Handbook of Clinical Neurology, Vol.

166 (3rd series)

Cingulate Cortex
B.A. Vogt, Editor
https://doi.org/10.1016/B978-0-444-64196-0.00003-0
Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 3

Cingulate cortex in the three limbic subsystems

BRENT A. VOGT*
Cingulum Neurosciences Institute, Manlius, NY, United States
Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, United States

Abstract
Broca’s (1878) definition of the limbic lobe referred to its being located at the edge of the cerebral cortex,
and Papez (1937) and MacLean (1990) welded a series of medial surface structures into what we now know
as the limbic system. The last four decades of research have provided a wealth of detailed information on
the connectivity and functions of the limbic system and one can only conclude that it is not a uniform and
single system. The cingulate cortex itself has three major divisions: anterior primarily for emotion, middle
mainly for response selection and feedback-guided decision making, and posterior/retrosplenial cortices
for visuospatial orientation and assessing the self-relevance of objects and events. Each of these divisions
has a different cytoarchitecture and set of connections. The cingulate observations lead to a new framework
of limbic organization: three limbic subsystems that include the amygdala, orbitofrontal cortex, the insula,
the hippocampus, and, of course, the cingulate cortex. This concept is expanded in terms of connectivity
among them and the underlying functions of each subsystem. The three limbic subsystems considered here
are the “anterior emotional subsystem,” the “middle sensorimotor subsystem,” and the “posterior cognitive
spatial map subsystem” for localizing personally relevant objects and episodes. A defining characteristic of
the anterior emotional subsystem is its input from the amygdala. Another interesting outcome of this anal-
ysis is that the middle hippocampus and anterior midcingulate cortex share a role in approach-avoidance
decision making suggesting a potential for connectional synergy. Thus, the concept of “a” limbic system
needs radical revision to accommodate a minimum of three limbic subsystems. As this approach was
initiated by the three-part composition of the cingulate cortex, a finer-grain analysis of the cingulate region
shows that six limbic subsystems may be a more accurate reflection of limbic organization.

OVERVIEW
After Broca’s (1878) observation of the Great Limbic
Lobe, Papez (1937) conceptualized a limbic system as
a series of interconnected structures mainly lying on
the medial surface. Based on large stroke and tumor
cases, he concluded that the mammillary bodies, anterior
thalamic nuclei, and cingulate cortex were intercon-
nected and were involved in emotional experience.
Classic studies by MacLean (1990) added the amygdala
and hypothalamus to the limbic system, which is now
referred to as the Papez/MacLean model. For an excel-
lent review of the transition from Broca’s concept to
the limbic system concept, see Pessoa and Hof (2015).
It is important to note that as it stood during MacLean’s
life, the limbic system, even with his wealth of data and
modifications, was essentially a reverberating circuit
that received no external input (even though he recorded
visual responses) and had no output for motor or auto-
nomic control; even though his electrical stimulation
studies themselves evoked activity in both, including
vocalization. Without a structural/connection substrate,
however, his views were not widely accepted and he
was an investigator working on problems that were
innovative before his time.

*Correspondence to: Brent A. Vogt, Ph.D., President, Cingulum Neurosciences Institute, 4435 Stephanie Drive, Manlius, NY,
13104, United States. Tel: +1-315-280-6847, Fax: +1-617-358-2105, E-mail: bavogt@bu.edu
40 B.A. VOGT
From our studies of the cingulate cortex, it has become
clear that we cannot simply adopt the single limbic system
concept. Indeed, Rolls (2015) proposed that there are
two limbic systems: an anterior “emotion limbic system”
including the amygdala, orbitofrontal cortex (OFC), and
anterior cingulate cortex (ACC) and a posterior system or
“hippocampal memory system” that receives information
from neocortical areas about spatial location and objects
and includes the posterior cingulate cortex (PCC) and ret-
rosplenial cortex (RSC). However, this view still does not
accommodate cingulate heterogeneity and some of its key
functions, nor those of other cortical parts of the limbic
systems. Most important is the fact that the anterior mid-
cingulate cortex (aMCC) is an action-monitoring system
that regulates somatomotor output (see Chapters 1 and 4)
and should not be included with the two systems recog-
nized in the two–limbic system model. Of course, the
pMCC and dPCC subserve orientation of the body in
space and are part of an attentional system. The purpose
of this chapter is to put forward the theoretical basis for at
least three limbic subsystems. Each of the relevant struc-
tures is considered in terms of its primate connections
and functions. In order to keep this review to a manage-
able length, this assessment does not include subcortical
structures including the nucleus accumbens, cholinergic
septum/basal forebrain, thalamus, hypothalamus, mam-
millary bodies, periaqueductal gray, or parabrachial
nuclei. These latter structures will need to be added to
the three–limbic subsystem networks at a future time.
We conclude with the proposition based on the organiza-
tion of the cingulate cortex that there may actually be six
limbic subsystems.
In brief the three limbic subsystems considered here are
the “anterior emotional subsystem,” the “middle sensori-
motor subsystem,” and the “posterior cognitive spatial
map subsystem” for localizing personally relevant objects
and episodes. Due to the substantial connectivity of each
subsystem with the hippocampus (HPC), it does not
appear to be accurate to stipulate that any one subsystem
has a predominant role in memory. Finally, I propose that
each subsystem has a connection substrate summarized in
Figs.3.4 and 3.5 with the latter emphasizing directional
flow in the limbic networks that guide these functions
from sensory to skeletomotor and autonomic output.
If we are to propose multiple limbic systems, we
must consider the content of emotion before attempting
to understand their connections and functions. Rolls
(2014) defines emotion as states elicited by rewards
and punishers; i.e., by instrumental reinforcers, which
are the goals for action. The goal must be motivating
and elicited by emotional states that are rewarding and
reinforce the action just made, and the goal must exist
to direct behavior independently of prespecified
responses or habits. Emotional and motivational states
may be contrasted with responses or reflexes, which
can occur unconditionally to stimuli (e.g., autonomic
responses to stimuli that prepare the body for activity
and reflexes such as freezing or flight), reflexes for which
no intervening state of motivation or emotion is required.
Value coding systems must be separate from purely sen-
sory or motor systems, and while a goal is being sought
or if a goal is not obtained, the value-related representa-
tion must remain to direct further goal-directed behavior,
and it is these continuing goal-related states to which
emotion is related. Critical to this definition is the fact
that they operate on a common value scale that leads
to the selection of different rewards with appropriately
balanced probabilities and often depending on modula-
tion by internal motivational signals. In this context,
the OFC provides two major types of information: value
assessment and value scaling such that options can be
assessed and prioritized via the action-outcome and mon-
itoring systems as in the midcingulate cortex (MCC).
OFC itself receives sensory and premotor inputs that
subserve these functions as noted later.
MACRO ORGANIZATION OF FOUR
LIMBIC REGIONS DEFINE THREE
LIMBIC SUBSYSTEMS
Early gross anatomy and cytoarchitectonic studies of
the amygdala, cingulate cortex, OFC, the insula, and hip-
pocampus shows that each of these regions in primates is
comprised of three major divisions as shown in Fig. 3.1.
(1) In OFC, Hof et al. (1995) identified three anteropos-
terior divisions of about equal volumes: an agranular
posterior division (periallocortex), an intermediate dys-
granular component, and an anteromedial/anterolateral
granular cortex (isocortex). (2) The cingulate cortex
has three divisions with an agranular ACC, an MCC
dysgranular division, and a granular PCC/RSC (see
Chapter 1). (3) The insula has long been known to have
three major components (Mesulam and Muffson, 1982).
These include a rostral agranular, a middle dysgranular,
and a caudal granular division (Fig. 3.1C.1). Fig. 3.1C.2
shows the regions of interest (ROIs) used by Taylor et al.
(2009) in human studies to assess interactions between
the insula and cingulate cortex. (4) While the amygdala
has as many as nine subnuclei, three divisions have been
proposed. Amunts et al. (2005) observed three primary
divisions using probabilistic mapping (Fig. 3.1D). (5)
The HPC formation is comprised of the dentate gyrus,
CA1–4 sectors, prosubiculum, subiculum, and presubicu-
lum. However, since the subiculum and CA1sector are the
primary output structures of the HPC, their connectivities
are emphasized here. Demeter et al. (1985; Fig. 3.1E.3)
first recognized three anteroposterior (septotemporal ori-
entation) components of the hippocampal formation in
the monkey: anterior body, middle body, and posterior
body. Lia et al. (2013; Fig. 3.1E.1) recognized a similar
 CINGULATE CORTEX IN THE THREE LIMBIC SUBSYSTEMS 41

Fig. 3.1. Macro layout of the three subsystems. (A) Hof et al. (1995). (B) Chapter 1. (C.1) Insula modified from Nieuwenhuys
(2012) and (C.2) from the three ROIs set by Taylor et al. (2009) for resting-state fMRI studies. (D) Three amygdala divisions
recognized by Amunts et al. (2005) in a probabilistic study. (E.1) Human hippocampus analyzed with arterial spin labeling by
Lia et al. (2013). (E.2) Human hippocampus nodes assessed for intrinsic functional networks by Qin et al. (2016). (E.3) Monkey
hippocampal divisions from Demeter et al. (1988).
42 B.A. VOGT
three divisions in humans using arterial spin labeling. Per-
fusion studies by this group indicated that anterior, mid-
dle, and posterior HPC segments have unique transit
times and regional cerebral blood flow values. Of these
three, the middle HPC (mHPC) has the highest perfusion
and the shortest transit time and the anterior HPC
(aHPC) has the lowest perfusion and the longest transit
time. Finally, Qin et al. (2016) analyzed large-scale intrin-
sic functional networks in three nodes of the HPC
(Fig. 3.1E.2). Thus, all the relevant players in the three
limbic subsystems have already been recognized. The
amygdala is an important part of the anterior agranular
and dysgranular subsystems and, with its extensive sen-
sory afferents, may be a key starting point of functional
activity in the anterior limbic subsystem.
INTRALIMBIC CONNECTIONS AND
EXTRINSIC POINTS OF CONVERGENCE
The anterior emotional subsystem has robust interactions
with the amygdala, the middle subsystem engaged in
decision making and movement in conjunction with neo-
cortical sensorimotor cortices, and a posterior subsystem
that engages in spatial orientation to extract personally
relevant objects from the visual environment; i.e., per-
sons, objects, and episodes in their appropriate context
(Bar and Aminoff, 2003). All of these general functions
relate to limbic functions as they involve emotion and
motivation. Finally, the HPC contributes to memory in
each subsystem and is unique only to the extent that it
subserves different memories in each.
The four limbic regions are highly interconnected;
however, connections often do not respect cytoarchitec-
tural borders, i.e., there are often overlaps in intrinsic and
extrinsic connectivity across each limbic region. To add
to the difficulty of summarizing connections, many dif-
ferent organization schemes have been reported for each
structure under consideration here, i.e., consensus is rare
rather than common. As most corticocortical connections
are reciprocal, we will begin by assuming this to be the
case to reduce complexity except in Fig. 3.5 where the
direction of information flow is shown across the various
limbic subsystems.
Amygdala
The amygdala has been implicated in implicit and
explicit emotional learning, it influences perception
and facilitates attention to salient stimuli, and it is
involved in social behavior and extinction of emotional
learning (Phelps and LeDoux, 2005). It plays a key role
in setting emotional states that are important substrates
for the three limbic subsystems and projects to the ante-
rior component of each subsystem upon which the other
subsystems operate. Turner et al. (1980) used the lesion/
Fink-Heimer method in monkeys and concluded that all
sensory systems contain areas that project to the amygda-
loid complex. These sources included the visual area TE
and ventral TG, auditory anterior TA and dorsal TG, taste
area in the anterior insula, and somesthesis SI. (Their
method did not show strong SI and SII connectivity,
but Amaral and Price (1984) used autoradiography of
projections in the opposite direction and showed them
to be quite robust.) Also the parabrachial nucleus is a
source of visceral nociceptive input (Bernard and
Besson, 1990; Bernard et al., 1994). Continuing with
the Turner study, within the visual system, progressively
heavier and more widespread efferents arose from suc-
cessively later stages of the amygdalar sources of input.
The posterior half of TE sends a moderate projection to
the dorsal part of the lateral nucleus, the anterior half of
TE sends a heavy projection to the dorsal parts of both the
lateral and basal nuclei, and the ventral part of TG sends a
heavy projection to the dorsal and medial parts of the lat-
eral and basal nuclei and to the dorsal part of the basal
accessory nucleus. Thus, they drew the very important
conclusion that progressively greater influences on
amygdaloid activity are made by successively more
highly processed sensory information.
In terms of the OFC, the accessory basal and lateral
amygdaloid nuclei project most strongly to areas in the
posterior and medial orbital cortex. The medial, anterior
cortical, and central amygdaloid nuclei and the peria-
mygdaloid cortex are connected with the posterior orbital
areas (Vogt and Pandya, 1987; Carmichael and Price,
1995b; Fig. 3.2A and B). These nuclei project primarily
to each area of the ACC and less so to aMCC. This latter
connection is noteworthy because the ventral bank of the
cingulate gyrus in aMCC is engaged in fear and may be
critical for somatomotor escape/avoidance responses
(Vogt et al., 2003). In terms of the insula, once again these
amygdaloid nuclei project primarily to the anterior, agra-
nular sector. Finally, Aggleton (2012) also recognized
three divisions of the HPC and noted projections that pre-
dominantly arise from the rostral HPC to include those to
the amygdala. Thus, the amygdala receives inputs from
all sensory modalities and projects to all parts of the ante-
rior limbic subsystem. Indeed, this latter fact is one of the
defining characteristics of this subsystem.
Damage to OFC has long been associated with defi-
cits in reversal learning. OFC damage also causes inflex-
ible associative encoding in basolateral amygdala (BLA)
during reversal learning. Stalnaker et al. (2007) showed
that rats with OFC lesions were slower to acquire rever-
sals than sham controls in a two-odor go/no-go discrim-
ination task, followed by two serial reversals of the final
problem. This impairment was abolished by accompany-
ing BLA lesions, while BLA lesions alone had no effect
on reversal learning. These results are consistent with the
 CINGULATE CORTEX IN THE THREE LIMBIC SUBSYSTEMS 43

Fig. 3.2. (A) Pronounced connections of medial OFC with both pACC (1) and vPCC (2). Reciprocal connections between these
cingulate subregions are apparent with cingulate injections (D.1). A remarkable overlap that has still not been explained that occurs
between OFC and PCC in pACC. (B) Tritiated amino acid injections mainly into pACC with spread into aMCC. (C) Injection into
pMCC. (D) Injection into dPCC with some spread into RSC. The middle panel of monkey brains was modified from Pandya et al.
(1991). (E) Human PET studies seeded in dPCC (1) and vPCC (2) modified from Vogt et al. (2006). Panel A: Modified from
Carmichael, S.T., Price, J.L. (1995b). Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys.
J Comp Neurol. 363, 515–641.

hypothesis that OFC facilitates cognitive flexibility by
promoting updating of associative encoding in down-
stream areas. Therefore, it is likely that the amygdala
plays a key role in the emotional functions of the anterior
limbic subsystem.
Orbitofrontal cortex
The medial/rostral part of OFC has robust connections
with ACC and PCC (Fig. 3.2A.1) in pACC and vPCC,
respectively. The intrinsic cingulate connections
(Pandya et al., 1981; Fig. 3.2B.1) mirror this interaction.
As the definition of emotion requires value scaling and
action-outcome modulation, it is particularly important
that OFC projects to MCC. Carmichael and Price
(1995a) showed the sensory and premotor connections
of individual areas in the OFC. Their results indicate that
these connections define a general organization such that
lateral orbital areas receive most of the sensory- and
premotor-related inputs, and posterior and central orbital
areas participate in several stages of convergent olfac-
tory, visceral, and gustatory processing as emphasized
in Fig. 3.4. While OFC has premotor connections, it is
surprising that it does not have pronounced projections
to MCC, which has key somatomotor outputs.
Carmichael and Price (1995b) present their findings in
a mediolateral orientation, so I have taken a few liberties
in translating them to the anteroposterior divisions
shown in Fig. 3.1A. Also note that the agranular area
is the most posterior region in contrast to that of the other
three components of the limbic subsystems. All of the
limbic structures are substantially connected with the fol-
lowing posterior and medial orbital areas: the posterome-
dial, medial, intermediate, and lateral agranular insular
areas (Iapm, Iam, Iai, and Ial, respectively) and areas
llm, 13a, 13b, 14c, and 14r. In contrast, lateral orbital
areas 12o, 12 m, and 12 L and medial wall areas 24a,
24b, and 32 are primarily connected with the amygdala
and the temporal pole. The projection from the HPC orig-
inates from the rostral subiculum and terminates in the
medial orbital areas. The parahippocampal cortical areas
(including the temporal polar, entorhinal, perirhinal, and
posterior parahippocampal cortices) are primarily con-
nected with posterior and medial orbital areas with some
projections to the dorsal part of the medial wall. The
ACC sends axons to the medial wall, the medial orbital
areas, and to lateral areas 12o, 12r, and Iai. The posterior
cingulate gyrus, including the caudomedial lobule,
which is the most caudal part of the cingulate gyrus,
was particularly strongly connected with area l and lm
as shown in Fig. 3.3A.1 and 2.
Vogt et al. (2006) used PET in the human with seeds
in the dPCC and vPCC to identify correlated voxels of
interest (VOI; Fig. 3.2E). While the OFC did not show
44 B.A. VOGT

Fig. 3.3. Connections of the amygdala and insula. (A.1) Retrogradely labeled neurons in the amygdala after horseradish perox-
idase (HRP) injections into the lateral insula and anterior OFC (2 and 4). (B.2) A large tritiated amino acid injection into the
amygdala (2) showing the topography of the cingulate projection (1) and its laminar distribution in areas 24 and 25 (3; Vogt
and Pandya, 1987). (C) Retrogradely labeled neurons following HRP injections into the anterior (1), middle (2), and posterior
(3) insula; modified from Mufson and Mesulam (1982). (D) Resting state functional connectivity modified from Taylor et al.
(2009). (E) Organization of the insula proposed by Nieuwenhuys (2012). Abbreviations: AA, agranular anterior zone; GI and
GII, primary and secondary gustatory areas; ILC, insular limbic cortex; INTC, insular nociceptive and thermoreceptive cortex;
ISAC, insular somatic association cortex; IVSC, insular viscerosensory cortex; OCI, primary olfactory cortex. Panel A: Modified
from Carmichael, S.T., Price, J.L. (1995b). Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys.
J Comp Neurol. 363, 515–641.

correlations of activity in the dPCC, those of the vPCC

did. Correlated VOIs were mainly in the middle parts
of OFC. Interestingly, the dPCC had strong correlated
VOIs in MCC, while vPCC did not. As these VOIs
entered the cingulate sulcus where the cingulate premotor
areas reside, it suggests that the visuospatial orientation of
dPCC plays an important role in somatomotor output.
Insula
For a thorough review of insular organization and func-
tions, the reader is referred to Nieuwenhuys (2012)
whose anatomic designations and viewpoints are quite
useful. He recognized the following divisions: AA, agra-
nular anterior zone; GI and GII, primary and secondary
 CINGULATE CORTEX IN THE THREE LIMBIC SUBSYSTEMS 45

Fig. 3.4. Summary of most of the important interactions among the three limbic subsystems as discussed in the text. Of particular note
are the extensive sensory inputs to the amygdala and OFC, the centrality of MCC with is somatomotor connections, and the fact that
the anterior part of each anterior subsystem receives amygdalar input, which is a defining feature of the anterior subsystems. Finally,
autonomic output arises from the amygdala and ACC. Abbreviations: GI, GII, primary and secondary gustatory cortex; HPC, hip-
pocampal complex; noci, nociception; PB, parabrachial nucleus; PirCx, piriform cortex; PreSMA/SMA, presupplementary motor
area/supplementary motor area; SI and SII, primary and secondary somatosensory cortex; STG, superior temporal gyrus.

gustatory areas, respectively; ILC, insular limbic cortex;
INTC, insular nociceptive and thermoreceptive cortex;
ISAC, insular somatic association cortex; IVSC, insular
viscerosensory cortex; and OCI, primary olfactory
cortex. The distribution of these structure/function divi-
sions is shown in Fig. 3.2E and many of the functional
summaries mentioned later are from this review.
Belin et al. (2000) discussed the auditory posterior
insula, as primates share the ability to reliably extract
affective- and identity-related cues from conspecific
vocalizations as in many other species. This information
arises from along the upper bank of the superior temporal
gyrus. Polymodal vestibular neurons are located in the
PIVC. Physiologic studies in rhesus monkeys have
shown that neurons in the granular part of the insula
respond to innocuous cutaneous stimuli as well as
nociceptive and thermal stimuli. The posterior insula
receives projections from the viscera, which is relayed
from the nucleus of the solitary tract and the parabrachial
complex.
The results of experimental neuroanatomic studies
and of stimulation and ablation experiments in monkeys
show a gustatory (taste) center in the anterior insula.
Olfaction is also part of insular function as electrical
stimulation of the anterior insula in humans evokes olfac-
tory sensations. Finally, visceromotor control has been
demonstrated with electrical stimulation of the insula
in humans and may elicit a variety of visceromotor
phenomena, including vomiting and other alterations
of the gastrointestinal tract, respiratory arrest, as well
as changes in cardiac rate and rhythm control, and
blood pressure. This “sensorimotor” area is situated in
the anterosuperior part of the posterior insular lobule.
Speech production was demonstrated in a series of
aphasic patients and revealed that in patients with a dis-
order in coordinating the movements for speech articula-
tion, an area in the anterosuperior insula was specifically
damaged.
A review of functional neuroimaging studies by Cole
and Schneider (2007) showed that the AIC is involved in
a large variety of cognitive control tasks that are more
complex than the sensorimotor responses noted earlier.
They provided evidence indicating that this insular
region forms, together with other cortical regions includ-
ing the ACC, presupplementary motor area, dorsal
premotor cortex, dorsolateral prefrontal cortex, and the
posterior parietal cortex, a highly interconnected cogni-
tive control network.
A meta-analysis of imaging studies of emotion
was presented by Phan et al. (2002) that suggested the
anterior insula is preferentially involved in the evaluative,
experiential, and expressive aspects of specific indivi-
dual emotions such as “happiness,” “sadness,” “fear,”
and “disgust.” These were also analyzed in the cingulate
cortex (Vogt et al., 2003) with ACC showing the highest
degree of emotional activity for all emotions analyzed
including “sadness” in sACC and “happiness” in pACC.
The cingulate gyral surface of aMCC expressed the high-
est density of studies reporting “fear” and the pMCC
was almost devoid of emotional activity, while the PCC
was engaged almost exclusively by “happiness” and con-
trol nonemotional activity. Furthermore, social species
employ social emotions to form group organizations that
extend beyond the individual. Studies by Lamm and
Singer (2010) indicate that the anterior insula is consis-
tently involved in social emotions, including empathy
46 B.A. VOGT
and compassion, and interpersonal interactions such as
fairness and cooperation and understanding the mental
state of others through language (Theory of Mind).
Neuroimaging has often shown that the AIC and ACC
are jointly activated in subjects experiencing emotion.
Because the ACC underlies motivation, it seems likely
that the AIC and ACC serve as complementary limbic
sensory and motor systems that work together in a way
similar to the somatosensory and somatomotor cortices.
The AIC and ACC contain salient components of a core
control network that guides all mental activity and
behavior in adult humans. The proviso to these observa-
tions is that while monkey studies show connections
between the anterior insula and ACC (Fig. 3.2C.1), the
human studies have still not resolved this connection
(Fig. 3.2D). Thus, the work of Taylor et al. (2009) in
human show that the anterior and middle insula are con-
nected with MCC, while the posterior insula is connected
mainly with pMCC and vPCC.
Hippocampus
Blatt and Rosene (1998) were the first to show that three
parts of the monkey HPC (Fig. 3.1E.3) had connections,
organized in columns, with specific proximal/distal
distributions. Their study of the direct HPC projections
to the temporal cortex revealed complementary, longitu-
dinal strips of neurons in CA1 and subiculum that pro-
jected to different temporal areas. In terms of afferents,
the rostral and medial entorhinal cortex projects to the
distal CA1 and proximal subiculum, while the caudal
and lateral entorhinal cortex preferentially projects to
the proximal CA1 and distal subiculum (Witter and
Amaral, 1991). Aggleton (2012) summarized projections
that predominantly arise from the anterior HPC and
include those to the amygdala, prefrontal cortex, temporal
pole, and nucleus accumbens (Aggleton, 1986;
Carmichael and Price, 1995b; Blatt and Rosene, 1998).
In contrast, projections to RSC, ACC area 24, and
area TE predominantly arise from the posterior HPC
(Aggleton and Brown, 2005; Kobayashi and
Amaral, 2003).
Projections to the medial prefrontal cortex originate in
areas 14, 25, and 32 and OFC areas 11 and 13 (Saunders
and Rosene, 1988). The hippocampal projections to area
TE also arise from the distal CA1 (Yukie, 2000) and prox-
imal subiculum (Insausti and Munoz, 2001). The inputs to
the amygdala arise from the proximal subiculum and from
CA1, which is found in the medial uncus and is separated
from the CA1 sector (Saunders et al., 1988). In contrast,
the HPC projections to the RSC preferentially arise from
the distal subiculum, along with efferents from the adja-
cent presubiculum and parasubiculum (Kobayashi and
Amaral, 2003).
Overall, the posterior HPC (subiculum, presubicu-
lum, parasubiculum) provides the majority of RSC
projections, which predominantly terminate in area
29 (Kobayashi and Amaral, 2003). However, it is the
anterior half of the subicular cortex that projects to ven-
tral areas v23a/b and 29 (the caudomedial lobule). In con-
trast, the more posterior subiculum, presubiculum, and
parasubiculum project to the remainder of the RSC
(Kobayashi and Amaral, 2003).
Just as the efferents from the primate HPC often show
a rostrocaudal gradient, so do some of its afferents. The
more lateral and posterior portion of the entorhinal cortex
projects to the posterior HPC, whereas the more medial
and anterior portion of the entorhinal cortex projects to
the anterior HPC (Witter and Amaral, 1991). Other
examples include projections from the amygdala and
the OFC, both of which preferentially terminate in anterior
CA1 and adjacent subiculum (Aggleton, 1986; Saunders
and Rosene, 1988; Carmichael and Price, 1995b).
Functional connectivity in human HPC is being
resolved with resting-state fMRI, correlation studies dur-
ing task challenges, and many other approaches. For
example, Libby et al. (2012) collected whole-brain
resting-state fMRI, and in another study they used
high-resolution fMRI to target the HPC in another sub-
ject sample. The first experiment showed that the peri-
rhinal cortex has preferential connectivity with the
anterior HPC (aHPC), while the parahippocampal cortex
has preferential connectivity with pHPC. The latter
experiment indicated that this anterior–posterior func-
tional connectivity dissociation was more evident for
subfields CA1 and subiculum than for a combined
CA2/CA3/dentate gyrus region as would be predicted
from monkey connection studies. The former experiment
revealed preferential perirhinal cortex connectivity with
an anterior temporal and frontal cortical network and
preferential parahippocampal connectivity with a poste-
rior medial temporal, parietal, and occipital network.
Thus, in the human medial temporal lobes, perirhinal
and parahippocampal cortices are associated with
distinct neocortical pathways that may differentially
interact with regions along the anterior–posterior axis
of the HPC.
The two-segment organization of the HPC, however,
has been extended to three segments that fit with the
three–limbic subsystem concept. Qin et al. (2016)
explored the large-scale intrinsic functional networks
of three levels of the hippocampus (also in parahippo-
campal cortex but not discussed here or shown in
Fig. 3.1E.2). Comparisons between the pHPC, mHPC,
and aHPC nodes showed that the pHPC, compared to
the aHPC, had stronger connectivity with multiple corti-
cal and subcortical regions. Cortical regions included
PCC, RSC, precuneus, ACC and MCC, ventromedial
 CINGULATE CORTEX IN THE THREE LIMBIC SUBSYSTEMS
prefrontal cortex, middle frontal gyrus, and visual asso-
ciation cortex. A similar but relatively weaker pattern
was in contrasts of the mHPC with the aHPC. Compared
to the mHPC, the aHPC showed significantly greater
connectivity with the amygdala, insula, temporal pole,
fusiform gyrus, lingual gyrus, superior temporal gyrus,
and motor cortex. ROI analyses for three hippocampal
nodes confirmed significant differences in connectivity
between anterior, middle, and posterior HPC nodes
and the amygdala, postcentral gyrus, temporal pole,
medial prefrontal cortex, fusiform gyrus, and PCC/
RSC. Thus, the functional connectivity of the hippocam-
pus is characterized by decreasing connectivity strength
along the posterior-to-anterior gradient with multiple
posterior midline structures. Compared to posterior and
middle subdivisions, the aHPC showed stronger connec-
tivity only with the bilateral anterior medial temporal
lobe and the left temporal pole. Thus, the anterior node
showed stronger connectivity with the anterior medial
temporal lobe, and the posterior node showed stronger
connectivity with widely distributed cortical and subcor-
tical regions including those involved in sensory and
reward processing.
AHPC
Ito and Lee (2016) reviewed the role of the aHPC in
approach-avoidance learning and highlight a few studies
that examined a role for the human aHPC in conflict pro-
cessing. Bach et al. (2014) reported that subjects were
required to forage for yellow virtual tokens within a
two-dimensional grid in the presence of a predator that
was asleep in one corner and would awake to take the
tokens unless the participant retreated to a safe corner.
Healthy subjects adapted their behavior when the prob-
ability of threat increased, showing greater avoidance
behavior and behavioral inhibition. This adaptive behav-
ior was accompanied by changes in greater aHPC activ-
ity and there was no evidence that this difference was
driven by a primary impairment in memory and/or spatial
cognition. Additionally, O’Neil et al. (2015) found signif-
icantly greater aHPC involvement during high- compared
to no-conflict face-scene pairs. Since perceptual and mem-
ory retrieval demands were matched across tasks with no-
and high-conflict trials, these findings provided further
evidence that the human aHPC plays an important role
in approach-avoidance conflict processing, a function
not usually associated with the HPC.
Ito and Lee (2016) also reviewed the more traditional
views of HPC functions but in its subfields. Different
subfields of the HPC subserve differential (but also over-
lapping) mnemonic functions. For instance, the dentate
gyrus has been implicated in mismatch detection, mem-
ory encoding, and the ability to discriminate two similar
47
memory representations (i.e., pattern separation). The
CA1 and CA3 sectors have been implicated to varying
degrees in pattern separation and completion (e.g.,
retrieval of a complete mnemonic representation based
on a partial input) depending on the nature of information
and/or degree of dissimilarity between mnemonic repre-
sentations and incoming sensory information. In addition
to this, these regions may also play a role in novelty/
mismatch detection. As this is a function of aMCC, we
predict that this is also a function of the mHPC and there
is likely a connection between these two subregions.
Rolls (2015) was the first to differentiate the limbic
system into two parts as already noted. In his formula-
tion, the anterior limbic system and related structures
including the OFC and amygdala are involved in emo-
tion, reward valuation, and reward-related decision mak-
ing (but not memory), with the value representations
transmitted to the ACC and aMCC for action-outcome
learning or an “emotion limbic system.” These are based
on feedforward projections that learn associations from
visual, olfactory, and auditory stimuli to primary rein-
forcers such as taste, touch, and noxious stimuli. The
OFC overshadows the amygdala in learning that is
important for social and emotional behavior. The aHPC
(Fig. 3.4) is likely part of this circuitry given its heavy
interactions with the amygdala and OFC. Emotion can
enter this memory system from the OFC and be recalled
to the OFC during memory recall, but the emotional and
HPC networks or “limbic systems” operate independently
of each other except as an emotional state or reward value
attribute that may be part of an episodic memory.
MHPC
This region of the HPC has received the least attention
from human connection and functional studies compared
to the aHPC and pHPC. However, as noted earlier, it has
some striking properties. Lia et al. (2013) showed that the
mHPC has the highest perfusion and the shortest transit
time and the aHPC has the lowest perfusion and the lon-
gest transit time. Using fMRI, K€ohler et al. (2005)
reported that the right mHPC responded to the novelty
of spatial and nonspatial relationships but not to the nov-
elty of individual objects vs familiar objects. This finding
did not hold for either of the other two divisions.
A similar finding has been reported for the MCC for
novel lists of words (Raichle et al., 1994) where verb
generation for a list of nouns for which verbs were to
be stated was practiced. The PET response declined
with practice but increased again with a new list of
nouns. The interaction of mHPC with aMCC must be
supportive of each other. The hippocampus has also
been implicated in approach-avoidance conflict monitor-
ing (Ito and Lee, 2016) as well as in pattern separation
48 B.A. VOGT
and completion (e.g., retrieval of a complete memory
representation based on a partial input) depending on
the nature of information and/or degree of dissimilarity
between memory representations and incoming sensory
information. Thus, the mHPC and aMCC may both play
a role in novelty/mismatch detection. We predict that
given the similar functions of aMCC and mHPC there
is likely a connection between these two subregions, i.e.,
the mid-CA1 sector synergizes with the aMCC.
PHPC
Rolls (2015) considered evidence that the pHPC and con-
nected limbic structures including the PCC, mammillary
body, and anterior thalamus are involved in episodic or
event memory, but not emotion. This view is supported
by the organization and functions of PCC. This
“hippocampal system” receives information from neo-
cortical areas about spatial location and objects, as is
the case for PCC (Bar and Aminoff, 2003), and can rap-
idly associate this information to engage in feedback
mechanisms. The system can later recall the whole of this
information in the CA3 sector from any component as a
feedback process and recall the information to neocortical
areas by a feedback recall process including the PCC/RSC.
The argument for three limbic subsystems, however, does
not depend solely on a “hippocampocentric” viewpoint
and the HPC has connections that subserve more than epi-
sodic memory and spatial orientation including novelty
detection and feedback-mediated decision making that
links it to other parts of the three limbic subsystems includ-
ing the OFC, insula, MCC, and PCC.
The HPC may use temporal information to retrieve
specific prior experiences, particularly when a represen-
tation shares common elements with a similar prior expe-
rience. A defining characteristic of episodic memory is
that events comprising an episode are linked together
in time (Tulving, 1984). It may be the role of the pHPC
to link events comprising an episodic memory together in
a sequential manner across time (Howard et al., 2005).
Ross et al. (2009) used fMRI to examine the role of
the HPC during the learning and retrieval of sequences.
Participants learned four sequences comprised of six
faces each. An overlapping condition, where sequences
shared common elements, was comprised of two
sequences in which two identical faces were shown as
the middle images of both sequences. A nonoverlapping
condition contained two sequences that did not share
any faces between them. The data were split into learning
and experienced phases. The pHPC was activated during
sequence learning and during the retrieval of learned
sequences. At the critical choice point of overlapping
stimuli, Ross et al. (2011) showed the left HPC had stron-
ger functional connectivity with the OFC and a small
part of aMCC in addition to the striatum. These functional
connectivity results suggest that the pHPC may play a role
in decision making by predicting the possibilities of
what might come next, allowing the OFC and striatum
to evaluate the expected choice options to make the correct
action at a choice point.
Finally, a substrate for recollection memory in the
pHPC may be determined by the volume of its posterior
vs anterior segments. Poppenk and Moscovitch (2011)
showed that volumetric measurements can reliably pre-
dict recollection where better memory is associated
with a larger pHPC than aHPC. They also observed that
functional connectivity with a neocortical network
was identified during a postencoding resting-state scan,
a relationship that was weakest when there was no
appreciable study-test interval.
Cingulate cortex
Chapter 1 summarizes the key functions of each cingu-
late subregion and will not be repeated. Fig. 3.4 shows
the complexity of interactions among the components
of the three limbic subsystems but does not show direc-
tionality that is crucial to determining the transition
from sensory input to the limbic subsystems engaged
in value scaling of potential options for action outcomes
and monitoring. Thus, Fig. 3.5 depicts cingulate con-
nectivity in a somewhat different light by providing
directionality to how the overall limbic system may
operate and includes MCC as a central hub for motor
output and, along with the amygadala, the ACC auto-
nomic projections. In this diagram, the pivotal nature
of amygdalar projections, mainly from the BLA and
accessory basal nuclei with their sensory afferents
and efferents to the anterior limbic subsystems, is
shown, particularly those to the pACC and less so those
to aMCC. Value scaling is performed in the OFC with its
full range of sensory afferents and precise understand-
ing of the organism’s internal needs. The anterior
insular cortex is thought to form a global representation
of the bodily state, because it is situated to integrate
homeostatic afferent activity from the dorsal posterior
insula with emotional salience (Craig, 2002).
Resting-state functional connectivity analysis iden-
tifies cortical areas that have strong temporally correlated
low-frequency (<0.1 Hz) activity in a nontask at rest.
Using this approach, the relationship between anatomi-
cally distinct, but functionally connected, brain regions
can be investigated. These low-frequency fluctuations
may be functionally relevant indices of connectivity
between brain regions subserving similar or related brain
functions (Birn, 2007). Taylor et al. (2009) used this
methodology and observed that activity in both the left
and right anterior insula was strongly correlated with
 CINGULATE CORTEX IN THE THREE LIMBIC SUBSYSTEMS 49

Fig. 3.5. Directionality of information flow from sensory afferents (amygdala) to value scaling (OFC) and action outcome and
monitoring MCC). Modified from Fig. 3.4. Of particular note is the wide distribution of amygdalar (BLA and accessory basal
nuclei) throughout the anterior limbic subsystems including projections of the sACC, and central nucleus of the amygdala to
the autonomic nervous system (ANS; nuc. Ambiguous, hypothalamus, periaqueductal gray, etc.) and that of the cingulate premotor
areas to the supplementary motor area/presupplementary motor area and spinal cord (SC). Note also that the amygdala has an
influence on this system as well via projections to aMCC.

the bilateral pACC/aMCC and bilateral pMCC. How-
ever, the fMRI signal in the middle and posterior insula
was strongly correlated with bilateral pMCC but not
with the pACC and aMCC. The anterior insula bilaterally
showed stronger resting-state connectivity with the
pACC/aMCC than either the middle or posterior insula.
However, the mid-insula was more strongly connected
with the pMCC than the posterior insula. Based on these
observations, Taylor et al. (2009) proposed that the sys-
tem linking the anterior insula with the pACC/aMCC
may be involved in emotional salience monitoring, while
the system linking the entire insula with the pMCC could
be a general salience and action system.
Seeley et al. (2007) suggested that a task-positive net-
work is composed of a “salience network” that includes
aMCC, OFC and insular cortices, and subcortical limbic
structures in an “executive-control network,” connecting
the dorsolateral frontal cortex with the parietal cortex.
They proposed that the “salience network” responds to
the amount of personal salience and not to the stimuli’s
specific nature (i.e., homeostatic, emotional, or cogni-
tive). A key conclusion from this work is that there is
a general salience and action system that links the entire
insula and MCC, a system involved in environmental
monitoring, response selection, and somatomotor body
orientation. This is likely the reason that cingulate and
insular cortices are so frequently activated in tandem.
The functions and connectivity of OFC have already
been discussed; however, here we will put it in the context
of the three limbic subsystems. Value scaling for selection
among the most effective (internally relevant) choices
requires a full set of sensory inputs that converge either
directly or via intrinsic circuitry. This I propose to happen
in the mOFC that projects to MCC, which is the critical
node for skeletomotor output from the three limbic sub-
systems. As discussed in Chapter 1, aMCC is critical for
feedback-mediated decision making and has key outputs
to the supplementary motor area/presupplementary motor
area and spinal cord. It is an interesting fact that MCC has
virtually no emotional function except for “fear” that likely
drives avoidance behaviors. The pACC and vPCC that are
engaged in emotion are reciprocally connected and bypass
MCC, which is the last stage for action and feedback
monitoring. Fig. 3.3B.1 emphasizes this arrangement with
MCC having extensive dorsal projections to sensorimotor
cortices that pACC and vPCC do not have.
This is not to say, however, that PCC has no role in
choice among behavioral options. Hayden et al. (2008)
recorded from neurons in dPCC in areas 23 and 31 in
the cingulate gyrus and ventral bank of the cingulate
sulcus, anterior to the intersection of the marginal and
horizontal rami. Single neurons in monkeys during per-
formance of a gambling task in which the reward outcome
of each choice strongly influenced subsequent choices.
PCC neurons were found to signal reward outcomes in
a nonlinear fashion, and outcome-contingent modulations
in firing rate persisted into subsequent trials. Moreover,
firing rate on any one trial predicted switching to the alter-
native option on the next trial. Finally, microstimulation in
dPCC following risky choices promoted a preference
reversal for the safe option on the following trial. Collec-
tively, these results demonstrate that PCC directly contrib-
utes to the evaluative processes that support dynamic
changes in decision making in volatile environments.
Finally, sACC has substantial projections into auto-
nomic motor structures. One set of connections arise
50 B.A. VOGT
from area 25 and terminate directly in the medial part of
the central nucleus (CeM; Yasui et al., 1985). Chiba et al.
(2001) reported projections to the BLA and accessory
basal nuclei, ventromedial hypothalamus, dorsolateral
periaqueductal gray, bed nucleus of the stria terminalis,
medial and lateral parabrachial nuclei, and locus coeru-
leus. It may be that this projection system operates in tan-
dem temporally to coordinate somatomotor and
autonomic responses.
SIX LIMBIC SUBSYSTEMS ARE LIKELY
RATHER THAN ONLY THREE
As these studies began with the cingulate cortex, we have
to revisit this region to determine limbic system organi-
zation. This region is comprised of ACC, vaMCC,
daMCC, pMCC, dPCC/RSC, and vPCC/RSC. Thus it
is likely that there are at least six limbic systems. As
ACC has two components, there could be further subsys-
tems. These subsystems will eventually be culled from
the three limbic systems designated in this chapter.
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FURTHER READING
Petrovich GD, Canteras NS, Swanson LW (2001).
Combinatorial amygdalar inputs to hippocampal domains
and hypothalamic behavior systems. Brain Res Rev 38:
247–289.