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Neuroscience and Biobehavioral Reviews 37 (2013) 1724– 1737

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

j our na l ho me pag e: www.elsev ier .com/ locate /neubiorev

eview

revised limbic system model for memory, emotion and behaviour

arco Catania,∗, Flavio Dell’Acquaa,b,c, Michel Thiebaut de Schottena,d,∗

Natbrainlab, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King’s College London, UKDepartment of Neuroimaging Sciences, Institute of Psychiatry, King’s College London, UKNIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King’s Collegeondon, UKUMR S 975; CNRS UMR 7225, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris,rance

r t i c l e i n f o

rticle history:eceived 27 November 2012eceived in revised form 15 May 2013ccepted 1 July 2013

eywords:imbic systemractographyhite matter connections

rain networksmotionemory

mnesia

a b s t r a c t

Emotion, memories and behaviour emerge from the coordinated activities of regions connected by thelimbic system. Here, we propose an update of the limbic model based on the seminal work of Papez,Yakovlev and MacLean. In the revised model we identify three distinct but partially overlapping networks:(i) the Hippocampal-diencephalic and parahippocampal-retrosplenial network dedicated to memory andspatial orientation; (ii) The temporo-amygdala-orbitofrontal network for the integration of visceral sen-sation and emotion with semantic memory and behaviour; (iii) the default-mode network involved inautobiographical memories and introspective self-directed thinking. The three networks share corticalnodes that are emerging as principal hubs in connectomic analysis. This revised network model of thelimbic system reconciles recent functional imaging findings with anatomical accounts of clinical disorderscommonly associated with limbic pathology.

© 2013 Elsevier Ltd. All rights reserved.

ementiantisocial behaviourchizophreniaepressionipolar disorder

bsessive–compulsive disorderutism spectrum disorder

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17252. Anatomy of the limbic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1726

2.1. Fornix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17262.2. Mammillo-thalamic tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17262.3. Anterior thalamic projections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17272.4. Cingulum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17272.5. Uncinate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1728

3. Functional anatomy of the limbic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17294. Limbic syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1730

4.1. Hippocampal-diencephalic and parahippocampal-retrosplenial syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17304.2. Temporal-amygdala-orbitofrontal syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17314.3. Default network syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1733

5. Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding authors at: Natbrainlab, Department of Forensic and NeurodevelopmeE-mail addresses: m.catani@iop.kcl.ac.uk (M. Catani), michel.thiebaut@gmail.com (M.

149-7634/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.neubiorev.2013.07.001

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1734

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1734 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1734

ntal Sciences, Institute of Psychiatry, 16 De Crespigny Park, London SE5 8AF, UK. Thiebaut de Schotten).

behavioral Reviews 37 (2013) 1724– 1737 1725

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M. Catani et al. / Neuroscience and Bio

. Introduction

The limbic system is a group of interconnected cortical andubcortical structures dedicated to linking visceral states and emo-ion to cognition and behaviour (Mesulam, 2000). The use of theerm ‘limbic’ has changed over time. Initially introduced by Thomas

illis (1664) to designate a cortical border encircling the brain-tem (limbus, Latin for ‘border’) (Fig. 1) the term has been usedn more recent times to indicate a progressively increasing num-er of regions dedicated to a wide range of functions (Marshallnd Magoun, 1998; Mega et al., 1997). Paul Broca (1878) held theiew that ‘le grand lobe limbique’ was mainly an olfactory structureommon to all mammalian brains, although he argued that its func-ions were not limited to olfaction (Fig. 2). After Broca’s publicationhe accumulation of experimental evidence from ablation studiesn animals broadened the role of the limbic structures to includether aspects of behaviour such as controlling social interactionsnd behaviour (Brown and Schäfer, 1888), consolidating memoriesBechterew, 1900), and forming emotions (Cannon, 1927).

Anatomical and physiological advancements in the field ledhristfield Jakob (1906) (Fig. 3) and James Papez (1937) (Fig. 4)o formulate the first unified network model for linking action anderception to emotion. According to Papez emotion arises eitherrom cognitive activity entering the circuit through the hippocam-us or from visceral and somatic perceptions entering the circuithrough the hypothalamus. In the case of emotion arising from cog-itive activity, for example, ‘incitations of cortical origin would passrst to the hippocampal formation and then down by way of the fornixo the mammillary body. From this they would pass upward throughhe mammillo-thalamic tract, or the fasciculus of Vicq d’Azyr, to thenterior nuclei of the thalamus and thence by the medial thalamocor-ical radiation [or anterior thalamic projections] to the cortex of theyrus cinguli [. . .] The cortex of the cingular gyrus may be looked ons the receptive region for the experiencing of emotion as the result ofmpulses coming from the hypothalamic region [or the hippocampalormation][. . .] Radiation of the emotive process from the gyrus cingulio other regions in the cerebral cortex would add emotional colouringo psychic processes occurring elsewhere (Papez, 1937)’

A decade later, Paul Yakovlev (1948), proposed that therbitofrontal cortex, insula, amygdala, and anterior temporal lobeorm a network underlying emotion and motivation (Fig. 5). In twoeminal papers published in 1949 and 1952, Paul. MacLean crys-allised previous works by incorporating both Papez and Yakovleview into a model of the limbic system that has remained almostnchanged since (MacLean, 1949, 1952). MacLean concluded thathe limbic cortex, together with the limbic subcortical structures,

s a functionally integrated system interconnected by short- andong-range fibre bundles (Fig. 6).

The development of tracing methods for studying long axonalathways added details to the anatomical model of the limbic

Fig. 2. Paul Broca (1878) identified the limbic system as m

Fig. 1. The limbic system described for the first time by Thomas Willis (1664) toindicate cortical regions located around the brainstem.

system (Crosby et al., 1962). These methods allowed, for example,the description of long and short connections of the cingulatecortex in animals. Further, the combination of anatomical methodswith experimental procedures was used to demonstrate a directlink between specific limbic structures and behavioural response(e.g. amygdala and aggressive response). Unfortunately, axonaltracing could not be applied to human anatomy for the study ofthe biological underpinnings of those abilities that characterisehuman mind (e.g. emotions; empathy). Also animal models werenot suitable for studying anatomical differences in psychiatricconditions such as autism and schizophrenia.

In the 1990s the use of functional neuroimaging methods (e.g.PET, fMRI) and later diffusion tractography offered the possibilityof studying the functional anatomy of the limbic system in the liv-ing human brain. A major finding that emerged initially from PETstudies and later confirmed with fMRI was the identification of a‘default network’, consisting of a set of regions that activate underresting-state condition and deactivate during task-related func-tions (Buckner et al., 2008; Raichle et al., 2001; Raichle and Snyder,2007; Shulman et al., 1997) (Fig. 7). The most medial regionsof the default network correspond to the most dorsal portionof the Papez circuit and are interconnected through the dorsalcingulum.

Diffusion imaging is an advanced MRI technique based on opti-mised pulse sequences, which permits the quantification of thediffusion characteristics of water molecules inside biological tis-sues (Le Bihan and Breton, 1985). Given that cerebral white mattercontains axons, and that water molecules diffuse more freely alongaxons than across them (Moseley et al., 1990), it is possible to

obtain in vivo estimates of white matter fibre orientation by mea-suring the diffusivity of water molecules along different directions(Basser et al., 1994). By following the orientation of the water

ainly an olfactory structure of the mammalian brain.

1726 M. Catani et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1724– 1737

F es linkJ r thalah

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ig. 3. The limbic system as an integrated system of cortical and subcortical structurakob in 1906. Cg, cingulum; Tr, trigonum; C. Call, corpus callosum; N.A.T., anterioippocampus; U, uncus; Bo, olfactory bulb; SL, Septum pellucidum.

olecules displacement, diffusion imaging tractography recon-tructs 3D trajectories of white matter pathways closely resemblingracts described in post-mortem animal tracing studies (Dauguett al., 2007; Thiebaut de Schotten et al., 2011a, 2012) and humanrain dissections (Basser et al., 2000; Catani et al., 2012a; Dell’Acquand Catani, 2012; Dell’Acqua et al., 2010, 2012; Jones, 2008; Lawest al., 2008; Thiebaut de Schotten et al., 2011b; Forkel et al., 2012).ne of the advantages of tractography is the ability to study the

nterindividual variability of white matter tracts in the healthy pop-lation and correlate white matter abnormalities with symptomseverity in patients with neurological and psychiatric disordershat involve the limbic system (Catani et al., 2012b; Catani et al.,013a). In the following paragraphs we will use integrated infor-ation from animal studies and tractography findings in human

o describe in detail the anatomy of the main limbic pathwaysFig. 8).

. Anatomy of the limbic system

.1. Fornix

The fornix is mainly a projection tract connecting the hip-ocampus with the mammillary body, the anterior thalamicuclei, and the hypothalamus; it also has a small commissuralomponent known as the hippocampal commissure (Aggleton,

ig. 4. The limbic system according to James Papez (Papez, 1937) is an exact duplicate ohat he didn’t know about his work, which was published in an Argentinean journal witetween the two models are striking. To give credit to the work of Jakob we suggest the uaudate nucleus; cp, cingulum posterior; d, gyrus dentatus; f, fornix; gc, gyrus cinguli; gh, gammillo-thalamic tract; p, pars optica hypothalami; pr, piriform area; sb, subcallosal bun

, uncus.

ed by projection and association tracts was described for the first time by Christfriedmic nuclei; Tal., thalamus; Az, bundle of Vicq d’Azyr; CM, mammillary bodies; H,

2008; Crosby et al., 1962; Nieuwenhuys et al., 2008). Fibres arisefrom the hippocampus (subiculum and entorhinal cortex) of eachside, run through the fimbria, and join beneath the splenium ofthe corpus callosum to form the body of the fornix. Other fimbrialfibres continue medially, cross the midline, and project to thecontralateral hippocampus (hippocampal commissure). Most ofthe fibres within the body of the fornix run anteriorly beneath thebody of the corpus callosum towards the anterior commissure.Above the interventricular foramen, the anterior body of the fornixdivides into right and left columns. As each column approachesthe anterior commissure it diverges again into two components.One of these, the posterior columns of the fornix, curve ventrallyin front of the interventricular foramen of Monroe and posteriorto the anterior commissure to enter the mammillary body (post-commissural fornix), adjacent areas of the hypothalamus, andanterior thalamic nucleus. The second component, the anteriorcolumns of the fornix, enter the hypothalamus and project to theseptal region and nucleus accumbens (Aggleton, 2008). The fornixalso contains some afferent fibres to the hippocampus from septaland hypothalamic nuclei (Nieuwenhuys et al., 2008).

2.2. Mammillo-thalamic tract

The fibres of the mammillo-thalamic tract (bundle of Vicqd’Azyr) originate from the mammillary bodies and after a very short

f Jakob’s original drawing. Papez never quoted the work of Jakob and it is possibleh scarce international diffusion (La Semana Médica). Nevertheless the similaritiesse of the eponym Jakob-Papez circuit. a, anterior nucleus; cc, corpus callosum; cn,yrus hippocampi; gs, gyrus subcallosus; h, hippocampus; m, mammillary body; mt,dle; t, tuber cinereum; td, tractus mammillo-tegmentalis; th, tractus hypophyseus;

M. Catani et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1724– 1737 1727

Fig. 5. Yakovlev’s amygdala-orbitofrontal network (Yakovlev and Locke, 1961; Yakovlev, 1948). AF, supralimbic corticocortical afferents to the limbic cortex; AM, anteriormedial nucleus of the limbic thalamus; Area diag., area diagonalis (Filimonov); Area periamgd., area periamygdalaris (Filimonov); Area entorhin., area entorhinalis; AV, anteriorventral nucleus of the limbic thalamus; cng-unc-om, orbitomesial interdigitation of the cingulum and uncinate bundle; cng-unc-tm, temporomesial interdigitation of thecingulum and uncinate bundle; cpf, callosoperforant fibres from the supralimbic cortex; Fascia Dent., fascia dentate of the Ammon’s horn; Fis. Hippoc., parahippocampal fissure;h, hippocampal efferents via fornix brevis; Hb, habenular nuclei; Lam. Zon., lamina zonalis; LD, lateral dorsal nucleus of the limbic thalamus; m, afferent and efferent fibres ofthe median thalamus (midline nuclei); Massa intrmd., massa intermedia; Pf, corticoperforant temporoammonic fibres (direct and crossed); pf, corticoperforant (direct andcrossed) fibres of the cingulum to the hippocampus; pm, afferent and efferent fibres of the paramedianthalamus (limbic nuclei); sbc, subcallosal radiations (lateral, ventrala limbo

cAtNfibm

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nd medial) of the cingulum to the septum and ipsi- and contra-lateral striatum andf the limbic thalamus.

ourse terminate in the anterior and dorsal nuclei of the thalamus. ventrally directed branch projects from the mammillary bodies

o the tegmental nuclei (mammillo-tegmental tract). According toauta (1958), the mammillo-tegmental tract, together with otherbres of the medial forebrain bundle, forms an important circuitetween medial limbic structures of the midbrain and hypothala-us to relate visceral perception to emotion and behaviour.

.3. Anterior thalamic projections

The anterior thalamic nuclei receive projections from the fornixnd mammillo-thalamic tract and connect through the anteriorhalamic projections to the orbitofrontal and anterior cingulate cor-ex. The anterior thalamic projections run in the anterior limb of thenternal capsule.

.4. Cingulum

The cingulum contains fibres of different lengths, the longestunning from the amygdala, uncus, and parahippocampal gyruso sub-genual areas of the frontal lobe (Crosby et al., 1962;

ig. 6. MacLean’s 1952 (MacLean, 1949, 1952) proposal for a unitary model of the limbic

ic thalamus; Sept. Ar., septal area; T.TH., taenia thalami; VA, ventral anterior nucleus

Nieuwenhuys et al., 2008). From the medial temporal lobe, thesefibres reach the occipital lobe and arch almost 180 degrees aroundthe splenium to continue anteriorly within the white matter of thecingulate gyrus. The dorsal and anterior fibres of the cingulum fol-low the shape of the superior aspect of the corpus callosum. Aftercurving around the genu of the corpus callosum, the fibres termi-nate in the subcallosal gyrus and the paraolfactory area (Crosbyet al., 1962). Shorter fibres that join and leave the cingulum alongits length, connect adjacent areas of the medial frontal gyrus,paracentral lobule, precuneus, cuneus, cingulate, lingual, andfusiform gyri (Dejerine, 1895; Nieuwenhuys et al., 2008). The cin-gulum can be divided into an anterior-dorsal component, whichconstitutes most of the white matter of the cingulate gyrus, and aposterior-ventral component running within the parahippocampalgyrus, retrosplenial cingulate gyrus, and posterior precuneus. Pre-liminary data suggest that these subcomponents of the cingulummay have different anatomical features. For example, a higher

fractional anisotropy has been found in the left anterior-dorsalsegment of the cingulum compared to right, but reduced fractionalanisotropy has been reported in the left posterior-ventral compo-nent compared to the right (Gong et al., 2005; Park et al., 2004;

system consisting of Papez circuit and Yakovlev’s amygdala-orbitofrontal network.

1728 M. Catani et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1724– 1737

F fault

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ig. 7. One of the first PET studies looking at the functional anatomy of the ‘deortex/precuneus and area 9 to the anterior cingulate/medial frontal cortex. Theses

akana et al., 2007). Notwithstanding this, the volume of theingulum is bilateral and symmetrical in most subjects (Thiebaute Schotten et al., 2011b).

.5. Uncinate

The uncinate fasciculus connects the anterior part of the tempo-al lobe with the orbital and polar frontal cortex (Fig. 8). The fibres

f the uncinate fasciculus originate from the temporal pole, uncus,arahippocampal gyrus, and amygdala, then after a U-turn, enterhe floor of the extreme capsule. Between the insula and the puta-

en, the uncinate fasciculus runs inferior to the fronto-occipital

ig. 8. Diagrammatic representation of the limbic system and tractography reconstructioegend.

networks’ (Shulman et al., 1997). Area 1 corresponds to the posterior cingulatereas are interconnected through the dorsal fibres of the cingulum.

fasciculus before entering the orbital region of the frontal lobe.Here, the uncinate splits into a ventro-lateral branch, which termi-nates in the anterior insula and lateral orbitofrontal cortex, and anantero-medial branch that continues towards the cingulate gyrusand the frontal pole (Crosby et al., 1962; Dejerine, 1895; Klinglerand Gloor, 1960). Whether the uncinate fasciculus is a lateralisedbundle is still debated. An asymmetry of the volume and density offibres of this fasciculus has been reported in a human post-mortem

neurohistological study in which the uncinate fasciculus was foundto be asymmetric in 80% of subjects, containing on average 30%more fibres in the right hemisphere compared to the left (Highleyet al., 2002). However, diffusion measurements have shown higher

n of its main pathways. The colours in both figures correspond to the tracts in the

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M. Catani et al. / Neuroscience and Bio

ractional anisotropy in the left uncinate compared to the right inhildren and adolescents (Eluvathingal et al., 2007) but not in adultsThiebaut de Schotten et al., 2011b).

. Functional anatomy of the limbic system

The limbic system has always been considered as a complexrrangement of transitional structures situated between a vis-eral ‘primitive’ subcortical brain and a more evolved cortical oneMacLean, 1952; Yakovlev, 1948). The subcortical limbic struc-ures include the amygdala, mammillary bodies, hypothalamus,ome thalamic nuclei (i.e. anterior, intralaminar, and medial dorsalroups) and the ventral striatum (i.e. nucleus accumbens). The neu-ons and fibres composing the subcortical limbic structures present

simple arrangement, not dissimilar to other subcortical nucleif the brainstem that regulate basic metabolism, respiration, andirculation.

The cortical components of the limbic system include areas ofncreasing complexity separated into limbic and paralimbic zonesMesulam, 2000). At the lower level the corticoid areas of the amyg-aloid complex, substantia innominata, together with septal andlfactory nuclei display an anatomical organisation that lacks con-istent lamination and dendritic orientation. These structures aren part subcortical and in part situated on the ventral and medialurfaces of the cerebral hemispheres. The next level of organisations the allocortex of the olfactory regions and hippocampal complex,

here the neurons are well differentiated into layers and their den-rites show an orderly pattern of orientation. The corticoid andllocortical regions are grouped together into the limbic zone ofhe cerebral cortex as distinct from the paralimbic zone. The lat-er is mainly composed of ‘mesocortex’, whose progressive level oftructural complexity ranges from a simplified arrangement similaro the allocortex, to the most complex six-layered isocortex.

The limbic and paralimbic zones can also be divided into olfac-ocentric and hippocampocentric groups (Fig. 9) (Mega et al., 1997;

esulam, 2000). Each division is organised around a central coref allocortex. The olfactocentric division is organised around the

ig. 9. Functional-anatomical separation of the limbic system into olfactocentric (blue) a6, 47) are connected to both divisions.

ioral Reviews 37 (2013) 1724– 1737 1729

primary olfactory piriform cortex and includes the orbitofrontal,insular and temporopolar region. The hippocampocentric divisionis organised around the hippocampus and includes the parahip-pocampal and cingulate cortex. Both divisions have reciprocalconnections with subcortical limbic structures and surroundingisocortical regions (Fig. 9). The two divisions overlap in the anteriorcingulate cortex.

Functionally the paralimbic areas contribute to the activity ofthree distinct networks (Fig. 10). The first network, composed of thehippocampal-diencephalic limbic circuit (connected through thefornix and mammillo-thalamic tract) and the parahippocampal-retrosplenial circuit (ventral cingulum), is dedicated to memoryand spatial orientation, respectively (Aggleton, 2008; Vann et al.,2009). Some structures of this network are particularly vulnerableto damage caused by viral infections (e.g. encephalitis) or alcohol(e.g. Korsakoff’s syndrome) (Fig. 10). Imaging studies have docu-mented altered metabolism and reduced functional activation ofthis network also in age-related neurodegenerative disorders suchas mild cognitive impairment (Minoshima et al., 1997; Nestor et al.,2003) and Alzheimer’s disease (Buckner et al., 2005).

The temporo-amygdala-orbitofrontal network (connectedthrough the uncinate fasciculus) is dedicated to the integrationof visceral and emotional states with cognition and behaviour(Mesulam, 2000). In animal studies, disconnection of the unci-nate fasciculus causes impairment of object-reward associationlearning and reduced performances in memory tasks involvingtemporally complex visual information (Gaffan and Wilson, 2008).In humans this network engages in tasks that involve naming,single word comprehension, response inhibition, face processingand monitoring of outcomes (Catani et al., 2013a; Amodio andFrith, 2006). Damage to this network manifests with cognitive andbehavioural symptoms characteristic of temporal lobe epilepsy,mood disorders, traumatic brain injury, psychopathy and neurode-

generative dementias, including advanced Alzheimer’s disease andsemantic dementia (Fig. 10).

The dorsomedial default-mode network consists of a groupof medial regions whose activity decreases during goal-directed

nd hippocampocentric (red) divisions. Some regions (e.g. BA 10, 11, 21, 22, 24, 32,

1730 M. Catani et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1724– 1737

Fig. 10. Proposed functional-anatomical division of the limbic system into three distinct but partially overlapping networks and corresponding clinical syndromes. Them nial ne ro-amf rk, wh

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ain connections of the hippocampal-diencephalic and parahippocampal-retrosplendstations of this network are indicated in yellow). The main nodes of the tempoasciculus. The dorsal cingulum is the main connection of the medial default netwo

asks (Raichle et al., 2001; Raichle and Snyder, 2007). The anterioringulate-medial prefrontal cortex and the posterior cingulate-recuneus form the medial default-mode network and are inter-onnected through the dorsal cingulum. In functional imaging stud-es the default-mode network is active during the ‘resting state’, aondition in which the majority of the subjects engage in an intro-pective, self-directed stream of thought (i.e. similar to daydream-ng). A synchronous deactivation of the default network is observedn the transition between the ‘resting state’ and the execution ofoal directed tasks, irrespective of the nature of the task. The deac-ivation of the default-mode network has been linked to a numberf functions including working memory, focusing attention to sen-orially driven activities, understanding other people’s intentionmentalising or theory of mind), prospective thinking (envision-ng the future) and memory for personal events (autobiographic

emory) (Amodio and Frith, 2006). Altered activation of the defaultetwork has been reported in functional imaging studies of patientsith neuropsychiatric disorders (Broyd et al., 2009) (Fig. 10).

. Limbic syndromes

The limbic system is affected by a wide range of disorders,ncluding neurodevelopmental conditions, traumatic brain injurynd neurodegeneration. In most psychiatric conditions a dysfunc-ion of the limbic structures involved with emotion regulation,ocial interaction and behaviour has been implicated. In the olderopulation neurodegenerative disorders affect primarily limbicystems dedicated to memory. These disorders take a heavy tall onffected individuals, families and society at large. The use of neu-oimaging methods could help to identify vulnerable phenotypesnd discover early markers of disease leading to the development ofovel treatment approaches. In the paragraphs that follow we applyhe proposed framework to the most common limbic syndromes.

.1. Hippocampal-diencephalic andarahippocampal-retrosplenial syndromes

Memory impairment is the most common condition in the age-ng population, affecting one in eight American citizens diagnosed

ith Alzheimer’s disease (Alzheimer’s Association, 2006; Hebert

etwork are the ventral cingulum, the fornix and the mammillo-thalamic tract (theygdala-orbitofrontal network (indicated in green) are connected by the uncinateose cortical projections are shown in blue.

et al., 2003). In younger population memory impairment is oftenassociated with traumatic conditions, alcoholism and epilepsy.Dementia alone had cost to the US economy $200 billion in2012: more than cancer and heart disease combined (Alzheimer’sAssociation, 2012).

Memory deficits are linked primarily to damage of the hip-pocampocentric division of the limbic system (Markowitsch, 2000).Some differences in the clinical presentation may be related to theexact location and extension of the damage, and its nature. Thecommon manifestations are those of a global amnesia where thepatient is unable to encode, associate, and retrieve new informa-tion (anterograde amnesia). In addition there is also some degreeof amnesia for events before the brain damage (or the onset of theneurodegenerative disorder) but temporally close to it (retrogradeamnesia). The remote memory is relatively well preserved.

The patient H.M., who underwent bilateral resection of themedial temporal lobe for pharmacologically intractable epilepsy,is a classical example of a pure global amnesic (Scoville and Milner,1957). Despite its inability to form new memories his memorybefore the surgery and insight were preserved. Loss of insightcan be associated with confabulation (the spontaneous narrativereport of events that never happened) in patients with diencephalicamnesias due to lesions of the mammillary bodies, the thalamicnuclei and their interconnections. Confabulation can be severein chronic alcoholics with Korsakoff’s syndrome, especially if thepathology affects the normal activity of the medial orbitofrontaland anterior cingulate cortex. In a 32-year-old alcoholic patientthat confabulated for 6 weeks, measurement of cerebral perfusionusing single photon emission computed tomography, showedhypoperfusion of the anterior and mediodorsal thalamic nuclei,anterior cingulate and orbitofrontal cortex (Benson et al., 1996).A second single photon emission computed tomography repeatedafter the patient stopped confabulating showed a ‘normalisation’of the orbitofrontal and anterior cingulate perfusion. The anteriorand mediodorsal thalamic nuclei remained hypoperfused and thepatient continued to suffer with profound amnesia (for a review of

the anatomy of confabulation see Dalla Barba and La Corte, 2013;Schneider, 2008).

In patients with vascular thalamic lesions (such as case A.B.reported by Markowitsch et al., 1993) the extension of the damage

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o the mammillo-thalamic tract is the best predictor of the severityf the memory deficit (von Cramon et al., 1985). In patients with col-oid cysts of the third ventricle, the surgical removal of the benignumour can damage the fornix and result in anterograde amnesia,lthough it is seemingly not as severe as that seen in diencephalicatients (Aggleton, 2008).

Another form of hippocampocentric memory dysfunction isssociated with lesions to the posterior parahippocampal cortex,etrosplenial cingulate cortex, and posterior precuneus (Valensteint al., 1987). These patients, in addition to memory deficits, showifficulties in spatial orientation due to the inability to deriveirectional information from landmark cues in familiar and newnvironments (Vann et al., 2009). Reduced metabolism of the ret-osplenial cortex has also been reported in patients with mildognitive impairment (Nestor et al., 2003) and early Alzheimer’sisease (Minoshima et al., 1997). More recently, a combined cor-ical morphometry and diffusion imaging study found reducedortical thickness and white matter abnormalities of these regionsAcosta-Cabronero et al., 2010). Compared to surrounding areas,he parahippocampal, posterior cingulate, and precuneus regionslso have a faster rate of atrophy in pre-symptomatic Alzheimer’sisease patients (autosomal dominant mutation carriers) (Scahillt al., 2002). Reduced fractional anisotropy has also been found inhe cingulum, hippocampus and the posterior corpus callosum ofognitively intact subjects with increased genetic risk of dementiaAPOE 4 carriers) (Persson et al., 2006).

Preliminary evidence suggests that diffusion changes in neu-odegenerative disorders are likely to reflect severity of underlyinghite matter pathology. Xie et al. (2005) reported a significantositive correlation between reduced fractional anisotropy val-es, atrophy of the hippocampus and decline in the mini-mentaltate examination scores in patients with Alzheimer’s disease. In

transgenic mouse model over-expressing beta-amyloid precur-or protein, the diffusivity parameters were significantly correlatedith the severity of Alzheimer’s disease-like pathology in the whiteatter (Song et al., 2004). In humans, Englund et al. (2004) con-

ucted a parallel post-mortem neuropathological examination andractional anisotropy quantification of two brains with dementiand reported that the degree of white matter pathology correlatedignificantly with gradually lower fractional anisotropy valuesampled in fifteen regions of interest. Overall, these studies sug-est that reduced fractional anisotropy in Alzheimer’s disease mayeflect white matter axonal degeneration and myelin loss followingeuronal degeneration of cortical neurons.

Damage to the limbic white matter tracts such as the fornixConcha et al., 2005) and the uncinate fasciculus (Diehl et al.,008) is also reported in patients with unilateral temporal lobepilepsy. This damage is diffuse and often extends contralaterallyrom the side of the suspected seizure. In temporal lobe epilepsyatients with mesial hippocampal sclerosis, the decreased frac-ional anisotropy of the fornix and the associated memory deficitsre correlated with reduced axonal diameter and myelin contentf the fornix fibres (Concha et al., 2010). The diffusion changes inhe left uncinate fasciculus also correlate with the severity of theeficits in delayed recall (Diehl et al., 2008). It is noteworthy topecify that pre-operative tractography assessment of the lateral-sation pattern of the temporal tracts can help to predict namingeficits after the operation in patients with temporal lobe epilepsyndergoing surgery (more left lateralised patients showed worseostoperative deficits) (Powell et al., 2008).

.2. Temporal-amygdala-orbitofrontal syndromes

The clinical profile of neurodegenerative disorders variesccording to the network affected by the illness. In advancedlzheimer’s disease, for example, the extension of the disease to the

ioral Reviews 37 (2013) 1724– 1737 1731

olfactory (orbitofrontal-amygdala) division is associated with clin-ical manifestations such as semantic deficits, language difficulties,personality changes and other behavioural symptoms (e.g. aggres-sion, disinhibition, etc.), which are not present if the pathology islimited to the hippocampocentric division. Alternatively, the earlystages of the temporal variant of the fronto-temporal dementiaand the semantic variant of primary progressive aphasia (Agostaet al., 2010; Borroni et al., 2007; Catani et al., 2013b) involve theolfactory division first leading to olfactory-gustatory-visceral dys-functions and semantic deficits. As the disease progresses, damageto the hippocampocentric division occur and involve other cogni-tive domains such as memory and spatial orientation.

In some patients with temporal lobe epilepsy the behaviouralsymptoms resemble those commonly observed in the Klüver–Bucysyndrome. In the 1930s, Klüver and Bucy conducted a series ofexperiments in rhesus monkeys that consisted of bilateral surgicalremoval of the anterior temporal lobe, which include the amygdalaand temporal pole (Klüver and Bucy, 1939). After the operationthe animals showed a strong tendency to examine objects orally(hyperorality), an irresistible impulse to touch (hypermetamor-phosis), loss of normal anger and fear responses, increased sexualactivity, and inability to recognise visually presented objects. Thesystematic experimental series conducted by Klüver and Bucy,although originally described by Brown and Schäfer in 1888, helpedto understand the functions of the anterior temporal lobe andbehavioural deficits associated with limbic damage in humans. Thefirst Klüver–Bucy syndrome in humans was described in a patientwho received bilateral temporal resection (Terzian and Ore, 1955).In recent times, this is a condition that clinicians observe in patientswith herpes or paraneoplastic encephalitis, tumours, or traumaticbrain injury involving the anterior temporal and orbitofrontal cor-tex (Hayman et al., 1998; Zappala et al., 2012).

In children with temporal lobe epilepsy, single-photon emissioncomputed tomography reveals hypoperfusion of the basal gan-glia and the adjacent frontal and temporal limbic regions. Mostof the patients recover after the acute phase, but those withabnormal diffusivity of the temporal and frontal white mattertracts exhibit long-term mental retardation, epilepsy, and persis-tent oral tendency (Maruyama et al., 2009). Some temporal lobeepilepsy patients present with Geschwind’s syndrome, a char-acteristic change in personality consisting of unusual tendenciesto write extensively and in a meticulous manner (hypergraphia),excessive and circumstantial verbal output, deepened cognitiveand emotional responses (e.g. excessive moral concerns), viscos-ity of thought, altered sexuality (usually lack of interest), andhyperreligiosity (Waxman and Geschwind, 1974). The emergenceof psychotic symptoms in temporal lobe epilepsy is associatedwith white matter changes extending to the frontal pathways(Flugel et al., 2006). Behavioural symptoms in epileptic patientscan respond to surgery. Mitchell et al. (1954) described a case oftemporal lobe epilepsy with fetish behaviour. The patient reportedhighly pleasurable ‘thought satisfaction’ derived from looking at asafety-pin and sought seclusion in a lavatory to indulge it. Unfor-tunately, the fetish object also triggered severe seizures, whichrequired surgical treatment. Relief not only of the epilepsy but alsoof the fetishism followed the temporal lobectomy.

Psychopathic personality disorder (psychopathy) is charac-terised by features of emotional detachment and antisocial traits(Patrick et al., 1993), and is strongly associated with criminalbehaviour and recidivism (Hare et al., 1999). Approximately 0.75%of male population meets the criteria for psychopathy with enor-mous costs for the society (Blair et al., 2005). It has been estimated,

for example, that 15% of the prison population are psychopaths andthey commit approximately 50% more criminal offences than non-psychopathic criminals (Hart and Hare, 1997). Since the report ofthe case of Phineas Gage (Harlow, 1848), who displayed ‘acquired

1732 M. Catani et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1724– 1737

Fig. 11. Anatomy of the antisocial behaviour. (A) Phineas Gage photographed with the bar that penetrated his skull through the left orbit and caused frontal damage. (B)T ortex,

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ractography reconstruction of the connections between amygdala, orbitofrontal cFA) show that psychopaths have a significantly reduced mean FA in the right unncinate fasciculus (P = 0.448) or in the two ‘non-limbic’ control tracts: the inferior

ociopathy’ following frontal lobe injury (Damasio et al., 1994), therbitofrontal cortex and other regions of the prefrontal cortex haveeen considered important for personality and social behaviourDamasio, 2000). For example, the orbitofrontal cortex is crucial touccessful reversal learning in which previously rewarded stimulire associated with punishment. Reversal learning is significantlympaired in adult psychopaths (Budhani et al., 2006) and in youngeople with psychopathic traits (Budhani and Blair, 2005). It haslso been reported that violent personality disordered offendersave reduced prefrontal cortex grey matter volume (Raine et al.,000) and glucose metabolism (Raine et al., 1997), and impairedrbitofrontal cortex activation during aversive conditioning (Veitt al., 2002). In contrast, other researchers have argued that amyg-ala dysfunction is central to the affective deficits and impairsoral socialisation of psychopathy (Blair, 2007; Delisi et al., 2009).

his latter view is supported by evidence that psychopaths showerformance deficits in tasks sensitive to amygdala damage (Blairt al., 2001; Levenston et al., 2000), and have significantly reducedmygdala volume (Tiihonen et al., 2000) and decreased amygdalactivation during verbal learning (Kiehl et al., 2001) and facial fearrocessing (Deeley et al., 2006). Furthermore, stimulation of themygdala can manifest with irritability, aggression, violent out-ursts, and antisocial behaviour. More recently, the dichotomyetween researchers postulating whether orbitofrontal cortex ormygdala dysfunction is central to psychopathy (Abbott, 2001) hasarrowed; and it has been suggested instead that the social andmotional deficits of psychopaths may reflect an altered interac-ion between orbitofrontal cortex and amygdala dysfunction (Blair,007; van Honk and Schutter, 2006). This view has received sup-ort from a DTI study that used tractography to measure theolume and integrity of the connections between orbitofrontal cor-ex and amygdala in psychopaths (Fig. 11) (Craig et al., 2009).

significantly reduced fractional anisotropy was reported in thencinate fasciculus of psychopaths compared to healthy subjects

ith similar age and intelligence. A correlation between measures

f antisocial behaviour (as assessed by the Psychopathy Check-ist) and anatomical differences in the uncinate fasciculus was alsoeported. To confirm that these findings were specific to the limbic

and posterior occipital areas. Tract-specific measurements of fractional anisotropy fasciculus (P = 0.003) compared to controls. There were no differences in the leftudinal fasciculus and inferior fronto-occipital fasciculus (Craig et al., 2009).

amygdala-orbitofrontal cortex network, other two ‘nonlimbic’control tracts connecting the posterior visual areas to amyg-dala or orbitofrontal cortex were studied, and no significantbetween-group differences were found. These results suggest thatabnormalities in a specific amygdala-orbitofrontal cortex networkunderpin the neurobiological basis of psychopathy (Fig. 11).

Post-mortem histological studies in patients with bipolar affec-tive disorder have found a reduction in the number and density ofglial cells (Ongur et al., 1998; Webster et al., 2005) and decreasedneuronal density in the subgenual region of the orbitofrontalcortex (Bouras et al., 2001) and in the dorsolateral prefrontalareas (BA 9) (Rajkowska et al., 2001). Myelin abnormalities inbipolar affective disorder may be related to a decreased expres-sion of genes involved in myelin synthesis and regulation (Astonet al., 2005). These histological findings are supported by neu-roimaging studies that reported a general increase in white matterhyperintensities on MRI images (Altshuler et al., 1995), selec-tive reduced white matter density (Bruno et al., 2004), anddecreased cortical metabolism and volume in the subgenual region(Drevets et al., 1997) of adults with a diagnosis of bipolar affectivedisorder. Findings from diffusion imaging studies using region-of-interest or voxel-based approaches have been inconsistent withreports of both decreased (Adler et al., 2004; Versace et al.,2008) and increased (Haznedar et al., 2005; Versace et al., 2008)fractional anisotropy in bipolar disorder compared to healthycontrols. Tractography of the subgenual-amygdala connectionsshowed increased tract volume (Houenou et al., 2007) and reducedfractional anisotropy in the uncinate and anterior thalamic pro-jections (McIntosh et al., 2008). In a recent single case study, apatient with a history of bipolar disorder and intractable recur-rent depression following a right thalamic stroke who underwentdeep brain stimulation of the subgenual cortex as experimen-tal treatment of his depression. The patient died 16 monthsafter the implants were positioned without any significant clini-

cal response. A high-resolution diffusion imaging dataset acquiredpost-mortem revealed markedly reduced limbic projections fromthe thalamus, subgenual region and amygdala in the stroke-affected (right) hemisphere. The authors concluded that reduced

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imbic connections assessed with diffusion imaging could be a con-raindication to deep brain stimulation for depression (McNab et al.,009).

.3. Default network syndromes

Major depression is the most common of all psychiatric dis-rders (Kessler et al., 2003) affecting at least one in six adults inSA (Kessler et al., 2005). Neuroimaging studies show that the

ubgenual cingulate region (BA 25) is metabolically overactive inepressed patients and its activation reduces in parallel with thentidepressant effect of pharmacological treatment (Mayberg et al.,000), electroconvulsive therapy (Nobler et al., 2001), and transcra-ial magnetic stimulation of more dorsal frontal regions (Mottaghyt al., 2002). Mayberg et al. (2005) have also shown that chronicirect deep brain stimulation of the white matter fibres adjacent tohe subgenual cortex resulted in a significant remission of depres-ion in four of six patients with treatment-resistant depressionFig. 12). The antidepressant effect was associated not only with aeduction in the local metabolism of the subgenual region, but alsoith increased metabolism of dorsal cingulate and other prefrontal

reas connected to the subgenual cortex. A recent preliminaryractography study in adolescents with major depressive disordereported lower fractional anisotropy in the white matter tract con-ecting the subgenual cingulate region to the amygdala in the rightemisphere (Cullen et al., 2010).

Autism spectrum disorder is a neurodevelopmental conditionharacterised by repetitive and stereotypic behaviour, impairedommunication and striking deficits in social reciprocity. Collec-ively, autism spectrum disorders affect 1 in 100 children with

female/male sex ratio of 1:4 (Baird et al., 2006). While somef the manifestations are explained in terms of impaired exec-tive functioning (Ozonoff et al., 1991), it has been suggestedhat the social and communication abnormalities typically foundn autism spectrum disorder are due to abnormalities in limbictructures (Damasio and Maurer, 1978) and perhaps also in theironnectivity (Courchesne and Pierce, 2005; Wickelgren, 2005).arly post-mortem investigations of both adults and children withutism reported reduced neuronal size and increased cell packing inhe hippocampus, amygdala and, to a lesser degree, the entorhinal

ortex, mammillary bodies and septal nuclei (Bauman and Kemper,005; Palmen et al., 2004; Raymond et al., 1996). Recent in vivooxel-based morphometry studies reported significant differencesn the anatomy of limbic regions, but with contrasting results with

ig. 12. Surgical treatment for mood, obsessive–compulsive and chronic pain disorder. Cundle, which results in the selective disconnection of two distant regions. An alternative

nserted into regions of white matter for the stimulation of selected groups of fibres. For otatter. Procedures include: (1) Anterior cingulotomy consiting in the bilateral section of th

isorder and chronic pain. (2) Capsulotomy or deep brain stimulation of the fibres runninf obsessive–compulsive disorder and depression. (3) Subcaudate tractotomy and deep brbsessive–compulsive disorder.

dapted from Lipsman et al. (2007).

ioral Reviews 37 (2013) 1724– 1737 1733

respect to the white matter compartment (Barnea-Goraly et al.,2004; Boddaert et al., 2004; Herbert et al., 2003; Kwon et al., 2004;Lee et al., 2007, 2009; McAlonan et al., 2005; Salmond et al., 2005).For example, several groups reported decreased grey and whitematter volumes in the inferior temporal regions and fusiform gyrusin both autism and Asperger’s syndrome in young adults (Boddaertet al., 2004; Kwon et al., 2004; McAlonan et al., 2005; Salmondet al., 2005). Herbert et al. (2004) also reported decreased greymatter volume in the same regions in young people with autismbut increased white matter volume in regions containing limbicpathways. White matter differences have been reported in a recentvoxel-based diffusion study, which found that children with autismhave significant microstructural differences (e.g. reduced fractionalanisotropy) in the anterior cingulum and medial temporal lobe(Barnea-Goraly et al., 2004). Another tractography study showedthat compared to healthy controls, adults with Asperger’s syn-drome had a significantly higher number of streamlines in thecingulum bilaterally and a lower number of streamlines in theright uncinate (Pugliese et al., 2009). Together the post-mortem andin vivo studies suggest anatomical changes of the dorsal cingulumand uncinate fasciculus in autism spectrum disorder.

Schizophrenia is a neurodevelopmental disorders that affectsapproximately one percent of the general population. The disor-der is characterised by positive (e.g. hallucinations, delusions. etc.)and negative (e.g. lack of motivation, blunt affect, etc.) symptoms.Some positive symptoms (e.g. hallucinations) have been attributedto hyperactivity in regions of the limbic system, while negativesymptoms are thought to derive from limbic hypofunctioning. Ina recent review of neuroimaging studies in patients with auditoryhallucinations, the anterior cingulate cortex and the medial tempo-ral regions are among the limbic structures that were consistentlyreported to be activated during auditory hallucinations (Allen et al.,2008). Abnormalities of both myelin and oligodendroglial architec-ture and aberrantly located neurons in myelinated fibre bundleshave been found in limbic regions (mainly frontal and anterior tem-poral) of patients with schizophrenia (Akbarian et al., 1996; Daviset al., 2003). Decreased volume of hippocampus (Bilder et al., 1995)medial temporal lobe, insula, anterior cingulate, and thalamus(Honea et al., 2005), have also been reported. Voxel-based (Kanaanet al., 2005; Kubicki et al., 2002), region of-interest, and tractog-

raphy (Jones et al., 2006) studies in patients with schizophreniareported micro-structural changes in the cingulum (Fujiwara et al.,2007), uncinate fasciculus (McIntosh et al., 2008), fornix (Kurokiet al., 2006; Takei et al., 2008), and the anterior thalamic radiations

ingulotomy, capsulotomy, and tractotomy consist of the surgical severing of a fibre to the surgical disconnection is deep brain stimulation, in which the electrodes areher disorders, like Parkinson disease, the electrodes are implanted in the deep greye anterior cingulum fibres; this is performed in patients with obsessive–compulsiveg within the anterior internal capsule; both procedures are used for the treatmentain stimulation of the frontostriatal fibres are used in patients with depression, and

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McIntosh et al., 2008). However, larger studies (Catani et al., 2011;anaan et al., 2009) and a recent meta-analysis (Ellison-Wrightnd Bullmore, 2009) suggest that the reported deficits are likelyo be part of a wider process rather than be specific to limbicracts.

Obsessive–compulsive disorder is among the most commonental health causes of disability, affecting 1–2% of children and

dults. Current anatomical models of obsessive–compulsive dis-rder include a network composed of the medial orbitofrontalortex, the anterior-dorsal cingulate and the striatum. Functionalnd structural imaging studies support this model (Radua andataix-Cols, 2009). A recent study, for example, found increased

unctional connectivity between the striatum and the orbitofrontalortex (Harrison et al., 2009). The activity of the regions involvedn obsessive–compulsive disorder can be reduced with the sur-ical severing or the electrophysiological inactivation of theirnterconnecting fibres. The white matter of the anterior-dorsalingulate and medial frontal regions are the common targets forhe treatment with deep brain stimulation and psychosurgeryi.e. cingulotomy and capsulotomy) in patients with drug-resistantbsessive–compulsive disorder (Fig. 12). The surgical disconnec-ion causes distant structural changes to the interconnected regionss suggested by a study that showed that individuals undergo-ng cingulotomy had significant reductions in the volume of theaudate nucleus several months after the operation (Rauch et al.,000). The anatomical changes in the orbitofrontal cortex are lessonsistently reported despite clear evidence of its altered activ-ty in functional imaging studies (Harrison et al., 2009; Radua and

ataix-Cols, 2009). Together, structural and functional imagingtudies suggest that, in obsessive–compulsive disorder, the pri-ary anatomical abnormalities occur in the striatum with a distant

odological effect on the paralimbic areas of the anterior cingulatend medial orbitofrontal regions.

. Conclusions and future directions

In this review we propose an update of the limbic model basedn the work of pioneer anatomists and more recent findings fromunctional imaging and tractography. In the revised circuit we iden-ify three distinct but partially overlapping networks.

The hippocampal-diencephalic and parahippocampal-etrosplenial network is dedicated to memory and spatialrientation and lesions to this division cause severe anterogradend spatial disorientation. The temporo-amygdala-orbitofrontaletwork dedicated to the integration of visceral and emotionaltates with cognition and behaviour is often altered in patients withlüver–Bucy syndrome, temporolimbic epilepsy, fronto-temporalementia, autism, psychosis and psychopathy. The dorsomedialefault-mode network consists of a group of limbic regions whosectivity decreases during goal-directed tasks. Lesions to divisionay present with emotional indifference to pain, altered olfaction,

mpaired ability to express emotions, reduced attention andotivation.The model proposed could help clinicians that use neuroimag-

ng to identify pathological changes occurring to different regions ofhe networks and their correlation with symptoms. Future studieshould aim at testing this revised model in a wide range of neuro-ogical and psychiatric disorders at a very early stage and identifynatomical inter-individual variability that could help to developovel therapeutic approaches that modulate individual networks.

cknowledgment

We thank the Natbrainlab (http://www.natbrainlab.com),milio Verche, Guy’s and St. Thomas’ Charity and the French Agence

ioral Reviews 37 (2013) 1724– 1737

Nationale de la Recherche (project CAFORPFC, no. ANR-09-RPDOC-004-01 and project HM-TC, no. ANR-09-EMER-006).

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