A Revised Limbic System Model for Memory, Emotion and Behaviour

Neuroscience and Biobehavioral Reviews 37 (2013) 1724–1737

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

j ournal homepage: www.elsevier.com/locate/neubiorev

Review

A revised limbic system model for memory, emotion and behaviour

a,∗ a,b,c a,d,∗

Marco Catani , Flavio Dell’Acqua , Michel Thiebaut de Schotten

Natbrainlab, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King’s College London, UK

Department of Neuroimaging Sciences, Institute of Psychiatry, King’s College London, UK

NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King’s College

London, UK

UMR S 975; CNRS UMR 7225, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris,

France

a r t i c l e i n f o a b s t r a c t

Article history: Emotion, memories and behaviour emerge from the coordinated activities of regions connected by the

Received 27 November 2012

limbic system. Here, we propose an update of the limbic model based on the seminal work of Papez,

Received in revised form 15 May 2013

Yakovlev and MacLean. In the revised model we identify three distinct but partially overlapping networks:

Accepted 1 July 2013

(i) the Hippocampal-diencephalic and parahippocampal-retrosplenial network dedicated to memory and

spatial orientation; (ii) The temporo-amygdala-orbitofrontal network for the integration of visceral sen-

Keywords:

sation and emotion with semantic memory and behaviour; (iii) the default-mode network involved in

Limbic system

autobiographical memories and introspective self-directed thinking. The three networks share cortical

Tractography

nodes that are emerging as principal hubs in connectomic analysis. This revised network model of the

White matter connections

limbic system reconciles recent functional imaging ﬁndings with anatomical accounts of clinical disorders

Brain networks

Antisocial behaviour Schizophrenia Depression

Bipolar disorder

Obsessive–compulsive disorder

Autism spectrum disorder

Contents

1. Introduction ...... 1725

2. Anatomy of the limbic system ...... 1726

2.1. Fornix ...... 1726

2.2. Mammillo-thalamic tract ...... 1726

2.3. Anterior thalamic projections ...... 1727

2.4. Cingulum ...... 1727

2.5. Uncinate ...... 1728

3. Functional anatomy of the limbic system ...... 1729

4. Limbic syndromes ...... 1730

4.1. Hippocampal-diencephalic and parahippocampal-retrosplenial syndromes ...... 1730

4.2. Temporal-amygdala-orbitofrontal syndromes ...... 1731

4.3. Default network syndromes...... 1733

5. Conclusions and future directions ...... 1734

Acknowledgment ...... 1734

References ...... 1734

∗

Corresponding authors at: Natbrainlab, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, 16 De Crespigny Park, London SE5 8AF, UK.

E-mail addresses: [email protected] (M. Catani), [email protected] (M. Thiebaut de Schotten).

M. Catani et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1724–1737 1725

1. Introduction

The limbic system is a group of interconnected cortical and

subcortical structures dedicated to linking visceral states and emo-

tion to cognition and behaviour (Mesulam, 2000). The use of the

term ‘limbic’ has changed over time. Initially introduced by Thomas

Willis (1664) to designate a cortical border encircling the brain-

stem (limbus, Latin for ‘border’) (Fig. 1) the term has been used

in more recent times to indicate a progressively increasing num-

ber of regions dedicated to a wide range of functions (Marshall

and Magoun, 1998; Mega et al., 1997). Paul Broca (1878) held the

view that ‘le grand lobe limbique’ was mainly an olfactory structure

common to all mammalian brains, although he argued that its func-

tions were not limited to olfaction (Fig. 2). After Broca’s publication

the accumulation of experimental evidence from ablation studies

Fig. 1. The limbic system described for the ﬁrst time by Thomas Willis (1664) to

in animals broadened the role of the limbic structures to include

indicate cortical regions located around the brainstem.

other aspects of behaviour such as controlling social interactions

and behaviour (Brown and Schäfer, 1888), consolidating memories

(Bechterew, 1900), and forming emotions (Cannon, 1927). system (Crosby et al., 1962). These methods allowed, for example,

Anatomical and physiological advancements in the ﬁeld led the description of long and short connections of the cingulate

Christﬁeld Jakob (1906) (Fig. 3) and James Papez (1937) (Fig. 4) cortex in animals. Further, the combination of anatomical methods

to formulate the ﬁrst uniﬁed network model for linking action and with experimental procedures was used to demonstrate a direct

perception to emotion. According to Papez emotion arises either link between speciﬁc limbic structures and behavioural response

from cognitive activity entering the circuit through the hippocam- (e.g. amygdala and aggressive response). Unfortunately, axonal

pus or from visceral and somatic perceptions entering the circuit tracing could not be applied to human anatomy for the study of

through the hypothalamus. In the case of emotion arising from cog- the biological underpinnings of those abilities that characterise

nitive activity, for example, ‘incitations of cortical origin would pass human mind (e.g. emotions; empathy). Also animal models were

ﬁrst to the hippocampal formation and then down by way of the fornix not suitable for studying anatomical differences in psychiatric

to the mammillary body. From this they would pass upward through conditions such as autism and schizophrenia.

the mammillo-thalamic tract, or the fasciculus of Vicq d’Azyr, to the In the 1990s the use of functional neuroimaging methods (e.g.

anterior nuclei of the thalamus and thence by the medial thalamocor- PET, fMRI) and later diffusion tractography offered the possibility

tical radiation [or anterior thalamic projections] to the cortex of the of studying the functional anatomy of the limbic system in the liv-

. . .

gyrus cinguli [ ] The cortex of the cingular gyrus may be looked on ing human brain. A major ﬁnding that emerged initially from PET

as the receptive region for the experiencing of emotion as the result of studies and later conﬁrmed with fMRI was the identiﬁcation of a

impulses coming from the hypothalamic region [or the hippocampal ‘default network’, consisting of a set of regions that activate under

. . .

formation][ ] Radiation of the emotive process from the gyrus cinguli resting-state condition and deactivate during task-related func-

to other regions in the cerebral cortex would add emotional colouring tions (Buckner et al., 2008; Raichle et al., 2001; Raichle and Snyder,

to psychic processes occurring elsewhere (Papez, 1937)’ 2007; Shulman et al., 1997) (Fig. 7). The most medial regions

A decade later, Paul Yakovlev (1948), proposed that the of the default network correspond to the most dorsal portion

orbitofrontal cortex, insula, amygdala, and anterior temporal lobe of the Papez circuit and are interconnected through the dorsal

form a network underlying emotion and motivation (Fig. 5). In two cingulum.

seminal papers published in 1949 and 1952, Paul. MacLean crys- Diffusion imaging is an advanced MRI technique based on opti-

tallised previous works by incorporating both Papez and Yakovlev mised pulse sequences, which permits the quantiﬁcation of the

view into a model of the limbic system that has remained almost diffusion characteristics of water molecules inside biological tis-

unchanged since (MacLean, 1949, 1952). MacLean concluded that sues (Le Bihan and Breton, 1985). Given that cerebral white matter

the limbic cortex, together with the limbic subcortical structures, contains axons, and that water molecules diffuse more freely along

is a functionally integrated system interconnected by short- and axons than across them (Moseley et al., 1990), it is possible to

long-range ﬁbre bundles (Fig. 6). obtain in vivo estimates of white matter ﬁbre orientation by mea-

The development of tracing methods for studying long axonal suring the diffusivity of water molecules along different directions

pathways added details to the anatomical model of the limbic (Basser et al., 1994). By following the orientation of the water

Fig. 2. Paul Broca (1878) identiﬁed the limbic system as mainly an olfactory structure of the mammalian brain.

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

Fig. 3. The limbic system as an integrated system of cortical and subcortical structures linked by projection and association tracts was described for the ﬁrst time by Christfried

Jakob in 1906. Cg, cingulum; Tr, trigonum; C. Call, corpus callosum; N.A.T., anterior thalamic nuclei; Tal., thalamus; Az, bundle of Vicq d’Azyr; CM, mammillary bodies; H,

hippocampus; U, uncus; Bo, olfactory bulb; SL, Septum pellucidum.

molecules displacement, diffusion imaging tractography recon- 2008; Crosby et al., 1962; Nieuwenhuys et al., 2008). Fibres arise

structs 3D trajectories of white matter pathways closely resembling from the hippocampus (subiculum and entorhinal cortex) of each

tracts described in post-mortem animal tracing studies (Dauguet side, run through the ﬁmbria, and join beneath the splenium of

et al., 2007; Thiebaut de Schotten et al., 2011a, 2012) and human the corpus callosum to form the body of the fornix. Other ﬁmbrial

brain dissections (Basser et al., 2000; Catani et al., 2012a; Dell’Acqua ﬁbres continue medially, cross the midline, and project to the

and Catani, 2012; Dell’Acqua et al., 2010, 2012; Jones, 2008; Lawes contralateral hippocampus (hippocampal commissure). Most of

et al., 2008; Thiebaut de Schotten et al., 2011b; Forkel et al., 2012). the ﬁbres within the body of the fornix run anteriorly beneath the

One of the advantages of tractography is the ability to study the body of the corpus callosum towards the anterior commissure.

interindividual variability of white matter tracts in the healthy pop- Above the interventricular foramen, the anterior body of the fornix

ulation and correlate white matter abnormalities with symptoms divides into right and left columns. As each column approaches

severity in patients with neurological and psychiatric disorders the anterior commissure it diverges again into two components.

that involve the limbic system (Catani et al., 2012b; Catani et al., One of these, the posterior columns of the fornix, curve ventrally

2013a). In the following paragraphs we will use integrated infor- in front of the interventricular foramen of Monroe and posterior

mation from animal studies and tractography ﬁndings in human to the anterior commissure to enter the mammillary body (post-

to describe in detail the anatomy of the main limbic pathways commissural fornix), adjacent areas of the hypothalamus, and

(Fig. 8). anterior thalamic nucleus. The second component, the anterior

columns of the fornix, enter the hypothalamus and project to the

septal region and nucleus accumbens (Aggleton, 2008). The fornix

2. Anatomy of the limbic system

also contains some afferent ﬁbres to the hippocampus from septal

and hypothalamic nuclei (Nieuwenhuys et al., 2008).

2.1. Fornix

The fornix is mainly a projection tract connecting the hip- 2.2. Mammillo-thalamic tract

pocampus with the mammillary body, the anterior thalamic

nuclei, and the hypothalamus; it also has a small commissural The ﬁbres of the mammillo-thalamic tract (bundle of Vicq

component known as the hippocampal commissure (Aggleton, d’Azyr) originate from the mammillary bodies and after a very short

Fig. 4. The limbic system according to James Papez (Papez, 1937) is an exact duplicate of Jakob’s original drawing. Papez never quoted the work of Jakob and it is possible

that he didn’t know about his work, which was published in an Argentinean journal with scarce international diffusion (La Semana Médica). Nevertheless the similarities

between the two models are striking. To give credit to the work of Jakob we suggest the use of the eponym Jakob-Papez circuit. a, anterior nucleus; cc, corpus callosum; cn,

caudate nucleus; cp, cingulum posterior; d, gyrus dentatus; f, fornix; gc, gyrus cinguli; gh, gyrus hippocampi; gs, gyrus subcallosus; h, hippocampus; m, mammillary body; mt,

mammillo-thalamic tract; p, pars optica hypothalami; pr, piriform area; sb, subcallosal bundle; t, tuber cinereum; td, tractus mammillo-tegmentalis; th, tractus hypophyseus;

u, uncus.

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, anterior

medial nucleus of the limbic thalamus; Area diag., area diagonalis (Filimonov); Area periamgd., area periamygdalaris (Filimonov); Area entorhin., area entorhinalis; AV, anterior

ventral nucleus of the limbic thalamus; cng-unc-om, orbitomesial interdigitation of the cingulum and uncinate bundle; cng-unc-tm, temporomesial interdigitation of the

cingulum 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 of

the median thalamus (midline nuclei); Massa intrmd., massa intermedia; Pf, corticoperforant temporoammonic ﬁbres (direct and crossed); pf, corticoperforant (direct and

crossed) ﬁbres of the cingulum to the hippocampus; pm, afferent and efferent ﬁbres of the paramedianthalamus (limbic nuclei); sbc, subcallosal radiations (lateral, ventral

and medial) of the cingulum to the septum and ipsi- and contra-lateral striatum and limbic thalamus; Sept. Ar., septal area; T.TH., taenia thalami; VA, ventral anterior nucleus

of the limbic thalamus.

course terminate in the anterior and dorsal nuclei of the thalamus. Nieuwenhuys et al., 2008). From the medial temporal lobe, these

A ventrally directed branch projects from the mammillary bodies ﬁbres reach the occipital lobe and arch almost 180 degrees around

to the tegmental nuclei (mammillo-tegmental tract). According to the splenium to continue anteriorly within the white matter of the

Nauta (1958), the mammillo-tegmental tract, together with other cingulate gyrus. The dorsal and anterior ﬁbres of the cingulum fol-

ﬁbres of the medial forebrain bundle, forms an important circuit low the shape of the superior aspect of the corpus callosum. After

between medial limbic structures of the midbrain and hypothala- curving around the genu of the corpus callosum, the ﬁbres termi-

mus to relate visceral perception to emotion and behaviour. nate in the subcallosal gyrus and the paraolfactory area (Crosby

et al., 1962). Shorter ﬁbres that join and leave the cingulum along

2.3. Anterior thalamic projections its length, connect adjacent areas of the medial frontal gyrus,

paracentral lobule, precuneus, cuneus, cingulate, lingual, and

The anterior thalamic nuclei receive projections from the fornix fusiform gyri (Dejerine, 1895; Nieuwenhuys et al., 2008). The cin-

and mammillo-thalamic tract and connect through the anterior gulum can be divided into an anterior-dorsal component, which

thalamic projections to the orbitofrontal and anterior cingulate cor- constitutes most of the white matter of the cingulate gyrus, and a

tex. The anterior thalamic projections run in the anterior limb of the posterior-ventral component running within the parahippocampal

internal capsule. gyrus, retrosplenial cingulate gyrus, and posterior precuneus. Pre-

liminary data suggest that these subcomponents of the cingulum

may have different anatomical features. For example, a higher

2.4. Cingulum

fractional anisotropy has been found in the left anterior-dorsal

segment of the cingulum compared to right, but reduced fractional

The cingulum contains ﬁbres of different lengths, the longest

anisotropy has been reported in the left posterior-ventral compo-

running from the amygdala, uncus, and parahippocampal gyrus

nent compared to the right (Gong et al., 2005; Park et al., 2004;

to sub-genual areas of the frontal lobe (Crosby et al., 1962;

Fig. 6. MacLean’s 1952 (MacLean, 1949, 1952) proposal for a unitary model of the limbic system consisting of Papez circuit and Yakovlev’s amygdala-orbitofrontal network.

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

Fig. 7. One of the ﬁrst PET studies looking at the functional anatomy of the ‘default networks’ (Shulman et al., 1997). Area 1 corresponds to the posterior cingulate

cortex/precuneus and area 9 to the anterior cingulate/medial frontal cortex. Theses two areas are interconnected through the dorsal ﬁbres of the cingulum.

Wakana et al., 2007). Notwithstanding this, the volume of the fasciculus before entering the orbital region of the frontal lobe.

cingulum is bilateral and symmetrical in most subjects (Thiebaut Here, the uncinate splits into a ventro-lateral branch, which termi-

de Schotten et al., 2011b). nates in the anterior insula and lateral orbitofrontal cortex, and an

antero-medial branch that continues towards the cingulate gyrus

2.5. Uncinate and the frontal pole (Crosby et al., 1962; Dejerine, 1895; Klingler

and Gloor, 1960). Whether the uncinate fasciculus is a lateralised

The uncinate fasciculus connects the anterior part of the tempo- bundle is still debated. An asymmetry of the volume and density of

ral lobe with the orbital and polar frontal cortex (Fig. 8). The ﬁbres ﬁbres of this fasciculus has been reported in a human post-mortem

of the uncinate fasciculus originate from the temporal pole, uncus, neurohistological study in which the uncinate fasciculus was found

parahippocampal gyrus, and amygdala, then after a U-turn, enter to be asymmetric in 80% of subjects, containing on average 30%

the ﬂoor of the extreme capsule. Between the insula and the puta- more ﬁbres in the right hemisphere compared to the left (Highley

men, the uncinate fasciculus runs inferior to the fronto-occipital et al., 2002). However, diffusion measurements have shown higher

Fig. 8. Diagrammatic representation of the limbic system and tractography reconstruction of its main pathways. The colours in both ﬁgures correspond to the tracts in the legend.

M. Catani et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1724–1737 1729

fractional anisotropy in the left uncinate compared to the right in primary olfactory piriform cortex and includes the orbitofrontal,

children and adolescents (Eluvathingal et al., 2007) but not in adults insular and temporopolar region. The hippocampocentric division

(Thiebaut de Schotten et al., 2011b). is organised around the hippocampus and includes the parahip-

pocampal and cingulate cortex. Both divisions have reciprocal

3. Functional anatomy of the limbic system connections with subcortical limbic structures and surrounding

isocortical regions (Fig. 9). The two divisions overlap in the anterior

The limbic system has always been considered as a complex cingulate cortex.

arrangement of transitional structures situated between a vis- Functionally the paralimbic areas contribute to the activity of

ceral ‘primitive’ subcortical brain and a more evolved cortical one three distinct networks (Fig. 10). The ﬁrst network, composed of the

(MacLean, 1952; Yakovlev, 1948). The subcortical limbic struc- hippocampal-diencephalic limbic circuit (connected through the

tures include the amygdala, mammillary bodies, hypothalamus, fornix and mammillo-thalamic tract) and the parahippocampal-

some thalamic nuclei (i.e. anterior, intralaminar, and medial dorsal retrosplenial circuit (ventral cingulum), is dedicated to memory

groups) and the ventral striatum (i.e. nucleus accumbens). The neu- and spatial orientation, respectively (Aggleton, 2008; Vann et al.,

rons and ﬁbres composing the subcortical limbic structures present 2009). Some structures of this network are particularly vulnerable

a simple arrangement, not dissimilar to other subcortical nuclei to damage caused by viral infections (e.g. encephalitis) or alcohol

of the brainstem that regulate basic metabolism, respiration, and (e.g. Korsakoff’s syndrome) (Fig. 10). Imaging studies have docu-

circulation. mented altered metabolism and reduced functional activation of

The cortical components of the limbic system include areas of this network also in age-related neurodegenerative disorders such

increasing complexity separated into limbic and paralimbic zones as mild cognitive impairment (Minoshima et al., 1997; Nestor et al.,

(Mesulam, 2000). At the lower level the corticoid areas of the amyg- 2003) and Alzheimer’s disease (Buckner et al., 2005).

daloid complex, substantia innominata, together with septal and The temporo-amygdala-orbitofrontal network (connected

olfactory nuclei display an anatomical organisation that lacks con- through the uncinate fasciculus) is dedicated to the integration

sistent lamination and dendritic orientation. These structures are of visceral and emotional states with cognition and behaviour

in part subcortical and in part situated on the ventral and medial (Mesulam, 2000). In animal studies, disconnection of the unci-

surfaces of the cerebral hemispheres. The next level of organisation nate fasciculus causes impairment of object-reward association

is the allocortex of the olfactory regions and hippocampal complex, learning and reduced performances in memory tasks involving

where the neurons are well differentiated into layers and their den- temporally complex visual information (Gaffan and Wilson, 2008).

drites show an orderly pattern of orientation. The corticoid and In humans this network engages in tasks that involve naming,

allocortical regions are grouped together into the limbic zone of single word comprehension, response inhibition, face processing

the cerebral cortex as distinct from the paralimbic zone. The lat- and monitoring of outcomes (Catani et al., 2013a; Amodio and

ter is mainly composed of ‘mesocortex’, whose progressive level of Frith, 2006). Damage to this network manifests with cognitive and

structural complexity ranges from a simpliﬁed arrangement similar behavioural symptoms characteristic of temporal lobe epilepsy,

to the allocortex, to the most complex six-layered isocortex. mood disorders, traumatic brain injury, psychopathy and neurode-

The limbic and paralimbic zones can also be divided into olfac- generative dementias, including advanced Alzheimer’s disease and

tocentric and hippocampocentric groups (Fig. 9) (Mega et al., 1997; semantic dementia (Fig. 10).

Mesulam, 2000). Each division is organised around a central core The dorsomedial default-mode network consists of a group

of allocortex. The olfactocentric division is organised around the of medial regions whose activity decreases during goal-directed

Fig. 9. Functional-anatomical separation of the limbic system into olfactocentric (blue) and hippocampocentric (red) divisions. Some regions (e.g. BA 10, 11, 21, 22, 24, 32,

36, 47) are connected to both divisions.

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. The

main connections of the hippocampal-diencephalic and parahippocampal-retrosplenial network are the ventral cingulum, the fornix and the mammillo-thalamic tract (the

endstations of this network are indicated in yellow). The main nodes of the temporo-amygdala-orbitofrontal network (indicated in green) are connected by the uncinate

fasciculus. The dorsal cingulum is the main connection of the medial default network, whose cortical projections are shown in blue.

tasks (Raichle et al., 2001; Raichle and Snyder, 2007). The anterior et al., 2003). In younger population memory impairment is often

cingulate-medial prefrontal cortex and the posterior cingulate- associated with traumatic conditions, alcoholism and epilepsy.

precuneus form the medial default-mode network and are inter- Dementia alone had cost to the US economy $200 billion in

connected through the dorsal cingulum. In functional imaging stud- 2012: more than cancer and heart disease combined (Alzheimer’s

ies the default-mode network is active during the ‘resting state’, a Association, 2012).

condition in which the majority of the subjects engage in an intro- Memory deﬁcits are linked primarily to damage of the hip-

spective, self-directed stream of thought (i.e. similar to daydream- pocampocentric division of the limbic system (Markowitsch, 2000).

ing). A synchronous deactivation of the default network is observed Some differences in the clinical presentation may be related to the

in the transition between the ‘resting state’ and the execution of exact location and extension of the damage, and its nature. The

goal directed tasks, irrespective of the nature of the task. The deac- common manifestations are those of a global amnesia where the

tivation of the default-mode network has been linked to a number patient is unable to encode, associate, and retrieve new informa-

of functions including working memory, focusing attention to sen- tion (anterograde amnesia). In addition there is also some degree

sorially driven activities, understanding other people’s intention of amnesia for events before the brain damage (or the onset of the

(mentalising or theory of mind), prospective thinking (envision- neurodegenerative disorder) but temporally close to it (retrograde

ing the future) and memory for personal events (autobiographic amnesia). The remote memory is relatively well preserved.

memory) (Amodio and Frith, 2006). Altered activation of the default The patient H.M., who underwent bilateral resection of the

network has been reported in functional imaging studies of patients medial temporal lobe for pharmacologically intractable epilepsy,

with neuropsychiatric disorders (Broyd et al., 2009) (Fig. 10). is a classical example of a pure global amnesic (Scoville and Milner,

1957). Despite its inability to form new memories his memory

4. Limbic syndromes before the surgery and insight were preserved. Loss of insight

can be associated with confabulation (the spontaneous narrative

The limbic system is affected by a wide range of disorders, report of events that never happened) in patients with diencephalic

including neurodevelopmental conditions, traumatic brain injury amnesias due to lesions of the mammillary bodies, the thalamic

and neurodegeneration. In most psychiatric conditions a dysfunc- nuclei and their interconnections. Confabulation can be severe

tion of the limbic structures involved with emotion regulation, in chronic alcoholics with Korsakoff’s syndrome, especially if the

social interaction and behaviour has been implicated. In the older pathology affects the normal activity of the medial orbitofrontal

population neurodegenerative disorders affect primarily limbic and anterior cingulate cortex. In a 32-year-old alcoholic patient

systems dedicated to memory. These disorders take a heavy tall on that confabulated for 6 weeks, measurement of cerebral perfusion

affected individuals, families and society at large. The use of neu- using single photon emission computed tomography, showed

roimaging methods could help to identify vulnerable phenotypes hypoperfusion of the anterior and mediodorsal thalamic nuclei,

and discover early markers of disease leading to the development of anterior cingulate and orbitofrontal cortex (Benson et al., 1996).

novel treatment approaches. In the paragraphs that follow we apply A second single photon emission computed tomography repeated

the proposed framework to the most common limbic syndromes. after the patient stopped confabulating showed a ‘normalisation’

of the orbitofrontal and anterior cingulate perfusion. The anterior

and mediodorsal thalamic nuclei remained hypoperfused and the

4.1. Hippocampal-diencephalic and

patient continued to suffer with profound amnesia (for a review of

parahippocampal-retrosplenial syndromes

the anatomy of confabulation see Dalla Barba and La Corte, 2013;

Schneider, 2008).

Memory impairment is the most common condition in the age-

In patients with vascular thalamic lesions (such as case A.B.

ing population, affecting one in eight American citizens diagnosed

reported by Markowitsch et al., 1993) the extension of the damage

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

M. Catani et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1724–1737 1731

to the mammillo-thalamic tract is the best predictor of the severity olfactory (orbitofrontal-amygdala) division is associated with clin-

of the memory deficit (von Cramon et al., 1985). In patients with col- ical manifestations such as semantic deficits, language difficulties,

loid cysts of the third ventricle, the surgical removal of the benign personality changes and other behavioural symptoms (e.g. aggres-

tumour can damage the fornix and result in anterograde amnesia, sion, disinhibition, etc.), which are not present if the pathology is

although it is seemingly not as severe as that seen in diencephalic limited to the hippocampocentric division. Alternatively, the early

patients (Aggleton, 2008). stages of the temporal variant of the fronto-temporal dementia

Another form of hippocampocentric memory dysfunction is and the semantic variant of primary progressive aphasia (Agosta

associated with lesions to the posterior parahippocampal cortex, et al., 2010; Borroni et al., 2007; Catani et al., 2013b) involve the

retrosplenial cingulate cortex, and posterior precuneus (Valenstein olfactory division ﬁrst leading to olfactory-gustatory-visceral dys-

et al., 1987). These patients, in addition to memory deﬁcits, show functions and semantic deﬁcits. As the disease progresses, damage

difﬁculties in spatial orientation due to the inability to derive to the hippocampocentric division occur and involve other cogni-

directional information from landmark cues in familiar and new tive domains such as memory and spatial orientation.

environments (Vann et al., 2009). Reduced metabolism of the ret- In some patients with temporal lobe epilepsy the behavioural

rosplenial cortex has also been reported in patients with mild symptoms resemble those commonly observed in the Klüver–Bucy

cognitive impairment (Nestor et al., 2003) and early Alzheimer’s syndrome. In the 1930s, Klüver and Bucy conducted a series of

disease (Minoshima et al., 1997). More recently, a combined cor- experiments in rhesus monkeys that consisted of bilateral surgical

tical morphometry and diffusion imaging study found reduced removal of the anterior temporal lobe, which include the amygdala

cortical thickness and white matter abnormalities of these regions and temporal pole (Klüver and Bucy, 1939). After the operation

(Acosta-Cabronero et al., 2010). Compared to surrounding areas, the animals showed a strong tendency to examine objects orally

the parahippocampal, posterior cingulate, and precuneus regions (hyperorality), an irresistible impulse to touch (hypermetamor-

also have a faster rate of atrophy in pre-symptomatic Alzheimer’s phosis), loss of normal anger and fear responses, increased sexual

disease patients (autosomal dominant mutation carriers) (Scahill activity, and inability to recognise visually presented objects. The

et al., 2002). Reduced fractional anisotropy has also been found in systematic experimental series conducted by Klüver and Bucy,

the cingulum, hippocampus and the posterior corpus callosum of although originally described by Brown and Schäfer in 1888, helped

cognitively intact subjects with increased genetic risk of dementia to understand the functions of the anterior temporal lobe and

(APOE 4 carriers) (Persson et al., 2006). behavioural deﬁcits associated with limbic damage in humans. The

Preliminary evidence suggests that diffusion changes in neu- ﬁrst Klüver–Bucy syndrome in humans was described in a patient

rodegenerative disorders are likely to reﬂect severity of underlying who received bilateral temporal resection (Terzian and Ore, 1955).

white matter pathology. Xie et al. (2005) reported a signiﬁcant In recent times, this is a condition that clinicians observe in patients

positive correlation between reduced fractional anisotropy val- with herpes or paraneoplastic encephalitis, tumours, or traumatic

ues, atrophy of the hippocampus and decline in the mini-mental brain injury involving the anterior temporal and orbitofrontal cor-

state examination scores in patients with Alzheimer’s disease. In tex (Hayman et al., 1998; Zappala et al., 2012).

a transgenic mouse model over-expressing beta-amyloid precur- In children with temporal lobe epilepsy, single-photon emission

sor protein, the diffusivity parameters were signiﬁcantly correlated computed tomography reveals hypoperfusion of the basal gan-

with the severity of Alzheimer’s disease-like pathology in the white glia and the adjacent frontal and temporal limbic regions. Most

matter (Song et al., 2004). In humans, Englund et al. (2004) con- of the patients recover after the acute phase, but those with

ducted a parallel post-mortem neuropathological examination and abnormal diffusivity of the temporal and frontal white matter

fractional anisotropy quantiﬁcation of two brains with dementia tracts exhibit long-term mental retardation, epilepsy, and persis-

and reported that the degree of white matter pathology correlated tent oral tendency (Maruyama et al., 2009). Some temporal lobe

signiﬁcantly with gradually lower fractional anisotropy values epilepsy patients present with Geschwind’s syndrome, a char-

sampled in ﬁfteen regions of interest. Overall, these studies sug- acteristic change in personality consisting of unusual tendencies

gest that reduced fractional anisotropy in Alzheimer’s disease may to write extensively and in a meticulous manner (hypergraphia),

reﬂect white matter axonal degeneration and myelin loss following excessive and circumstantial verbal output, deepened cognitive

neuronal degeneration of cortical neurons. and emotional responses (e.g. excessive moral concerns), viscos-

Damage to the limbic white matter tracts such as the fornix ity of thought, altered sexuality (usually lack of interest), and

(Concha et al., 2005) and the uncinate fasciculus (Diehl et al., hyperreligiosity (Waxman and Geschwind, 1974). The emergence

2008) is also reported in patients with unilateral temporal lobe of psychotic symptoms in temporal lobe epilepsy is associated

epilepsy. This damage is diffuse and often extends contralaterally with white matter changes extending to the frontal pathways

from the side of the suspected seizure. In temporal lobe epilepsy (Flugel et al., 2006). Behavioural symptoms in epileptic patients

patients with mesial hippocampal sclerosis, the decreased frac- can respond to surgery. Mitchell et al. (1954) described a case of

tional anisotropy of the fornix and the associated memory deﬁcits temporal lobe epilepsy with fetish behaviour. The patient reported

are correlated with reduced axonal diameter and myelin content highly pleasurable ‘thought satisfaction’ derived from looking at a

of the fornix ﬁbres (Concha et al., 2010). The diffusion changes in safety-pin and sought seclusion in a lavatory to indulge it. Unfor-

the left uncinate fasciculus also correlate with the severity of the tunately, the fetish object also triggered severe seizures, which

deﬁcits in delayed recall (Diehl et al., 2008). It is noteworthy to required surgical treatment. Relief not only of the epilepsy but also

specify that pre-operative tractography assessment of the lateral- of the fetishism followed the temporal lobectomy.

isation pattern of the temporal tracts can help to predict naming Psychopathic personality disorder (psychopathy) is charac-

deﬁcits after the operation in patients with temporal lobe epilepsy terised by features of emotional detachment and antisocial traits

undergoing surgery (more left lateralised patients showed worse (Patrick et al., 1993), and is strongly associated with criminal

postoperative deﬁcits) (Powell et al., 2008). behaviour and recidivism (Hare et al., 1999). Approximately 0.75%

of male population meets the criteria for psychopathy with enor-

4.2. Temporal-amygdala-orbitofrontal syndromes mous costs for the society (Blair et al., 2005). It has been estimated,

for example, that 15% of the prison population are psychopaths and

The clinical proﬁle of neurodegenerative disorders varies they commit approximately 50% more criminal offences than non-

according to the network affected by the illness. In advanced psychopathic criminals (Hart and Hare, 1997). Since the report of

Alzheimer’s disease, for example, the extension of the disease to the the 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)

Tractography reconstruction of the connections between amygdala, orbitofrontal cortex, and posterior occipital areas. Tract-speciﬁc measurements of fractional anisotropy

(FA) show that psychopaths have a signiﬁcantly reduced mean FA in the right uncinate fasciculus (P = 0.003) compared to controls. There were no differences in the left

uncinate fasciculus (P = 0.448) or in the two ‘non-limbic’ control tracts: the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus (Craig et al., 2009).

sociopathy’ following frontal lobe injury (Damasio et al., 1994), the amygdala-orbitofrontal cortex network, other two ‘nonlimbic’

orbitofrontal cortex and other regions of the prefrontal cortex have control tracts connecting the posterior visual areas to amyg-

been considered important for personality and social behaviour dala or orbitofrontal cortex were studied, and no signiﬁcant

(Damasio, 2000). For example, the orbitofrontal cortex is crucial to between-group differences were found. These results suggest that

successful reversal learning in which previously rewarded stimuli abnormalities in a speciﬁc amygdala-orbitofrontal cortex network

are associated with punishment. Reversal learning is signiﬁcantly underpin the neurobiological basis of psychopathy (Fig. 11).

impaired in adult psychopaths (Budhani et al., 2006) and in young Post-mortem histological studies in patients with bipolar affec-

people with psychopathic traits (Budhani and Blair, 2005). It has tive disorder have found a reduction in the number and density of

also been reported that violent personality disordered offenders glial cells (Ongur et al., 1998; Webster et al., 2005) and decreased

have reduced prefrontal cortex grey matter volume (Raine et al., neuronal density in the subgenual region of the orbitofrontal

2000) and glucose metabolism (Raine et al., 1997), and impaired cortex (Bouras et al., 2001) and in the dorsolateral prefrontal

orbitofrontal cortex activation during aversive conditioning (Veit areas (BA 9) (Rajkowska et al., 2001). Myelin abnormalities in

et al., 2002). In contrast, other researchers have argued that amyg- bipolar affective disorder may be related to a decreased expres-

dala dysfunction is central to the affective deﬁcits and impairs sion of genes involved in myelin synthesis and regulation (Aston

moral socialisation of psychopathy (Blair, 2007; Delisi et al., 2009). et al., 2005). These histological ﬁndings are supported by neu-

This latter view is supported by evidence that psychopaths show roimaging studies that reported a general increase in white matter

performance deﬁcits in tasks sensitive to amygdala damage (Blair hyperintensities on MRI images (Altshuler et al., 1995), selec-

et al., 2001; Levenston et al., 2000), and have signiﬁcantly reduced tive reduced white matter density (Bruno et al., 2004), and

amygdala volume (Tiihonen et al., 2000) and decreased amygdala decreased cortical metabolism and volume in the subgenual region

activation during verbal learning (Kiehl et al., 2001) and facial fear (Drevets et al., 1997) of adults with a diagnosis of bipolar affective

processing (Deeley et al., 2006). Furthermore, stimulation of the disorder. Findings from diffusion imaging studies using region-of-

amygdala can manifest with irritability, aggression, violent out- interest or voxel-based approaches have been inconsistent with

bursts, and antisocial behaviour. More recently, the dichotomy reports of both decreased (Adler et al., 2004; Versace et al.,

between researchers postulating whether orbitofrontal cortex or 2008) and increased (Haznedar et al., 2005; Versace et al., 2008)

amygdala dysfunction is central to psychopathy (Abbott, 2001) has fractional anisotropy in bipolar disorder compared to healthy

narrowed; and it has been suggested instead that the social and controls. Tractography of the subgenual-amygdala connections

emotional deﬁcits of psychopaths may reﬂect an altered interac- showed increased tract volume (Houenou et al., 2007) and reduced

tion between orbitofrontal cortex and amygdala dysfunction (Blair, fractional anisotropy in the uncinate and anterior thalamic pro-

2007; van Honk and Schutter, 2006). This view has received sup- jections (McIntosh et al., 2008). In a recent single case study, a

port from a DTI study that used tractography to measure the patient with a history of bipolar disorder and intractable recur-

volume and integrity of the connections between orbitofrontal cor- rent depression following a right thalamic stroke who underwent

tex and amygdala in psychopaths (Fig. 11) (Craig et al., 2009). deep brain stimulation of the subgenual cortex as experimen-

A signiﬁcantly reduced fractional anisotropy was reported in the tal treatment of his depression. The patient died 16 months

uncinate fasciculus of psychopaths compared to healthy subjects after the implants were positioned without any signiﬁcant clini-

with similar age and intelligence. A correlation between measures cal response. A high-resolution diffusion imaging dataset acquired

of antisocial behaviour (as assessed by the Psychopathy Check- post-mortem revealed markedly reduced limbic projections from

list) and anatomical differences in the uncinate fasciculus was also the thalamus, subgenual region and amygdala in the stroke-

reported. To confirm that these findings were specific to the limbic affected (right) hemisphere. The authors concluded that reduced

M. Catani et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1724–1737 1733

limbic connections assessed with diffusion imaging could be a con- respect to the white matter compartment (Barnea-Goraly et al.,

traindication to deep brain stimulation for depression (McNab et al., 2004; Boddaert et al., 2004; Herbert et al., 2003; Kwon et al., 2004;

2009). Lee et al., 2007, 2009; McAlonan et al., 2005; Salmond et al., 2005).

For example, several groups reported decreased grey and white

matter volumes in the inferior temporal regions and fusiform gyrus

4.3. Default network syndromes

in both autism and Asperger’s syndrome in young adults (Boddaert

et al., 2004; Kwon et al., 2004; McAlonan et al., 2005; Salmond

Major depression is the most common of all psychiatric dis-

et al., 2005). Herbert et al. (2004) also reported decreased grey

orders (Kessler et al., 2003) affecting at least one in six adults in

matter volume in the same regions in young people with autism

USA (Kessler et al., 2005). Neuroimaging studies show that the

but increased white matter volume in regions containing limbic

subgenual cingulate region (BA 25) is metabolically overactive in

pathways. White matter differences have been reported in a recent

depressed patients and its activation reduces in parallel with the

voxel-based diffusion study, which found that children with autism

antidepressant effect of pharmacological treatment (Mayberg et al.,

have signiﬁcant microstructural differences (e.g. reduced fractional

2000), electroconvulsive therapy (Nobler et al., 2001), and transcra-

anisotropy) in the anterior cingulum and medial temporal lobe

nial magnetic stimulation of more dorsal frontal regions (Mottaghy

(Barnea-Goraly et al., 2004). Another tractography study showed

et al., 2002). Mayberg et al. (2005) have also shown that chronic

that compared to healthy controls, adults with Asperger’s syn-

direct deep brain stimulation of the white matter ﬁbres adjacent to

drome had a signiﬁcantly higher number of streamlines in the

the subgenual cortex resulted in a signiﬁcant remission of depres-

cingulum bilaterally and a lower number of streamlines in the

sion in four of six patients with treatment-resistant depression

right uncinate (Pugliese et al., 2009). Together the post-mortem and

(Fig. 12). The antidepressant effect was associated not only with a

in vivo studies suggest anatomical changes of the dorsal cingulum

reduction in the local metabolism of the subgenual region, but also

and uncinate fasciculus in autism spectrum disorder.

with increased metabolism of dorsal cingulate and other prefrontal

Schizophrenia is a neurodevelopmental disorders that affects

areas connected to the subgenual cortex. A recent preliminary

approximately one percent of the general population. The disor-

tractography study in adolescents with major depressive disorder

der is characterised by positive (e.g. hallucinations, delusions. etc.)

reported lower fractional anisotropy in the white matter tract con-

and negative (e.g. lack of motivation, blunt affect, etc.) symptoms.

necting the subgenual cingulate region to the amygdala in the right

Some positive symptoms (e.g. hallucinations) have been attributed

hemisphere (Cullen et al., 2010).

to hyperactivity in regions of the limbic system, while negative

Autism spectrum disorder is a neurodevelopmental condition

symptoms are thought to derive from limbic hypofunctioning. In

characterised by repetitive and stereotypic behaviour, impaired

a recent review of neuroimaging studies in patients with auditory

communication and striking deﬁcits in social reciprocity. Collec-

hallucinations, the anterior cingulate cortex and the medial tempo-

tively, autism spectrum disorders affect 1 in 100 children with

ral regions are among the limbic structures that were consistently

a female/male sex ratio of 1:4 (Baird et al., 2006). While some

reported to be activated during auditory hallucinations (Allen et al.,

of the manifestations are explained in terms of impaired exec-

2008). Abnormalities of both myelin and oligodendroglial architec-

utive functioning (Ozonoff et al., 1991), it has been suggested

ture and aberrantly located neurons in myelinated ﬁbre bundles

that the social and communication abnormalities typically found

have been found in limbic regions (mainly frontal and anterior tem-

in autism spectrum disorder are due to abnormalities in limbic

poral) of patients with schizophrenia (Akbarian et al., 1996; Davis

structures (Damasio and Maurer, 1978) and perhaps also in their

et al., 2003). Decreased volume of hippocampus (Bilder et al., 1995)

connectivity (Courchesne and Pierce, 2005; Wickelgren, 2005).

medial temporal lobe, insula, anterior cingulate, and thalamus

Early post-mortem investigations of both adults and children with

(Honea et al., 2005), have also been reported. Voxel-based (Kanaan

autism reported reduced neuronal size and increased cell packing in

et al., 2005; Kubicki et al., 2002), region of-interest, and tractog-

the hippocampus, amygdala and, to a lesser degree, the entorhinal

raphy (Jones et al., 2006) studies in patients with schizophrenia

cortex, mammillary bodies and septal nuclei (Bauman and Kemper,

reported micro-structural changes in the cingulum (Fujiwara et al.,

2005; Palmen et al., 2004; Raymond et al., 1996). Recent in vivo

2007), uncinate fasciculus (McIntosh et al., 2008), fornix (Kuroki

voxel-based morphometry studies reported signiﬁcant differences

et al., 2006; Takei et al., 2008), and the anterior thalamic radiations

in the anatomy of limbic regions, but with contrasting results with

Fig. 12. Surgical treatment for mood, obsessive–compulsive and chronic pain disorder. Cingulotomy, capsulotomy, and tractotomy consist of the surgical severing of a ﬁbre

bundle, which results in the selective disconnection of two distant regions. An alternative to the surgical disconnection is deep brain stimulation, in which the electrodes are

inserted into regions of white matter for the stimulation of selected groups of ﬁbres. For other disorders, like Parkinson disease, the electrodes are implanted in the deep grey

matter. Procedures include: (1) Anterior cingulotomy consiting in the bilateral section of the anterior cingulum ﬁbres; this is performed in patients with obsessive–compulsive

disorder and chronic pain. (2) Capsulotomy or deep brain stimulation of the ﬁbres running within the anterior internal capsule; both procedures are used for the treatment

of obsessive–compulsive disorder and depression. (3) Subcaudate tractotomy and deep brain stimulation of the frontostriatal ﬁbres are used in patients with depression, and

obsessive–compulsive disorder.

Adapted from Lipsman et al. (2007).

1734 M. Catani et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1724–1737

(McIntosh et al., 2008). However, larger studies (Catani et al., 2011; Nationale de la Recherche (project CAFORPFC, no. ANR-09-RPDOC-

Kanaan et al., 2009) and a recent meta-analysis (Ellison-Wright 004-01 and project HM-TC, no. ANR-09-EMER-006).

and Bullmore, 2009) suggest that the reported deﬁcits are likely

to be part of a wider process rather than be speciﬁc to limbic

tracts. References

Obsessive–compulsive disorder is among the most common

Abbott, A., 2001. Into the mind of a killer. Nature 410, 296–298.

mental health causes of disability, affecting 1–2% of children and

Acosta-Cabronero, J., Williams, G.B., Pengas, G., Nestor, P.J., 2010. Absolute diffusivi-

adults. Current anatomical models of obsessive–compulsive dis- ties deﬁne the landscape of white matter degeneration in Alzheimer’s disease.

Brain 133, 529–539.

order include a network composed of the medial orbitofrontal

Adler, C.M., Holland, S.K., Schmithorst, V., Wilke, M., Weiss, K.L., Pan, H., Strakowski,

cortex, the anterior-dorsal cingulate and the striatum. Functional

S.M., 2004. Abnormal frontal white matter tracts in bipolar disorder: a diffusion

and structural imaging studies support this model (Radua and tensor imaging study. Bipolar Disord. 6, 197–203.

Mataix-Cols, 2009). A recent study, for example, found increased Aggleton, J.P., 2008. EPS Mid-Career Award 2006. Understanding anterograde amne-

sia: disconnections and hidden lesions. Q. J. Exp. Psychol. (Colchester) 61,

functional connectivity between the striatum and the orbitofrontal

1441–1471.

cortex (Harrison et al., 2009). The activity of the regions involved

Agosta, F., Henry, R.G., Migliaccio, R., Neuhaus, J., Miller, B.L., Dronkers, N.F., Brambati,

in obsessive–compulsive disorder can be reduced with the sur- S.M., Filippi, M., Ogar, J.M., Wilson, S.M., Gorno-Tempini, M.L., 2010. Language

networks in semantic dementia. Brain 133, 286–299.

gical severing or the electrophysiological inactivation of their

Akbarian, S., Kim, J.J., Potkin, S.G., Hetrick, W.P., Bunney Jr., W.E., Jones, E.G., 1996.

interconnecting ﬁbres. The white matter of the anterior-dorsal

Maldistribution of interstitial neurons in prefrontal white matter of the brains

cingulate and medial frontal regions are the common targets for of schizophrenic patients. Arch. Gen. Psychiatry 53, 425–436.

Allen, P., Laroi, F., McGuire, P.K., Aleman, A., 2008. The hallucinating brain: a review

the treatment with deep brain stimulation and psychosurgery

of structural and functional neuroimaging studies of hallucinations. Neurosci.

(i.e. cingulotomy and capsulotomy) in patients with drug-resistant

Biobehav. Rev. 32, 175–191.

obsessive–compulsive disorder (Fig. 12). The surgical disconnec- Altshuler, L.L., Curran, J.G., Hauser, P., Mintz, J., Denicoff, K., Post, R., 1995. T2 hyper-

intensities in bipolar disorder: magnetic resonance imaging comparison and

tion causes distant structural changes to the interconnected regions

literature meta-analysis. Am. J. Psychiatry 152, 1139–1144.

as suggested by a study that showed that individuals undergo-

Alzheimer’s Association, 2006. Early-Onset Dementia: A National Challenge, A

ing cingulotomy had signiﬁcant reductions in the volume of the Future Crisis. Alzheimer’s Association, Washington, DC.

Alzheimer’s Association, 2012. 2012 Alzheimer’s Disease Facts and Figures.

caudate nucleus several months after the operation (Rauch et al.,

Alzheimer’s Association, Washington, DC.

2000). The anatomical changes in the orbitofrontal cortex are less

Amodio, D.M., Frith, C.D., 2006. Meeting of minds: the medial frontal cortex and

consistently reported despite clear evidence of its altered activ- social cognition. Nat. Rev. Neurosci. 7, 268–277.

ity in functional imaging studies (Harrison et al., 2009; Radua and Aston, C., Jiang, L., Sokolov, B.P., 2005. Transcriptional proﬁling reveals evidence

for signaling and oligodendroglial abnormalities in the temporal cortex from

Mataix-Cols, 2009). Together, structural and functional imaging

patients with major depressive disorder. Mol. Psychiatry 10, 309–322.

studies suggest that, in obsessive–compulsive disorder, the pri-

Baird, G., Simonoff, E., Pickles, A., Chandler, S., Loucas, T., Meldrum, D., Charman, T.,

mary anatomical abnormalities occur in the striatum with a distant 2006. Prevalence of disorders of the autism spectrum in a population cohort of

children in South Thames: the Special Needs and Autism Project (SNAP). Lancet

hodological effect on the paralimbic areas of the anterior cingulate

368, 210–215.

and medial orbitofrontal regions.

Barnea-Goraly, N., Kwon, H., Menon, V., Eliez, S., Lotspeich, L., Reiss, A.L., 2004. White

matter structure in autism: preliminary evidence from diffusion tensor imaging.

Biol. Psychiatry 55, 323–326.

5. Conclusions and future directions Basser, P.J., Mattiello, J., Le Bihan, D., 1994. MR diffusion tensor spectroscopy and

imaging. Biophys. J. 66, 259–267.

Basser, P.J., Pajevic, S., Pierpaoli, C., Duda, J., Aldroubi, A., 2000. In vivo ﬁber tractog-

In this review we propose an update of the limbic model based

raphy using DT-MRI data. Magn. Reson. Med. 44, 625–632.

on the work of pioneer anatomists and more recent ﬁndings from Bauman, M.L., Kemper, T.L., 2005. Neuroanatomic observations of the brain in

autism: a review and future directions. Int. J. Dev. Neurosci. 23, 183–187.

functional imaging and tractography. In the revised circuit we iden-

Bechterew, W., 1900. Demonstration eines gehirns mit Zestörung der vor- deren

tify three distinct but partially overlapping networks.

und inneren Theile der Hirnrinde beider Schläfenlappen. Neurol. Centralbl. 20,

The hippocampal-diencephalic and parahippocampal- 990–991.

retrosplenial network is dedicated to memory and spatial Benson, D.F., Djenderedjian, A., Miller, B.L., Pachana, N.A., Chang, L., Itti, L., Mena, I.,

1996. Neural basis of confabulation. Neurology 46, 1239–1243.

orientation and lesions to this division cause severe anterograde

Bilder, R.M., Bogerts, B., Ashtari, M., Wu, H., Alvir, J.M., Jody, D., Reiter, G., Bell, L.,

and spatial disorientation. The temporo-amygdala-orbitofrontal

Lieberman, J.A., 1995. Anterior hippocampal volume reductions predict frontal

network dedicated to the integration of visceral and emotional lobe dysfunction in ﬁrst episode schizophrenia. Schizophr. Res. 17, 47–58.

Blair, R.J., 2007. The amygdala and ventromedial prefrontal cortex in morality and

states with cognition and behaviour is often altered in patients with

psychopathy. Trends Cogn. Sci. 11, 387–392.

Klüver–Bucy syndrome, temporolimbic epilepsy, fronto-temporal

Blair, R.J., Colledge, E., Murray, L., Mitchell, D.G., 2001. A selective impairment in

dementia, autism, psychosis and psychopathy. The dorsomedial the processing of sad and fearful expressions in children with psychopathic

tendencies. J. Abnorm. Child Psychol. 29, 491–498.

default-mode network consists of a group of limbic regions whose

Blair, R.J., Mitchell, D.G., Blair, K., 2005. The Psychopath: Emotion and the Brain.

activity decreases during goal-directed tasks. Lesions to division

Blackwell, Malden, MA.

may present with emotional indifference to pain, altered olfaction, Boddaert, N., Chabane, N., Gervais, H., Good, C.D., Bourgeois, M., Plumet, M.H.,

Barthelemy, C., Mouren, M.C., Artiges, E., Samson, Y., Brunelle, F., Frackowiak,

impaired ability to express emotions, reduced attention and

R.S., Zilbovicius, M., 2004. Superior temporal sulcus anatomical abnormalities

motivation.

in childhood autism: a voxel-based morphometry MRI study. Neuroimage 23,

The model proposed could help clinicians that use neuroimag- 364–369.

Borroni, B., Brambati, S.M., Agosti, C., Gipponi, S., Bellelli, G., Gasparotti, R., Garibotto,

ing to identify pathological changes occurring to different regions of

V., Di Luca, M., Scifo, P., Perani, D., Padovani, A., 2007. Evidence of white matter

the networks and their correlation with symptoms. Future studies

changes on diffusion tensor imaging in frontotemporal dementia. Arch. Neurol.

should aim at testing this revised model in a wide range of neuro- 64, 246–251.

logical and psychiatric disorders at a very early stage and identify Bouras, C., Kovari, E., Hof, P.R., Riederer, B.M., Giannakopoulos, P., 2001. Anterior

cingulate cortex pathology in schizophrenia and bipolar disorder. Acta Neu-

anatomical inter-individual variability that could help to develop

ropathol. 102, 373–379.

novel therapeutic approaches that modulate individual networks.

Broca, P., 1878. Anatomie comparée des circonvolutions cérébrales: le grand lobe

limbique. Rev. Anthropol. 1, 385–498.

Brown, S., Schäfer, E.A., 1888. An investigation into the functions of the occipi-

Acknowledgment tal and temporal lobes of the monkey’s brain. Philos. Trans. R. Soc. Lond. B,

303–327.

Broyd, S.J., Demanuele, C., Debener, S., Helps, S.K., James, C.J., Sonuga-Barke, E.J.S.,

We thank the Natbrainlab (http://www.natbrainlab.com),

2009. Default-mode brain dysfunction in mental disorders: a systematic review.

Emilio Verche, Guy’s and St. Thomas’ Charity and the French Agence Neurosci. Biobehav. Rev. 33, 279–296.

M. Catani et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1724–1737 1735

Bruno, S.D., Barker, G.J., Cercignani, M., Symms, M., Ron, M.A., 2004. A study of bipolar Drevets, W.C., Price, J.L., Simpson Jr., J.R., Todd, R.D., Reich, T., Vannier, M., Raichle,

disorder using magnetization transfer imaging and voxel-based morphometry. M.E., 1997. Subgenual prefrontal cortex abnormalities in mood disorders. Nature

Brain 127, 2433–2440. 386, 824–827.

Buckner, R.L., Andrews-Hanna, J.R., Schacter, D.L., 2008. The brain’s default network: Ellison-Wright, I., Bullmore, E., 2009. Meta-analysis of diffusion tensor imaging stud-

anatomy, function, and relevance to disease. Ann. N.Y. Acad. Sci. 1124, 1–38. ies in schizophrenia. Schizophr. Res. 108, 3–10.

Buckner, R.L., Snyder, A.Z., Shannon, B.J., LaRossa, G., Sachs, R., Fotenos, A.F., She- Eluvathingal, T.J., Hasan, K.M., Kramer, L.A., Fletcher, J.M., Ewing-Cobbs, L., 2007.

line, Y.I., Klunk, W.E., Mathis, C.A., Morris, J.C., Mintun, M.A., 2005. Molecular, Quantitative diffusion tensor tractography of association and projection ﬁbers

structural, and functional characterization of Alzheimer’s disease: evidence for in normally developing children and adolescents. Cereb. Cortex 17, 2760–2768.

a relationship between default activity, amyloid, and memory. J. Neurosci. 25, Englund, E., Sjobeck, M., Brockstedt, S., Latt, J., Larsson, E.M., 2004. Diffusion tensor

7709–7717. MRI post mortem demonstrated cerebral white matter pathology. J. Neurol. 251,

Budhani, S., Blair, R.J., 2005. Response reversal and children with psychopathic ten- 350–352.

dencies: success is a function of salience of contingency change. J. Child Psychol. Flugel, D., Cercignani, M., Symms, M.R., O’Toole, A., Thompson, P.J., Koepp, M.J.,

Psychiatry 46, 972–981. Foong, J., 2006. Diffusion tensor imaging ﬁndings and their correlation with neu-

Budhani, S., Richell, R.A., Blair, R.J., 2006. Impaired reversal but intact acquisition: ropsychological deﬁcits in patients with temporal lobe epilepsy and interictal

probabilistic response reversal deﬁcits in adult individuals with psychopathy. J. psychosis. Epilepsia 47, 941–944.

Abnorm. Psychol. 115, 552–558. Forkel, S.J., Thiebaut de Schotten, M., Kawadler, J.M., Dell’acqua, F., Danek,

Cannon, W.B., 1927. The James-Lange theory of emotion: a critical examination and A., Catani, M., 2012. The anatomy of fronto-occipital connections

an alternate theory. Am. J. Psychol. 39, 106–124. from early blunt dissections to contemporary tractography. Cortex,

Catani, M., Craig, M.C., Forkel, S.J., Kanaan, R., Picchioni, M., Toulopoulou, T., Shergill, http://dx.doi.org/10.1016/j.cortex.2012.09.005 (in press).

S., Williams, S., Murphy, D.G., McGuire, P., 2011. Altered integrity of perisylvian Fujiwara, H., Hirao, K., Namiki, C., Yamada, M., Shimizu, M., Fukuyama, H., Hayashi, T.,

language pathways in schizophrenia: relationship to auditory hallucinations. Murai, T., 2007. Anterior cingulate pathology and social cognition in schizophre-

Biol. Psychiatry 70, 1143–1150. nia: a study of gray matter, white matter and sulcal morphometry. Neuroimage

Catani, M., Dell’Acqua, F., Vergani, F., Malik, F., Hodge, H., Roy, P., Valabregue, R., 36, 1236–1245.

Thiebaut de Schotten, M., 2012a. Short frontal lobe connections of the human Gaffan, D., Wilson, C.R., 2008. Medial temporal and prefrontal function: recent

brain. Cortex 48, 273–291. behavioural disconnection studies in the macaque monkey. Cortex 44, 928–935.

Catani, M., Dell’acqua, F., Bizzi, A., Forkel, S.J., Williams, S.C., Simmons, A., Murphy, Gong, G., Jiang, T., Zhu, C., Zang, Y., Wang, F., Xie, S., Xiao, J., Guo, X., 2005. Asymme-

D.G., Thiebaut de Schotten, M., 2012b. Beyond cortical localization in clinico- try analysis of cingulum based on scale-invariant parameterization by diffusion

anatomical correlation. Cortex 48, 1262–1287. tensor imaging. Hum. Brain Mapp. 24, 92–98.

Catani, M., Thiebaut de Schotten, M., Slater, D., Dell’acqua, F., 2013a. Hare, R.D., Cooke, D.J., Hart, R.D., 1999. Psychopathy and sadistic personality

Connectomic approaches before the connectome. Neuroimage, disorder. In: Millon, T., Blaney, P.H., Davies, R.D. (Eds.), Oxford Textbook of

http://dx.doi.org/10.1016/j.neuroimage.2013.05.109 (in press). Psychopathology. Oxford University Press, Oxford, pp. 555–584.

Catani, M., Mesulam, M.M., Jakobsen, E., Malik, F., Matersteck, A., Wieneke, C., Harlow, J.M., 1848. Passage of an iron rod through the head. Boston Med. Surg. J. 39,

Thompson, C.K., Thiebaut de Schotten, M., Dell’acqua, F., Weintraub, S., Rogalski, 389–393.

E., 2013b. A novel frontal pathway underlies verbal ﬂuency in primary progres- Harrison, B.J., Soriano-Mas, C., Pujol, J., Ortiz, H., Lopez-Sola, M., Hernandez-Ribas,

sive aphasia. Brain, http://dx.doi.org/10.1093/brain/awt163 (in press). R., Deus, J., Alonso, P., Yucel, M., Pantelis, C., Menchon, J.M., Cardoner, N., 2009.

Concha, L., Beaulieu, C., Gross, D.W., 2005. Bilateral limbic diffusion abnormalities Altered corticostriatal functional connectivity in obsessive–compulsive disor-

in unilateral temporal lobe epilepsy. Ann. Neurol. 57, 188–196. der. Arch. Gen. Psychiatry 66, 1189–1200.

Concha, L., Livy, D.J., Beaulieu, C., Wheatley, B.M., Gross, D.W., 2010. In vivo diffu- Hart, S.D., Hare, R.D., 1997. Psychopathy: assessment and association with criminal

sion tensor imaging and histopathology of the ﬁmbria-fornix in temporal lobe conduct. In: Stoff, D.M., Breiling, J. (Eds.), Handbook of Antisocial Behaviour. John

epilepsy. J. Neurosci. 30, 996–1002. Wiley & Sons, New York.

Courchesne, E., Pierce, K., 2005. Why the frontal cortex in autism might be talk- Hayman, L.A., Rexer, J.L., Pavol, M.A., Strite, D., Meyers, C.A., 1998. Klüver–Bucy syn-

ing only to itself: local over-connectivity but long-distance disconnection. Curr. drome after bilateral selective damage of amygdala and its cortical connections.

Opin. Neurobiol. 15, 225–230. J. Neuropsychiatry Clin. Neurosci. 10, 354–358.

Craig, M.C., Catani, M., Deeley, Q., Latham, R., Daly, E., Kanaan, R., Picchioni, M., Haznedar, M.M., Roversi, F., Pallanti, S., Baldini-Rossi, N., Schnur, D.B., Licalzi, E.M.,

McGuire, P.K., Fahy, T., Murphy, D.G., 2009. Altered connections on the road Tang, C., Hof, P.R., Hollander, E., Buchsbaum, M.S., 2005. Fronto-thalamo-striatal

to psychopathy. Mol. Psychiatry 14, 946–953, 907. gray and white matter volumes and anisotropy of their connections in bipolar

Crosby, E.C., Humphrey, T., Lauer, E.W., 1962. Correlative Anatomy of the Nervous spectrum illnesses. Biol. Psychiatry 57, 733–742.

System. Macmillian Co., New York. Hebert, L.E., Scherr, P.A., Bienias, J.L., Bennett, D.A., Evans, D.A., 2003. Alzheimer

Cullen, K.R., Klimes-Dougan, B., Muetzel, R., Mueller, B.A., Camchong, J., Houri, A., disease in the US population: prevalence estimates using the 2000 census. Arch.

Kurma, S., Lim, K.O., 2010. Altered white matter microstructure in adolescents Neurol. 60, 1119–1122.

with major depression: a preliminary study. J. Am. Acad. Child Adolesc. Psychi- Herbert, M.R., Ziegler, D.A., Deutsch, C.K., O’Brien, L.M., Lange, N., Bakardjiev, A.,

atry 49, 173–183, e171. Hodgson, J., Adrien, K.T., Steele, S., Makris, N., Kennedy, D., Harris, G.J., Caviness

Dalla Barba, G., La Corte, V., 2013. The hippocampus, a time machine that makes Jr., V.S., 2003. Dissociations of cerebral cortex, subcortical and cerebral white

errors. Trends Cogn. Sci. 17, 102–104. matter volumes in autistic boys. Brain 126, 1182–1192.

Damasio, A.R., 2000. A neural basis for sociopathy. Arch. Gen. Psychiatry 57, 128–129. Herbert, M.R., Ziegler, D.A., Makris, N., Filipek, P.A., Kemper, T.L., Normandin, J.J.,

Damasio, A.R., Maurer, R.G., 1978. A neurological model for childhood autism. Arch. Sanders, H.A., Kennedy, D.N., Caviness Jr., V.S., 2004. Localization of white matter

Neurol. 35, 777–786. volume increase in autism and developmental language disorder. Ann. Neurol.

Damasio, H., Grabowski, T., Frank, R., Galaburda, A.M., Damasio, A.R., 1994. The return 55, 530–540.

of Phineas Gage: clues about the brain from the skull of a famous patient. Science Highley, J.R., Walker, M.A., Esiri, M.M., Crow, T.J., Harrison, P.J., 2002. Asymmetry of

264, 1102–1105. the uncinate fasciculus: a post-mortem study of normal subjects and patients

Dauguet, J., Peled, S., Berezovskii, V., Delzescaux, T., 2007. Comparison of ﬁber tracts with schizophrenia. Cereb. Cortex 12, 1218–1224.

derived from in-vivo DTI tractography with 3D histological neural tract tracer Honea, R., Crow, T.J., Passingham, D., Mackay, C.E., 2005. Regional deﬁcits in brain

reconstruction on a macaque brain. Neuroimage 37, 530–538. volume in schizophrenia: a meta-analysis of voxel-based morphometry studies.

Davis, K.L., Stewart, D.G., Friedman, J.I., Buchsbaum, M., Harvey, P.D., Hof, P.R., Am. J. Psychiatry 162, 2233–2234.

Buxbaum, J., Haroutunian, V., 2003. White matter changes in schizophrenia: Houenou, J., Wessa, M., Douaud, G., Leboyer, M., Chanraud, S., Perrin, M., Poupon,

evidence for myelin-related dysfunction. Arch. Gen. Psychiatry 60, 443–456. C., Martinot, J.L., Paillere-Martinot, M.L., 2007. Increased white matter connec-

Deeley, Q., Daly, E., Surguladze, S., Tunstall, N., Mezey, G., Beer, D., Ambikapathy, tivity in euthymic bipolar patients: diffusion tensor tractography between the

A., Robertson, D., Giampietro, V., Brammer, M.J., Clarke, A., Dowsett, J., Fahy, subgenual cingulate and the amygdalo-hippocampal complex. Mol. Psychiatry

T., Phillips, M.L., Murphy, D.G., 2006. Facial emotion processing in criminal 12, 1001–1010.

psychopathy. Preliminary functional magnetic resonance imaging study. Br. J. Jakob, C., 1906. Nueva contribución á la ﬁsio-patología de los lóbulos frontales. La

Psychiatry 189, 533–539. Semana Médica 13, 1325–1329.

Dejerine, J., 1895. Anatomie des Centres Nerveux. Rueff et Cie, Paris. Jones, D.K., 2008. Studying connections in the living human brain with diffusion MRI.

Delisi, M., Umphress, Z.R., Vaughn, M.G., 2009. The criminology of the amygdala. Cortex 44, 936–952.

Crim. Justice Behav. 36, 1241–1252. Jones, D.K., Catani, M., Pierpaoli, C., Reeves, S.J., Shergill, S.S., O’Sullivan, M.,

Dell’Acqua, F., Catani, M., 2012. Structural human brain networks: hot topics in Golesworthy, P., McGuire, P., Horsﬁeld, M.A., Simmons, A., Williams, S.C.,

diffusion tractography. Curr. Opin. Neurol. 25, 375–383. Howard, R.J., 2006. Age effects on diffusion tensor magnetic resonance imag-

Dell’Acqua, F., Scifo, P., Rizzo, G., Catani, M., Simmons, A., Scotti, G., Fazio, F., 2010. ing tractography measures of frontal cortex connections in schizophrenia. Hum.

A modiﬁed damped Richardson-Lucy algorithm to reduce isotropic background Brain Mapp. 27, 230–238.

effects in spherical deconvolution. Neuroimage 49, 1446–1458. Kanaan, R., Borgwardt, S., McGuire, P., Craig, M., Murphy, D.G.M., Picchioni, M.,

Dell’Acqua, F., Simmons, A., Williams, S.C.R., Catani, M., 2012. Can spherical deconvo- Shergill, S.S., Jones, D.K., Catani, M., 2009. Microstructural organization of cere-

lution provide more information than ﬁber orientations? Hindrance modulated bellar tracts in schizophrenia. Biol. Psychiatry 66, 1067–1069.

orientational anisotropy, a true-tract speciﬁc index to characterize white matter Kanaan, R.A., Kim, J.S., Kaufmann, W.E., Pearlson, G.D., Barker, G.J., McGuire,

diffusion. Hum. Brain Mapp., http://dx.doi.org/10.1002/hbm.22080. P.K., 2005. Diffusion tensor imaging in schizophrenia. Biol. Psychiatry 58,

Diehl, B., Busch, R.M., Duncan, J.S., Piao, Z., Tkach, J., Luders, H.O., 2008. Abnormalities 921–929.

in diffusion tensor imaging of the uncinate fasciculus relate to reduced memory Kessler, R.C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K.R., Rush, A.J.,

in temporal lobe epilepsy. Epilepsia 49, 1409–1418. Walters, E.E., Wang, P.S., 2003. The epidemiology of major depressive disorder:

1736 M. Catani et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1724–1737

results from the National Comorbidity Survey Replication (NCS-R). J. Am. Med. Mitchell, W., Falconer, M.A., Hill, D., 1954. Epilepsy with fetishism relieved by tem-

Assoc. 289, 3095–3105. poral lobectomy. Lancet 267, 626–630.

Kessler, R.C., Chiu, W.T., Demler, O., Merikangas, K.R., Walters, E.E., 2005. Preva- Moseley, M.E., Cohen, Y., Kucharczyk, J., Mintorovitch, J., Asgari, H.S., Wendland, M.F.,

lence, severity, and comorbidity of 12-month DSM-IV disorders in the National Tsuruda, J., Norman, D., 1990. Diffusion-weighted MR imaging of anisotropic

Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 617–627. water diffusion in cat central nervous system. Radiology 176, 439–445.

Kiehl, K.A., Smith, A.M., Hare, R.D., Mendrek, A., Forster, B.B., Brink, J., Liddle, P.F., Mottaghy, F.M., Keller, C.E., Gangitano, M., Ly, J., Thall, M., Parker, J.A., Pascual-Leone,

2001. Limbic abnormalities in affective processing by criminal psychopaths A., 2002. Correlation of cerebral blood ﬂow and treatment effects of repetitive

as revealed by functional magnetic resonance imaging. Biol. Psychiatry 50, transcranial magnetic stimulation in depressed patients. Psychiatry Res. 115,

677–684. 1–14.

Klingler, J., Gloor, P., 1960. The connections of the amygdala and the anterior tem- Nauta, W.J., 1958. Hippocampal projections and related neural pathways to the

poral cortex in the human brain. J. Comp. Neurol. 115, 333–369. midbrain in the cat. Brain 81, 319–340.

Klüver, H., Bucy, P.C., 1939. Preliminary analysis of functions of the temporal lobes Nestor, P.J., Graham, N.L., Fryer, T.D., Williams, G.B., Patterson, K., Hodges, J.R., 2003.

in monkeys. Arch. Neurol. Psychiatry 42, 979–1000. Progressive non-ﬂuent aphasia is associated with hypometabolism centred on

Kubicki, M., Westin, C.F., Maier, S.E., Frumin, M., Nestor, P.G., Salisbury, D.F., Kikinis, the left anterior insula. Brain 126, 2406–2418.

R., Jolesz, F.A., McCarley, R.W., Shenton, M.E., 2002. Uncinate fasciculus ﬁndings Nieuwenhuys, R., Voogd, J., van Huijzen, C., 2008. The Human Central Nervous Sys-

in schizophrenia: a magnetic resonance diffusion tensor imaging study. Am. J. tem. Springer, Berlin; New York.

Psychiatry 159, 813–820. Nobler, M.S., Oquendo, M.A., Kegeles, L.S., Malone, K.M., Campbell, C.C., Sackeim,

Kuroki, N., Kubicki, M., Nestor, P.G., Salisbury, D.F., Park, H.J., Levitt, J.J., Woolston, H.A., Mann, J.J., 2001. Decreased regional brain metabolism after ECT. Am. J.

S., Frumin, M., Niznikiewicz, M., Westin, C.F., Maier, S.E., McCarley, R.W., Shen- Psychiatry 158, 305–308.

ton, M.E., 2006. Fornix integrity and hippocampal volume in male schizophrenic Ongur, D., Drevets, W.C., Price, J.L., 1998. Glial reduction in the subgenual prefrontal

patients. Biol. Psychiatry 60, 22–31. cortex in mood disorders. Proc. Natl. Acad. Sci. U.S.A. 95, 13290–13295.

Kwon, H., Ow, A.W., Pedatella, K.E., Lotspeich, L.J., Reiss, A.L., 2004. Voxel-based Ozonoff, S., Pennington, B.F., Rogers, S.J., 1991. Executive function deﬁcits in high-

morphometry elucidates structural neuroanatomy of high-functioning autism functioning autistic individuals: relationship to theory of mind. J. Child Psychol.

and Asperger syndrome. Dev. Med. Child Neurol. 46, 760–764. Psychiatry 32, 1081–1105.

Lawes, I.N.C., Barrick, T.R., Murugam, V., Spierings, N., Evans, D.R., Song, M., Clark, Palmen, S.J., van Engeland, H., Hof, P.R., Schmitz, C., 2004. Neuropathological ﬁndings

C.A., 2008. Atlas-based segmentation of white matter tracts of the human brain in autism. Brain 127, 2572–2583.

using diffusion tensor tractography and comparison with classical dissection. Papez, J.W., 1937. A proposed mechanism of emotion. Arch. Neurol. Psychiatry 38,

Neuroimage 39, 62–79. 725–743.

Le Bihan, D., Breton, E., 1985. Imagerie de diffusion in-vivo par résonance magné- Park, H.J., Westin, C.F., Kubicki, M., Maier, S.E., Niznikiewicz, M., Baer, A., Frumin,

tique nucléaire. In: Comptes rendus de l’Académie des sciences, pp. 1109–1112. M., Kikinis, R., Jolesz, F.A., McCarley, R.W., Shenton, M.E., 2004. White matter

Lee, J.E., Bigler, E.D., Alexander, A.L., Lazar, M., DuBray, M.B., Chung, M.K., Johnson, hemisphere asymmetries in healthy subjects and in schizophrenia: a diffusion

M., Morgan, J., Miller, J.N., McMahon, W.M., Lu, J., Jeong, E.K., Lainhart, J.E., 2007. tensor MRI study. Neuroimage 23, 213–223.

Diffusion tensor imaging of white matter in the superior temporal gyrus and Patrick, C.J., Bradley, M.M., Lang, P.J., 1993. Emotion in the criminal psychopath:

temporal stem in autism. Neurosci. Lett. 424, 127–132. startle reﬂex modulation. J. Abnorm. Psychol. 102, 82–92.

Lee, J.E., Chung, M.K., Lazar, M., DuBray, M.B., Kim, J., Bigler, E.D., Lain- Persson, J., Lind, J., Larsson, A., Ingvar, M., Cruts, M., Van Broeckhoven, C., Adolfsson,

hart, J.E., Alexander, A.L., 2009. A study of diffusion tensor imaging by R., Nilsson, L.G., Nyberg, L., 2006. Altered brain white matter integrity in healthy

tissue-speciﬁc, smoothing-compensated voxel-based analysis. Neuroimage 44, carriers of the APOE epsilon4 allele: a risk for AD? Neurology 66, 1029–1033.

870–883. Powell, H.W.R., Parker, G.J.M., Alexander, D.C., Symms, M.R., Boulby, P.A., Barker,

Levenston, G.K., Patrick, C.J., Bradley, M.M., Lang, P.J., 2000. The psychopath as G.J., Thompson, P.J., Koepp, M.J., Duncan, J.S., 2008. Imaging language path-

observer: emotion and attention in picture processing. J. Abnorm. Psychol. 109, ways predicts postoperative naming deﬁcits. J. Neurol. Neurosurg. Psychiatry

373–385. 79, 327–330.

Lipsman, N., Neimat, J.S., Lozano, A.M., 2007. Deep brain stimulation for treatment- Pugliese, L., Catani, M., Ameis, S., Dell’Acqua, F., Thiebaut de Schotten, M., Murphy, C.,

refractory obsessive–compulsive disorder: the search for a valid target. Robertson, D., Deeley, Q., Daly, E., Murphy, D.G., 2009. The anatomy of extended

Neurosurgery 61, 1–11, discussion 11–13. limbic pathways in Asperger syndrome: a preliminary diffusion tensor imaging

MacLean, P.D., 1949. Psychosomatic disease and the ‘visceral brain’: recent develop- tractography study. Neuroimage 47, 427–434.

ments bearing on the Papez theory of emotion. Psychosom. Med. 11, 338–353. Radua, J., Mataix-Cols, D., 2009. Voxel-wise meta-analysis of grey matter changes in

MacLean, P.D., 1952. Some psychiatric implications of physiological studies on fron- obsessive–compulsive disorder. Br. J. Psychiatry 195, 393–402.

totemporal portion of limbic system (visceral brain). Electroencephalogr. Clin. Raichle, M.E., MacLeod, A.M., Snyder, A.Z., Powers, W.J., Gusnard, D.A., Shulman, G.L.,

Neurophysiol. 4, 407–418. 2001. A default mode of brain function. Proc. Natl. Acad. Sci. U.S.A. 98, 676–682.

Markowitsch, H., 2000. Memory and amnesia. In: Mesulam, M. (Ed.), Principles of Raichle, M.E., Snyder, A.Z., 2007. A default mode of brain function: a brief history of

Behavioural and Cognitive Neurology. , 2nd ed. Oxford University Press, New an evolving idea. Neuroimage 37, 1083–1090, discussion 1097–1099.

York. Raine, A., Buchsbaum, M., LaCasse, L., 1997. Brain abnormalities in murderers indi-

Markowitsch, H.J., von Cramon, D.Y., Schuri, U., 1993. Mnestic performance proﬁle cated by positron emission tomography. Biol. Psychiatry 42, 495–508.

of a bilateral diencephalic infarct patient with preserved intelligence and severe Raine, A., Lencz, T., Bihrle, S., LaCasse, L., Colletti, P., 2000. Reduced prefrontal gray

amnesic disturbances. J. Clin. Exp. Neuropsychol. 15, 627–652. matter volume and reduced autonomic activity in antisocial personality disor-

Marshall, L.H., Magoun, H.W., 1998. Discoveries in the Human Brain. Humana Press, der. Arch. Gen. Psychiatry 57, 119–127, discussion 128–129.

New Jersey. Rajkowska, G., Halaris, A., Selemon, L.D., 2001. Reductions in neuronal and glial

Maruyama, K., Itomi, S., Sofue, A., Natsume, J., 2009. Acute encephali- density characterize the dorsolateral prefrontal cortex in bipolar disorder. Biol.

tis/encephalopathy associated with transient involuntary movement and limbic Psychiatry 49, 741–752.

dysfunction in the recovery phase. No To Hattatsu 41, 33–36. Rauch, S.L., Kim, H., Makris, N., Cosgrove, G.R., Cassem, E.H., Savage, C.R., Price, B.H.,

Mayberg, H.S., Brannan, S.K., Tekell, J.L., Silva, J.A., Mahurin, R.K., McGinnis, S., Jer- Nierenberg, A.A., Shera, D., Baer, L., Buchbinder, B., Caviness Jr., V.S., Jenike,

abek, P.A., 2000. Regional metabolic effects of ﬂuoxetine in major depression: M.A., Kennedy, D.N., 2000. Volume reduction in the caudate nucleus following

serial changes and relationship to clinical response. Biol. Psychiatry 48, 830–843. stereotactic placement of lesions in the anterior cingulate cortex in humans: a

Mayberg, H.S., Lozano, A.M., Voon, V., McNeely, H.E., Seminowicz, D., Hamani, morphometric magnetic resonance imaging study. J. Neurosurg. 93, 1019–1025.

C., Schwalb, J.M., Kennedy, S.H., 2005. Deep brain stimulation for treatment- Raymond, G.V., Bauman, M.L., Kemper, T.L., 1996. Hippocampus in autism: a Golgi

resistant depression. Neuron 45, 651–660. analysis. Acta Neuropathol. 91, 117–119.

McAlonan, G.M., Cheung, V., Cheung, C., Suckling, J., Lam, G.Y., Tai, K.S., Yip, L., Salmond, C.H., Ashburner, J., Connelly, A., Friston, K.J., Gadian, D.G., Vargha-Khadem,

Murphy, D.G., Chua, S.E., 2005. Mapping the brain in autism. A voxel-based F., 2005. The role of the medial temporal lobe in autistic spectrum disorders. Eur.

MRI study of volumetric differences and intercorrelations in autism. Brain 128, J. Neurosci. 22, 764–772.

268–276. Scahill, R.I., Schott, J.M., Stevens, J.M., Rossor, M.N., Fox, N.C., 2002. Mapping the

McIntosh, A.M., Munoz Maniega, S., Lymer, G.K., McKirdy, J., Hall, J., Sussmann, J.E., evolution of regional atrophy in Alzheimer’s disease: unbiased analysis of ﬂuid-

Bastin, M.E., Clayden, J.D., Johnstone, E.C., Lawrie, S.M., 2008. White matter trac- registered serial MRI. Proc. Natl. Acad. Sci. U.S.A. 99, 4703–4707.

tography in bipolar disorder and schizophrenia. Biol. Psychiatry 64, 1088–1092. Schneider, A., 2008. The Confabulating Mind: How the Brain Creates Reality. Oxford

McNab, J.A., Voets, N.L., Jenkinson, N., Squier, W., Miller, K.L., Goodwin, G.M., Aziz, University Press, Oxford.

T.Z., 2009. Reduced limbic connections may contraindicate subgenual cingulate Scoville, W., Milner, B., 1957. Loss of recent memory after bilateral hippocampal

deep brain stimulation for intractable depression. J. Neurosurg. 111, 780–784. lesions. J. Neurol. Neurosurg. Psychiatry 20, 11–21.

Mega, M.S., Cummings, J.L., Salloway, S., Malloy, P., 1997. The limbic system: an Shulman, G., Fiez, J., Corbetta, M., Buckner, R., Miezin, F., Raichle, M., Petersen, S.,

anatomic, phylogenetic, and clinical perspective. J. Neuropsychiatry Clin. Neu- 1997. Common blood ﬂow changes across visual tasks. 2. Decreases in cerebral

rosci. 9, 315–330. cortex. J. Cogn. Neurosci. 9, 648–663.

Mesulam, M., 2000. Behavioural neuroanatomy: large-scale networks, association Song, S.-K., Kim, J.H., Lin, S.-J., Brendza, R.P., Holtzman, D.M., 2004. Diffusion tensor

cortex, frontal syndromes, the limbic system, and the hemispheric specializa- imaging detects age-dependent white matter changes in a transgenic mouse

tions. In: Mesulam, M. (Ed.), Principles of Behavioural and Cognitive Neurology. model with amyloid deposition. Neurobiol. Dis. 15, 640–647.

, pp. 1–120. Takei, K., Yamasue, H., Abe, O., Yamada, H., Inoue, H., Suga, M., Sekita, K., Sasaki, H.,

Minoshima, S., Giordani, B., Berent, S., Frey, K.A., Foster, N.L., Kuhl, D.E., 1997. Rogers, M., Aoki, S., Kasai, K., 2008. Disrupted integrity of the fornix is associ-

Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s ated with impaired memory organization in schizophrenia. Schizophr. Res. 103,

disease. Ann. Neurol. 42, 85–94. 52–61.

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

Terzian, H., Ore, G.D., 1955. Syndrome of Klüver and Bucy; reproduced in man by von Cramon, D.Y., Hebel, N., Schuri, U., 1985. A contribution to the anatomical basis

bilateral removal of the temporal lobes. Neurology 5, 373–380. of thalamic amnesia. Brain 108 (Pt 4), 993–1008.

Thiebaut de Schotten, M., Dell’Acqua, F., Forkel, S.J., Simmons, A., Vergani, F., Murphy, Wakana, S., Caprihan, A., Panzenboeck, M.M., Fallon, J.H., Perry, M., Gollub, R.L.,

D.G.M., Catani, M., 2011a. A lateralized brain network for visuospatial attention. Hua, K., Zhang, J., Jiang, H., Dubey, P., Blitz, A., van Zijl, P.C., Mori, S., 2007.

Nat. Neurosci. 14, 1245–1246. Reproducibility of quantitative tractography methods applied to cerebral white

Thiebaut de Schotten, M., Dell’Acqua, F., Valabregue, R., Catani, M., 2012. Monkey to matter. Neuroimage 36, 630–644.

human comparative anatomy of the frontal lobe association tracts. Cortex 48, Waxman, S.G., Geschwind, N., 1974. Hypergraphia in temporal lobe epilepsy. Neu-

82–96. rology 24, 629–636.

Thiebaut de Schotten, M., Ffytche, D.H., Bizzi, A., Dell’Acqua, F., Allin, M., Walshe, Webster, M.J., O’Grady, J., Kleinman, J.E., Weickert, C.S., 2005. Glial ﬁbrillary acidic

M., Murray, R., Williams, S.C., Murphy, D.G., Catani, M., 2011b. Atlasing location, protein mRNA levels in the cingulate cortex of individuals with depression,

asymmetry and inter-subject variability of white matter tracts in the human bipolar disorder and schizophrenia. Neuroscience 133, 453–461.

brain with MR diffusion tractography. Neuroimage 54, 49–59. Wickelgren, I., 2005. Neurology. Autistic brains out of synch? Science 308,

Tiihonen, J., Hodgins, S., Vaurio, O., 2000. Amygdaloid volume loss in psychopathy. 1856–1858.

Soc. Neurosci. Abstr., 2017. Willis, T., 1664. Cerebri Anatome. Martyn & Allestry, London.

Valenstein, E., Bowers, D., Verfaellie, M., Heilman, K.M., Day, A., Watson, R.T., 1987. Xie, S., Xiao, J.X., Wang, Y.H., Wu, H.K., Gong, G.L., Jiang, X.X., 2005. Evaluation

Retrosplenial amnesia. Brain 110 (Pt 6), 1631–1646. of bilateral cingulum with tractography in patients with Alzheimer’s disease.

van Honk, J., Schutter, D.J., 2006. From affective valence to motivational direction: Neuroreport 16, 1275–1278.

the frontal asymmetry of emotion revised. Psychol. Sci. 17, 963–965. Yakovlev, P.I., Locke, S., 1961. Limbic nuclei of thalamus and connections of lim-

Vann, S.D., Aggleton, J.P., Maguire, E.A., 2009. What does the retrosplenial cortex do? bic cortex. III. Corticocortical connections of the anterior cingulate gyrus,

Nat. Rev. Neurosci. 10, 792–802. the cingulum, and the subcallosal bundle in monkey. Arch. Neurol. 5,

Veit, R., Flor, H., Erb, M., Hermann, C., Lotze, M., Grodd, W., Birbaumer, N., 2002. Brain 364–400.

circuits involved in emotional learning in antisocial behavior and social phobia Yakovlev, P.J., 1948. Motility, behavior and the brain; stereodynamic organization

in humans. Neurosci. Lett. 328, 233–236. and neural coordinates of behavior. J. Nerv. Ment. Dis. 107, 313–335.

Versace, A., Almeida, J.R., Hassel, S., Walsh, N.D., Novelli, M., Klein, C.R., Kupfer, D.J., Zappala, G., Thiebaut de Schotten, M., Eslinger, P.J., 2012. Traumatic brain injury and

Phillips, M.L., 2008. Elevated left and reduced right orbitomedial prefrontal frac- the frontal lobes: what can we gain with diffusion tensor imaging? Cortex 48,

tional anisotropy in adults with bipolar disorder revealed by tract-based spatial 156–165.

statistics. Arch. Gen. Psychiatry 65, 1041–1052.