightly coupled, such that action can
reduce prediction error (e.g., [6,7]; see also [10]). Extending this logic to the limbic workspace
model, we speculate that both action and perception arise from the brain's hypotheses about
the world and the body beginning as predictions in limbic cortices. Predictions are then

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constrained by sensory inputs, such that perceptions are largely constructions based on past
experiences and their allostatic relevance, kept in check by the actual state of the world and the
body, rather than the other way around.

A Dynamic Global Workspace for Conscious Experience

The brain works as a generative model of the world using past experience to construct the
present. We speculate that it is not an objective, accurate model, but one that is shaped by the
information that the organism has encoded in its history and tailored to its allostatic needs and
motivations (see also [10]). In addition to their anatomical position at the top of sensory and
motor processing hierarchies, limbic cortices are strongly interconnected [14–19], and have
strong bidirectional connections with subcortical structures such as the amygdala, the ventral
striatum, and the hypothalamus [20–27]. Therefore, highly integrated neural representations in
limbic cortices are easily accessible by virtually the whole brain. Interestingly, information
accessibility and sharing, as well as the idea of a ‘workspace’, have been consistently described
as key features of conscious access (e.g., [71–73]). ‘Global workspace’ [74] theories of
consciousness propose the rapid activation or ‘ignition’ of a long-range neuronal system as
the neural basis of consciousness ([71], for a review see [72]). Other theories emphasize the
importance of corticothalamic loops (‘dynamic core’ theory, reviewed in [73]), or areas with
dense anatomical connections known as ‘rich club’ hubs [75] (Box 3). We contribute to these
ideas by proposing that limbic cortices, owing to their connectivity and position in hierarchical
cortical information flow, are in a privileged position to contribute to the neural basis of conscious
access and may provide a ‘workspace’ for conscious experience. Representations of informa-
tion in a given cortical system (e.g., visual, auditory, motor, etc.) or a combination thereof can be
dynamically selected and prioritized because of their predicted relevance for the organism in a
specific context [67,76]. This implies that limbic cortices issue their predictions based primarily
on the selected content. For example, as you read these lines there are many sensory details that
you are not currently aware of, but you could be if those became suddenly relevant to you (e.g.,
the pressure of your back against the chair). As you read, these words are gaining privileged
access to a workspace for consciousness, which we propose is integrated largely by cortical
limbic areas. The content of specific cortical systems may be selected for its situation-specific
relevance (based on priors) for the organism and sent to the workspace. From there, prioritized
information can be accessed by virtually all systems in the brain, allowing a unified conscious
experience. In every conscious moment, all modalities are represented, but the type of content
that is prioritized may determine whether we categorize the experience as ‘emotion’, ‘percep-
tion’, or ‘cognition’. This dynamic selection of contents in the workspace and its flexibility
guarantees both differentiation and integration, which are key properties of consciousness [73],
as well as overall brain function [77]: differentiation because an immense number of possible

Box 3. Functional Organization of Intrinsic Brain Networks and ‘Rich Club’ Hubs
‘Resting state functional connectivity magnetic resonance imaging’ is the measurement of correlations of low frequency
blood oxygen level-dependent (BOLD) signal fluctuations while a participant lays ‘at rest’ during functional magnetic
resonance imaging (i.e., is not probed with an external stimulus). Analyses reveal a number of ‘intrinsic’ brain networks
that are anatomically constrained [112–115], can be observed under light sedation [116], and account for a large
proportion of the brain's metabolic budget [117]. ‘Rich club’ hubs are the most highly connected brain areas and have
been identified using diffusion tensor imaging of white matter tracts in humans [86] and reviewing tract tracing studies in
monkeys [87,88]. A large proportion of the rich club hubs are contained in two of the brain's intrinsic networks [75],
conventionally known as the ‘default mode’ network [82] and the ‘salience’ network [80]; these two networks contain
most of the brain's cortical limbic circuitry, and many rich club hubs are, in fact, limbic (e.g., dorsal ACC and anterior
insula). Furthermore, different intrinsic networks such as sensory networks overlap in these hubs, communicating with
each other through them [75]. These findings provide a conceptual replication for the macaque tract tracing data,
because they indicate that all sensory systems share cortical areas with core networks that contain limbic cortices. They
suggest the intriguing hypothesis that these two networks are at the nexus of the brain's architecture for predictive
coding.

102 Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2

representations from each cortical system can be prioritized in the limbic workspace; integration
because it provides a plausible explanation for a unified conscious experience and ‘stream of
consciousness’.

Implications
Intrinsic Networks and ‘Rich Club’ Hubs
The limbic workspace model provides insight on the relationships between different cortical
areas within and across intrinsic networks (Box 3). The brain can be thought of as one large
structural network showing continuous, intrinsic activity [78]. This activity has been parsed as
interconnected subnetworks that follow the white matter tracts within the brain (see [79] for a
review of networks). Empirically, an intrinsic network is defined as those areas whose low
frequency blood oxygen level-dependent (BOLD) signal correlates over time when a person is ‘at
rest’ (i.e., not being probed with an external stimulus). Each intrinsic network includes areas with
varying degrees of laminar differentiation (including limbic cortices) such as the ‘salience
network’ [80] (which bears a strong resemblance to the ‘ventral attention’ [81] and ‘multimodal’
networks [52]) and the ‘default mode network’ [82] (sometimes called the mentalizing network
[83], the construction network [84], or semantic knowledge network [85]). Within the limbic
workspace model, intrinsic networks can be understood as hierarchical systems, with the flow of
prediction signals within each network dictated by the structure of the cortical areas involved. In
these networks, limbic cortices (e.g., the ventral anterior insula and dorsal anterior cingulate
cortex for the ‘salience’ network and the posterior cingulate cortex and sub/pregenual cingulate
cortex for the ‘default mode’ network) issue predictions to better laminated areas in the network.
This way, a single network may contain a diverse population of representations across multiple
levels of cortical processing.

Similarly, the limbic workspace model provides insights into the functions of brain areas that
have the strongest structural connections, known as ‘rich club hubs’ [75,86–88], because
these hubs also include areas with different degrees of laminar differentiation (Box 3).
Structural and functional imaging in humans indicates that rich club hubs are ‘connector
nodes’ for intrinsic networks [75] and they have been shown to play an important role in brain
communication [67,89]. Mathematical modeling indicates that when one or more rich club
areas are damaged (e.g., the anterior insula or the dorsal anterior cingulate cortex, as
occurs in psychopathology or chronic stress), modularity in the brain increases dramatically
[90].

Integrating Different Functional Domains and Disorders

In the past several years, there has been an explosion of predictive coding approaches beyond
the sensory domain, including memory [91–93], pain [94–97], emotion [10,98–100], conscious
presence [101], self-recognition [102], allostasis [103], the placebo effect [104], ‘fear’ learning
[105], as well as neuropsychiatric disorders [106–108]. Each of these phenomena arises from
the dynamic interaction of systems that contain cortical areas that vary in their degree of laminar
differentiation. We speculate that limbic cortices, because they are at the core of the brain's
architecture for prediction, serve as shared neural relevant substrate for varied phenomena
whose circuitry is usually assumed to be distinct. For example, in the case of neural processing of
nociception, similarly to interoception, visceromotor limbic areas (e.g., dorsal anterior cingulate)
might issue predictions, while areas with higher degree of laminar differentiation such as the
dorsal mid-to-posterior insula or subcortical structures such as the periaqueductal gray (PAG)
will be at lower levels in the hierarchy and will send prediction error back to limbic (agranular and
dysgranular) areas (for a review on connections between the PAG and limbic areas, see [109]). In
fact, evidence of predictions in expectance of pain in the anterior insula has been reported [94]
and prediction error signals have been described in the PAG [96]. Our proposed model also
suggests fruitful avenues to explore the common visceromotor predictive basis for psychiatric,

Trends in Cognitive Sciences, February 2016, Vol. 20, No. 2 103

metabolic, and immunological symptom convergence in illnesses such as depression, heart Outstanding Questions
disease, and cancer (see [10]). How flexible is our generative model of
the world? How easily can it be modi-
fied with new experiences?
Concluding Remarks
Research and theory are converging on the idea that the brain's architecture constructs a vast To what degree is our generative model
repertoire of functional states as a generative model of the world. This model of the world is of the world anchored in visceromotor
changes and interoception? How
shaped by the organism's history and tailored to its allostatic needs and motivational goals. In
much do interoceptive predictions con-
this paper, we hypothesized that limbic cortices send predictions within all cortical systems, tribute to ongoing experience? Are
driving cortical processing across the gradients of laminar differentiation. We hypothesized that there individual differences in this
limbic cortices issue low-dimensional, multimodal predictions that are specified into high- regard?
dimensional representations as they cascade to lower level cortical areas with better laminated
Are there structural and functional dif-
cytoarchitectural structure. We further speculated that cortical limbic areas, owing to their ferences between cortical rich club
privileged position in cortical hierarchies, their anatomical position within the brain (abutting hubs of different degree of laminar
all sensory systems), and their dense interconnectivity, are well suited to provide an integrated differentiation?

workspace enabling a unified experience. Ultimately, the limbic workspace model may offer a
Are there differences in limbic predic-
unifying anatomical and functional account to better understand the organizational principles of tions during the mental events that are
intrinsic networks and rich club hubs, as well as unify many healthy and pathological phenomena experienced as emotions, cognitions,
that have, until now, been considered as having separate circuitry (see Outstanding Questions). and perceptions?

How is a generative model of the world

Because limbic cortices function to represent integrated information across different modalities altered in different neuropsychiatric
according to their allostatic relevance based on past experience, this may be why scientists conditions? Are there transdisorder
continue to identify limbic cortices with goals, values, or motivation. The present model of cortical vulnerabilities?

processing emphasizes the importance of information integration and segregation in the brain
and may help explain how the brain constructs a diverse population of representations across
multiple scales of organization within a relatively constrained architecture.

Acknowledgments
The authors thank M.Á. García-Cabezas for helpful discussions, thoughtful feedback on earlier versions of this manuscript,
and preparation of Figure I in Box 2. We also thank T. Cleland for guidance on predictive coding account of olfactory and
gustatory systems. This work was supported by a US National Institute on Aging grant (R01AG030311), a US National
Institute of Child Health and Human Development grant (R21 HD076164), and contracts from the US Army Research
Institute for the Behavioral and Social Sciences (contracts W5J9CQ12C0049 and W5J9CQ11C0046) to L.F.B., as well as a
Fyssen Foundation postdoctoral fellowship to L.C.

Disclaimer Statement
The views, opinions and findings contained in this article are those of the authors and should not be construed as an official
position, policy, or decision of the US National Institutes of Health or Department of the Army unless so designated by other
documents.

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