diffusion mri || the connectional anatomy of language

403Diffusion MRI Copyright © 2009 Elsevier Inc. All rights reserved

AbstrAct

Tractography methods based on diffusion tensor imaging can be used to re-explore the anatomical basis of language and its disorders. This chapter is devoted to a harmonization of findings from post-mortem dissection with more recent evidence emerging from DTI tractography. Attention is focused first on the anatomy of the arcuate fasciculus, its heterogeneity in the normal population, and possible functional and behavioral correlates of different patterns of lateralization. Then other tracts relevant to language, such as the inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and uncinate tract, will be discussed. One outcome of this review will be to underlie the merits of the hodological (pathway-based) approach to neurology and psychiatry and its modern pursuit with DTI tractography as applied to the connectional anatomy of language.

Keywords: Arcuate fasciculus, connections, white matter, lateralization, language, aphasia, Geschwind’s territory, diffusion tensor imaging (DTI), tractography

I. Introduction 404

II. the Anatomy of the Arcuate Fasciculus: from blunt Dissections to tractography 404

III. Lateralization of the Arcuate Fasciculus 406

IV. comparative Anatomy of Perisylvian Language Networks 407

V. beyond the Arcuate Fasciculus: the Ventral Pathway 407

VI. Application of DtI tractography to Language Disorders 408A. Normal Neurodevelopment and Autism

Spectrum Disorder 408B. Schizophrenia 408C. Stroke and Neurosurgery 409D. Neurodegenerative Disorders 410

VII. Future Directions and conclusions 410

Acknowledgments 411

references 412

o u t l I n E

C H A P t E R

18

the Connectional Anatomy of language: Recent Contributions from Diffusion

tensor tractographyMarco Catani

III. DIffusIon MRI foR In-VIVo nEuRoAnAtoMY

18. tHE ConnECtIonAl AnAtoMY of lAnGuAGE404

I. INtroDuctIoN

Language is an exceedingly complex faculty that allows us to encode, elaborate, and communicate thou-ghts and experiences through the mediation of arbi-trary symbols known as words. The coherent function of the language network and its interactions with other neurocognitive networks depend on an orderly set of interconnections. Much of current understanding of the anatomy of the language-related pathways is based on the pioneering work of 19th century neuroanatomists, such as Johann Christian Reil, Karl Burdach, Theodor Meynert, Carl Wernicke, Hugo Liepmann, and Jules Dejerine. But their work encountered a fierce opposition with the emergence of holistic approaches during the first half of the 20th century. In the 1960s, in a series of influential papers, Norman Geschwind revitalized the field and crystallized those early anatomical findings adding new insights into brain connectivity as derived from anatomical, physiological, and neuronographic studies both in animals and humans (Geschwind, 1965, 1970; Geschwind and Levitsky, 1968). The dilemma, however, that aphasiologists specifically, and behavio-ral neurologists in general, had to face stemmed princi-pally from the lack of sufficient information on human neuroanatomy. In contrast to the giant strides made in unraveling the connectivity of the monkey brain, the details of connection pathways in the human brain remained stuck in the blunt dissection methodology of the 19th century.

Recent developments in magnetic resonance imaging have introduced new methods, based on diffusion ten-sor imaging (DTI) tractography, that can reconstruct the trajectories of white matter tracts in the living human brain (Basser et al., 2000; Le Bihan, 2003). The resultant influx of information on human connectional anatomy is likely to reinvigorate models of cognition based on distributed large-scale networks and modernize the disconnection approach to language disorders in neu-rology and psychiatry (Catani and Mesulam, 2008). An overview of the recent contribution of DTI tractography to the anatomy of the arcuate fasciculus and language constitutes the subject matter of this chapter.

II. the ANAtomy oF the ArcuAte FAscIcuLus: From bLuNt

DIssectIoNs to trActogrAPhy

Johann Christian Reil was the first to identify a group of fibers running deeply into the white matter of the temporal, parietal, and frontal regions located around

the Sylvian fissure of each hemisphere (Figure 18.1) (Reil, 1809, 1812). In 1822 Karl Burdach described in detail this system of perisylivan fibers and named it the Fasciculus Arcuatus (Arcuate fasciculus), for the arch-ing shape of its longest fibers (Burdach, 1819–1826). Subsequently, Jules Dejerine confirmed the findings of the German neuroanatomists (Dejerine, 1895) but also believed that the arcuate fasciculus was mainly composed of short associative fibers connecting neigh-boring perisylvian cortex. The first to be credited with attributing a role in language to the perisylvian network was Carl Wernicke, who postulated that lan-guage relies on the integrity of a ‘‘psychic reflex arc’’ between temporal and frontal regions. But the arcu-ate fasciculus was not part of Wernicke’s original ana-tomical model as he thought that the temporal and frontal language areas were mutually interconnected by fibers passing through the external capsule and relaying in the cortex of the insula (Wernicke, 1874). It was Constatin von Monakow who first identified the arcuate fasciculus as the tract connecting Broca’s and Wernicke’s areas, a view later accepted by Wernicke himself in 1908 (Geschwind, 1967). Von Monakow’s statement soon became a dogma in neurology and still today provides the backbone of almost all anatomical models of language.

Although the existence of the arcuate fasciculus has been confirmed in several post-mortem studies in humans, these methods (e.g. blunt dissections, axonal staining of degenerating axons, etc.) have not shed much light on the detailed anatomy of the relevant fibers. More powerful methods have been used to trace homologous axonal pathways in the monkey but the absence of language in non-human primates raises doubts on the possibility of translating connectional anatomy of putative language pathways from animals to humans.

The advent of diffusion tensor imaging has opened a new era in the field and promises to revolutionize the field on two fronts. First, we can use tractography to reveal structural features unique to humans and by studying large populations we can infer the degree of anatomical heterogeneity from subject to subject. Second, tractography allows us to take a pathway- based approach to disorders of language across the lifespan. The first tractography studies applied to the language pathways showed that the anatomy of the arcuate fasciculus is more complex than previ-ously thought (Figure 18.2) (Catani et al., 2005; Parker et al., 2005). In addition to the long direct segment connecting Wernicke’s area with Broca’s territory (i.e. the arcuate fasciculus sensu strictu), there is an indirect pathway consisting of two segments, an anterior seg-ment linking Broca’s territory with the inferior parietal


405

lobule (Geschwind’s territory) and a posterior segment linking the inferior parietal lobule with Wernicke’s territory (Catani et al., 2005).

This arrangement not only supports the more flexible architecture of parallel processing (Mesulam, 1990), but

also is in keeping with some of the classical neurologi-cal models of aphasia, contemporary models of verbal working memory (Baddeley, 2003), and recent functional neuroimaging findings (Jung-Beeman, 2005; Sakai, 2005; Stephan et al., 2003). Additional support for the existence of the three perisylvian segments of the ‘‘arcuate fascic-ulus’’ comes from other DTI studies (Lawes et al., 2008; Eluvathingal et al., 2007), human intraoperative electro-corticography (Matsumoto et al., 2004), functional con-nectivity (Schmithorst and Holland, 2007), post-mortem dissections (Lawes et al., 2008), and experiments in homologous parts of the monkey brain (Deacon, 1992).

Tractography is also revealing unexpected findings about the projection of the arcuate fasciculus, whose cortical terminations extend beyond the classical limits of Wernicke’s and Broca’s areas to include part of the posterior middle temporal gyrus and middle and pre-central frontal gyrus, respectively (Catani et al., 2005). On the other hand, more anterior and ventral portions of Broca’s territory seem to be connected to posterior temporal and occipital regions through the uncinate and the inferior fronto-occipital fasciculus of the ven-tral pathway system (see below) (Anwander et al., 2007; Barrick et al., 2007). Finally tractography applied to language pathways highlights the importance of the

tHE AnAtoMY of tHE ARCuAtE fAsCICulus: fRoM Blunt DIssECtIons to tRACtoGRAPHY

Johann Christian Reil(1759–1813)

Karl Burdach(1776–1847)

Norman Geschwind(1926–1984)

Carl Wernicke(1848–1905)

Jules Dejerine(1849–1917)

Constatin von Monakow(1853–1930)

ARCUATE FASCICULUS

FIgure 18.1 Neuroanatomists that have contributed to elucidate the anatomy of the arcuate fasciculus (here visualized with tractography) and its functions in the last two centuries.

Anterior indirectsegment

BROCA’STERRITORY(frontal lobe)

Long directsegment

Posterior indirectsegment

WERNICKE’STERRITORY(temporal lobe)

GESCHWIND’STERRITORY(parietal lobe)

FIgure 18.2 The parallel pathways model of the arcuate fas-ciculus derived from tractography dissections. Numbers indicate the cortical projections of the three segments: 1, superior temporal lobe; 2, middle temporal lobe; 3, inferior frontal and precentral gyrus; 4, middle frontal and precentral gyrus; 5, supramarginal gyrus; 6, angu-lar gyrus (modified from Catani et al., 2005).



inferior parietal cortex as a separate primary language area with dense connections to classical language areas through the indirect pathway. The Geschwind’s ter-ritory corresponds to BA39 and 40, and although its importance as a language region has been recognized for some time, the exact role of this area is still largely unknown. Recent functional neuroimaging studies have shown that the Geschwind’s territory is part of an extended network activated during comprehension of global coherence of narratives (Martin-Loeches et al., 2008), processing concrete concepts (Sabsevitz et al., 2005), episodic memory retrieval of words (Vilberg and Rugg, 2008), and verbal working memory (Jacquemot and Scott, 2006). Also thanks to its anatomical position, the Geschwind’s territory is a convergence and inte-gration zone for sensory and motor information and their temporal dynamics, and is therefore well suited to play a key role in the self-awareness of speech and actions in general (Jardri et al., 2007).

III. LAterALIzAtIoN oF the ArcuAte FAscIcuLus

Hemispheric asymmetry is a key feature of the lan-guage network. Left-right differences in the anatomy of perisylvian cortex and its connections have been dem-onstrated by microscopic examination of post-mortem specimens (Galuske et al., 2000), by structural T1 MRI (Paus et al., 1999), and by DTI (Buchel et al., 2004; Catani et al., 2007; Hagmann et al., 2006; Nucifora et al., 2005;

Powell et al., 2006; Vernooij et al., 2007). Tractography analysis of the degree of lateralization of the three seg-ments (as measured by the number of streamlines as an indirect index of segment volume) showed an extreme degree of leftward lateralization for the direct long seg-ment in 60% of the normal population (Figure 18.3) (Catani et al., 2007). The remaining 40% of the popula-tion shows either a mild leftward lateralization (20%) or a bilateral, symmetrical pattern (20%). Similar results are reported for younger groups of children and adolescents (aged 6–17 years) (Eluvathingal et al., 2007). The degree of lateralization of the direct long segment in left-handed males is less clear, as it has been reported to be similar to right-handed subjects (Vernooij et al., 2007) or more bilateral (Hagmann et al., 2006). Of par-ticular interest is the report of a sexual dimorphism with regard to the lateralization of the direct long seg-ment, with females more likely to have a bilateral pat-tern compared to males (Figure 18.3b–c) (Catani et al., 2007; Hagmann et al., 2006).

An important question is the extent to which struc-tural differences between the two hemispheres correlate with functional lateralization, and whether the anatom-ical lateralization of language pathways reflects differ-ences in language performance. Preliminary studies combining DTI tractography and fMRI show no corre-lation between the lateralization of the arcuate fascicu-lus volume and the degree of functional lateralization as determined by fMRI during tasks of verbal fluency, verb generation, and reading comprehension (Powell et al., 2006; Vernooij et al., 2007). The lateralization of the fractional anisotropy (a possible index of microstructural

Group1 extreme leftlateralization (∼60%)

Group2 mild leftlateralization (∼20%)

Group3 bilateral,symmetrical (∼20%)

Group1(40%)

Group2 (30%)

Group3(30%)

Group2 (10%)Group1(85%)

Group3(5%)

Females Males

(a)

(b) (c)

80

70

60

1 2Groups

3

50

CV

LT (

tota

l wor

ds r

ecal

led)

FIgure 18.3 Left, distribution of the pattern of lateralization of the long segment in the normal population (a) and between genders (b, c). Right, correlation between the pattern of lateralization of the long segment and CVLT performance (*p , 0.01; †p , 0.001) (from Catani et al., 2007).


407

architecture of fibers) of the arcuate fasciculus seems to correlate better with the functional lateralization as demonstrated in healthy individuals (Powell et al., 2006) and in patients with temporal lobe epilepsy (Rodrigo et al., 2008).

There are also preliminary findings showing that a bilateral pattern of lateralization of the direct long seg-ment is associated with better performance on a complex verbal memory task that relies on semantic clustering for retrieval (i.e. California Verbal Learning Test, CVLT). The correlation remained significant after splitting the group according to gender, suggesting that the main determi-nant of CVLT performance is the anatomy (symmetry) of the language pathways, not the gender. Overall these findings support the notion that lateralization of lan-guage to the left hemisphere is an important aspect of human brain organization but paradoxically a bilateral representation might ultimately be advantageous for certain cognitive functions (Catani et al., 2007).

Other components of the perisylvian networks seem to have a more bilateral distribution or rightward later-alization. Inter-hemispheric differences have been found in the fractional anisotropy of the anterior indirect seg-ment with higher values in the right side (Catani et al., 2007; Eluvathingal et al., 2007). Another tract connect-ing the superior temporal lobe to the superior parietal lobe shows a similar rightward lateralization (Barrick et al., 2007). This may be related to the specialization of the right parietal and frontal cortex for visuo-spatial processing (Doricchi et al., 2008; Thiebaut de Schotten et al., 2008).

In conclusion, the above preliminary studies suggest an overall prevalence of leftward asymmetry (Group 1 and 2 in Figure 18.3) for the arcuate fasciculus of around 80%. Considering that the prevalence of left functional ‘‘dominance’’ for language is 90%, asym-metry of the long direct segment may represent a more critical anatomical substrate for language lateralization than planum temporale asymmetry, whose leftward lateralization is found only in around 65% of the right-handed population (Geschwind and Levitsky, 1968).

IV. comPArAtIVe ANAtomy oF PerIsyLVIAN LANguAge

Networks

Differences in neuronal connectivity of animal brains account for most of the behavioral differences between species (Striedter, 2005). Hence, by comparing human and simian connectional anatomy we may unveil the architectural backbone of human cognition and identify, for example, the evolutionary changes underlying the

development of language. One theory of the evolution of language from monkey to human is that it involves a change in the strengths of perisylvian connections (Aboitiz and Garcia, 1997). These authors argue that two evolutionary tendencies are involved. First, pos-terior temporal and inferior parietal regions became increasingly connected, linking the auditory system and a pre-existing parietal–premotor loop involved in the generation of complex vocalizations. Second, the development of connections between posterior supe-rior temporal and inferior frontal regions links auditory information to orofacial premotor regions. One may speculate that these two tendencies correspond to the evolution of posterior and long segments of the arcu-ate fasciculus, respectively, the anterior segment being, phylogenetically, the oldest component of the perisyl-vian network. This hypothesis can now be tested using DTI tractography and comparing the parallel pathways model described in humans to the findings from both axonal tracing and tractography studies in monkeys.

Perisylvian connections in the monkey brain have been studied extensively using axonal tracing tech-niques; however, their significance with respect to language remains controversial because the homolo-gies between cortical areas in monkeys and humans are unclear (Deacon, 1992; Schmahmann and Pandya, 2006). Furthermore the findings on the segments of the arcuate fasciculus are contradictory as some stud-ies conclude that there is no equivalent of the arcuate fasciculus in the monkey (Petrides and Pandya, 1988; Schmahmann and Pandya, 2006), whereas others show a pattern of connectivity in monkey brain similar to the segments described in humans (Deacon, 1992; Petrides and Pandya, 2002). Recent tractography studies sug-gest that a rudiment of the arcuate fasciculus may exist in monkeys and that it increases in complexity in chim-panzee and human brain (Rilling et al., 2008). Overall old axonal and more recent tractography studies sup-port the theory that evolution of language from monkey to human involved change in a pre-existing pattern of perisylvian connections.

V. beyoND the ArcuAte FAscIcuLus: the VeNtrAL

PAthwAy

The arcuate fasciculus belongs to the core perisyl-vian circuitry underlying language. However, functional imaging experiments in a language-based neurodegen-erative syndrome known as primary progressive aphasia (Mesulam, 2003; Mummery et al., 1999), clinico-anatomi-cal observations in stroke patients (Sharp et al., 2004),

BEYonD tHE ARCuAtE fAsCICulus: tHE VEntRAl PAtHWAY



and intraoperative stimulation studies (Mandonnet et al., 2007) have been expanding the boundaries of this core circuitry. One of the most interesting developments has been the demonstration that areas in the medial, inferior, and anterior temporal cortices, traditionally considered outside the canonical language network, may play cru-cial roles in semantic processing. The interaction of these additional areas with the canonical perisylvian language network may be mediated by a set of ventral tracts such as the inferior longitudinal fasciculus, the uncinate fas-ciculus, and the inferior fronto-occipital fasciculus (Figure 18.4) (Catani and Mesulam, 2008). The inferior longitudinal fasciculus carries visual information from occipital areas to the temporal lobe (Catani et al., 2003a) and it is likely to play an important role in visual object recognition, semantic processing and in linking object representations to their lexical labels (Mummery et al., 1999). The uncinate fasciculus interconnects the anterior temporal lobe to the orbitofrontal area, including the IFG (Catani et al., 2002), and may play an important role in lexical retrieval, semantic associations, and aspects of naming that require connections from temporal to fron-tal components of the language network (e.g. the nam-ing of actions) (Grossman et al., 2004; Lu et al., 2002). The inferior fronto-occipital fasciculus is part of the mirror neuron system and arguably the only direct connection between occipital and frontal cortex in the human brain (Catani, 2007). It is considered part of the mirror neuron system and there is preliminary evidence suggesting that this tract is not present in monkey (Schmahmann et al., 2007). The relevance of this fasciculus to language is not fully understood but may involve reading and writing. These ventral pathways are linked to the peri-sylvian network at least in two different regions, pos-teriorly, through short U-shaped fibers connecting Wernicke’s territory to ventral temporo-occipital cor-tex and anteriorly, through intralobar fibers connecting

lateral orbitofrontal cortex to Broca’s territory (Catani and Mesulam, 2008).

VI. APPLIcAtIoN oF DtI trActogrAPhy to LANguAge

DIsorDers

Language is affected in several neurological and psy-chiatric disorders across the lifespan. The application of DTI tractography to language disorders may offer insights about how different pathologies affect lan-guage networks and lead to new approaches for early diagnosis and treatment.

A. Normal Neurodevelopment and Autism spectrum Disorder

Several studies have used DTI tractography to map the developmental trajectories of the arcuate fasciculus during early years of life. Dubois et al. used both voxel-based and tractography analysis to show some degree of left lateralization in the fractional anisotropy of the temporal portion of the arcuate fasciculus in infants aged 1–4 months. However, the leftward asymmetry seems to be not specific to the language pathways as it also occurs in sensory-motor projection pathways (Dubois et al., 2008). Lebel et al. (2008) have recently shown that the fractional anisotropy of the arcuate fas-ciculus increases by 25% from the age of 5 years to 30 years. However, the majority of these changes seem to occur before the age of 20 years.

Sundaram et al. (2008) performed dissections of the arcuate fasciculus in a group of children with global developmental delay and age-matched controls (age range 1–8 years). They were able to dissect the arcu-ate bilaterally in all typically developing children but only in half of the children with developmental delay (bilateral absence of the arcuate fasciculus).

Abnormalities in cortical long-range connectivity and white matter enlargement during brain matura-tion have been reported in autism spectrum disorders using voxel-based approaches (Herbert et al., 2004). In particular, children with autism and language impair-ment have reversed asymmetry in frontal language- related cortex (De Fosse et al., 2004). The arcuate fas-ciculus connects perisylvian fronto-parietal-temporal areas, which are activated in tasks involving theory of mind, language, and social cognition. Preliminary comparisons between subjects with Asperger syn-drome and healthy controls suggest differences in the developmental trajectories of the posterior indirect seg-ment, whose fibers seem to undergo structural changes

Inferior Fronto-Occipital Fasciculus

Inferior Longitudinal Fasciculus

Uncinate Fasciculus

FIgure 18.4 Tractography reconstruction of the ventral path-ways of the left hemisphere (from Catani and Mesulam, 2008).


409

(reduced volume in the right hemisphere) during ado-lescence and early adulthood in normal subjects but not in subjects with Asperger syndrome (Figure 18.5) (Pugliese et al., 2008).

b. schizophrenia

The hypothesis that schizophrenia symptoms may result from a breakdown in communication between cortical areas can be rooted back to early 19th century associationist theories of brain function (Kraepelin, 1919; Wernicke, 1906). Only in the last decade has it been possible, thanks to functional neuroimaging and electrophysiological methods, to test a ‘‘discon-nectivity’’ hypothesis directly in patients with schizo-phrenia (Friston and Frith, 1995; Stephan et al., 2006). For example, functional MRI (Lawrie et al., 2002) and electroencephalography (Ford et al., 2002) studies in schizophrenia patients with auditory hallucinations performing language tasks shows altered interaction between frontal, parietal, and temporal brain regions. These shared perisylvian areas are also increasingly activated during episodes of auditory hallucina-tions (Lennox et al., 2000). DTI tractography applied to schizophrenia shows that these changes are also accompanied by structural modifications (i.e. reduced fractional anisotropy) in the white matter of the arcu-ate fasciculus (Jones et al., 2006), which are particu-larly evident in schizophrenic patients with auditory hallucinations (Figure 18.6).

c. stroke and Neurosurgery

Every year, an estimated 122 000 people in the UK have a stroke (Langton Hewer, 1993) and about one third

of acute stroke patients have communication problems (Pedersen et al., 1995). Aphasia has an adverse effect on functional outcomes, mood, quality of life, and ability to return to work (Ferro et al., 1999). Early identification of simple anatomical predictors of aphasia recovery may significantly reduce the burden of the disorder to the individuals, families, and society. Currently, only 40% of patients with acute aphasia eventually recover by 12 months (Kertesz and McCabe, 1977). Recovery is often associated with reorganization of language networks in both ipsilateral and contralateral hemispheres (Ferro et al., 1999). Individual differences in the asymmetry of the arcuate fasciculus detected by DTI tractography could conceivably help to assess recovery potential in apha-sias. For example, in the general population 40% of sub-jects have a direct connection between the homologous of Broca’s and Wernicke’s area in the right hemisphere. It is not unreasonable to assume that greater symmetry is likely to lead to better recovery following stroke or neurosurgery. This is an assumption that can be tested experimentally with currently available methodology.

APPlICAtIon of DtI tRACtoGRAPHY to lAnGuAGE DIsoRDERs

2.0

1.0

0.0

10 20 30 40 50 10 20 30 40 50 10 20 30 40 50

�1.0

�2.0

Posterior segment Anterior segment Long segment

Age (years) Age (years) Age (years)

AScontrol

Late

ralit

y in

dex

FIgure 18.5 Age-related changes in the pattern of lateralization for the posterior indirect, anterior indirect, and long direct segment of the arcuate fasciculus (quadratic fit lines mean 95% confidence intervals). Differences between subjects with Asperger syndrome (pink lines) and controls (blue lines) are statistically significant for the lateralization of the number of streamlines of the posterior segment (Z –obs 2.46) (Pugliese et al., 2008).

.48

.46

.44

.42

.40

.38

.00

Controlgroup

Schizophrenia withouthallucinations

Schizophreniawith hallucinations

Frac

tiona

l ani

sotr

opy .48

.46

.44

.42

.40

.38

.00

‡

FIgure 18.6 Fractional anisotropy changes in the arcuate fas-ciculus of patients with schizophrenia. Reduced fractional anisot-ropy is particularly evident in subjects with schizophrenia affected by chronic auditory hallucinations (Pugliese et al., 2007).



Similarly in neurosurgery, pre-operative tractog-raphy assessment of the anatomical organization of white matter tracts may also help improve accuracy in the identification of eloquent white matter tracts, and minimize neurological sequelae of tumor excision (Figure 18.7). Bello et al. (2008) have demonstrated that DTI tractography in combination with intraop-erative mapping reduces the duration of surgery, patient fatigue, and intraoperative seizures. This is particularly important in light of recent studies that demonstrate poor correlation between structural and functional lateralization of the perisylvian networks (Powell et al., 2006; Vernooij et al., 2007). Recently, Powell et al. (2008) reported preliminary findings on the use of probabilistic tracking for predicting lan-guage deficits in epileptic patients undergoing left anterior temporal lobe resection. Those subjects with more left lateralized frontal connections showed greater deficits in naming after the operation.

D. Neurodegenerative Disorders

DTI tractography also has the potential of detecting pathway changes at early stages of neurodegenerative processes affecting language function so that the effects of such changes upon the resultant aphasias can be studied. In primary progressive aphasia, for example, the loss of cortical neurons is accompanied by axonal degeneration along specific white matter pathways

(Figure 18.8) (Borroni et al., 2007; Catani et al., 2003b). Up to now, morphometric work on primary progres-sive aphasia had focused on the relationship of cortical degeneration to details of the language impairment. An equally interesting development would be to use DTI to measure microstructural changes in specific tracts and correlate them with the symptom profile in various neurodegenerative disorders affecting language.

VII. Future DIrectIoNs AND coNcLusIoNs

The possibility of visualizing white matter tracts with tractography is reawakening the interest in cor-relating symptom profiles to brain network lesions. In this regard tractography, together with other tech-niques for exploring brain connectivity, is contribut-ing to shifting the paradigm from localizationism to connectionism once again. This hodological (path-way-based) approach to disorders of cognitive func-tion can potentially help resolve dilemmas posed by cases that superficially appear to defy established neurocognitive models. The hodological approach can be applied to any clinico-anatomical correlation study and does not necessarily require the use of DTI trac-tography. For example, one of the most widely used methods for localizing the site of a lesion responsible for a specific symptom consists of overlapping the brain images (MRI or CT) of patients with a similar

Perilesional edema

Tumor

FA0.60

0.40

0.20

0.00

FIgure 18.7 Tractography reconstruction of the arcuate in a patient with brain tumor in left hemisphere presenting with bucco-facial apraxia and conduction aphasia. Note that the arcuate tract is not directly affected by the tumor; however, reduced fractional anisotropy (an indirect index of microstructural integrity) is evident for the streamlines passing through the perilesional edema. This information can help predict potential functional recovery after tumor excision (which occurred in this patient due to reduction of the edema and sparing of the arcuate fibers) (data set courtesy of Dr Alberto Bizzi; Institute ‘‘Besta’’ Milan).

PPA (agrammatic and logopenic variants)/Cortico-basal degeneration

PPA (semantic variant)/Fronto-temporal dementia

Alzheimer’s disease

FIgure 18.8 Tractography reconstruction of the white matter pathways involved in the most frequent neurodegenerative disor-ders, which frequently affect language function (from Catani and Mesulam, 2008).


411

clinical presentation (Figure 18.9). In these studies the hypothesis that one is testing is crucial for the inter-pretation of the results. The site of maximal lesion overlap for a specific syndrome may extend into axonal pathways that interconnect a different set of remote areas, raising the possibility that the critical factor is not necessarily the destruction in the cortical area of overlap but a disconnection of the two remote areas (Catani and Ffytche, 2005; Catani and Mesulam, 2008). Several groups are now trying to develop meth-ods that take into account white matter anatomy for case-control studies (see, for example, Rudrauf et al., 2008; Thiebaut de Schotten et al., 2008).

In this chapter I have tried to highlight the advan-tages of the hodological approach to the anatomy of language and its disorders. This approach, by means of DTI tractography, may become critical in the near future for reaching new conclusions and establishing new models of language. However DTI tractography is still a method in its infancy. Many of the DTI studies reported in this chapter have been conducted in small groups of subjects and need to be confirmed in large samples or with other complementary techniques. It is

also important to realize that mapping symptoms onto single tracts is subject to the same criticisms directed to narrow cortical localizationism. Our knowledge of human white matter anatomy is still very limited, and giant strides are needed to reach the level of pathway characterization that has been obtained in the monkey. Nonetheless, DTI tractography applied to the arcuate fasciculus and other pathways is likely to offer pro-ductive insights into the connectional anatomy of the human brain.

AckNowLeDgmeNts

I would like to thank Luca Pugliese from the Natbrainlab (www.natbrainlab.com) for the analy-sis of the data presented in Figures 18.5 and 18.6, Valentina Valentini for her help with Figure 18.7 and Alberto Bizzi from the Institute ‘‘Besta’’ Milan for pro-viding the data set for Figure 18.5. Stephanie Forkel was extremely helpful in guiding me through the old German literature. Trackvis was used to produce

ACknoWlEDGMEnts

Neurological deficit Neurological deficit

a b c

341

2

a b c

341

2

Topological approach Hodological approach

(a)

(c)

(b)

(d)

FIgure 18.9 Topological and hodological approaches to clinico-anatomical correlation (from Catani and Mesulam, 2008). (a) A strict topological approach considers brain functions as localized in specific cortical regions. Within this framework the neuroanatomical correlate of a neurological deficit manifested for example, by a group of stroke patients (four in the example, from 1 to 4) is represented by the area of maximum lesion overlap between the four patients (region b in the example). (b) The hodological approach to brain-behavior correla-tion includes a consideration of the brain pathways that pass through the damaged area. Within this framework, the neurological deficit could also be attributed to a disconnection between a and c. (c) Image of the brain of Broca’s aphasic patient showing a lesion to the inferior frontal cortex. Broca, who worked within a topological framework, considered that his patient’s speech deficit was the consequence of the cortical lesion in the inferior frontal lobe. (d) Sagittal MRI image (modified from Dronkers et al., 2007) of the same brain shown in (c). Clearly the lesion extends into the white matter of the arcuate (red arrows) of the left hemisphere. If Broca had worked within a hodological framework and per-formed dissections of his patient’s brain it is probable that he would have attributed the speech deficit to a lesion of the arcuate fasciculus.

www.natbrainlab.com



Figures 18.7 and 18.8 and an in-house software written by Derek Jones for the other figures. Marco Catani is funded by the Medical Research Council (UK-AIMS) network, The Wellcome Trust and the Guy’s and St Thomas’ Charity (GSST).

reFereNcesAboitiz F, Garcia R (1997) The anatomy of language revisited. Biol

Res 30(4):171–183. Anwander A, Tittgemeyer M, Von Cramon DY, Friederici AD,

Knosche TR (2007) Connectivity-based parcellation of Broca’s area. Cerebral Cortex 17(4):816–825.

Baddeley A (2003) Working memory: looking back and looking for-ward. Nat Rev Neurosci 4(10):829–839.

Barrick TR, Lawes IN, Mackay CE, Clark CA (2007) White matter pathway asymmetry underlies functional lateralization. Cerebral Cortex 17(3):591–598.

Basser PJ, Pajevic S, Pierpaoli C, Duda J, Aldroubi A (2000) In vivo fiber tractography using DT-MRI data. Magn Reson Med 44(4):625–632.

Bello L, Gambini A, Castellano A, Carrabba G, Acerbi F, Fava E, Giussani C, Cadioli M, Blasi V, Casarotti A, et al. (2008) Motor and language DTI Fiber Tracking combined with intraoperative subcortical mapping for surgical removal of gliomas. Neuroimage 39(1):369–382.

Borroni B, Brambati SM, Agosti C, Gipponi S, Bellelli G, Gasparotti R, Garibotto V, Di Luca M, Scifo P, Perani D, et al. (2007) Evidence of white matter changes on diffusion tensor imaging in fronto-temporal dementia. Arch Neurol 64(2):246–251.

Buchel C, Raedler T, Sommer M, Sach M, Weiller C, Koch MA (2004) White matter asymmetry in the human brain: a diffusion tensor MRI study. Cerebral Cortex 14(9):945–951.

Burdach K (1819-1826) Vom baue und leben des gehims und ruckenmarks. Leipzig: Dyk.

Catani M (2007) From hodology to function. Brain 130(Pt 3):602–605. Catani M, Allin MP, Husain M, Pugliese L, Mesulam MM, Murray

RM, Jones DK (2007) Symmetries in human brain language pathways correlate with verbal recall. Proc Natl Acad Sci USA 104(43):17163–17168.

Catani M, Ffytche DH (2005) The rises and falls of disconnection syndromes. Brain 128(10):2224–2239.

Catani M, Howard RJ, Pajevic S, Jones DK (2002) Virtual in vivo interactive dissection of white matter fasciculi in the human brain. Neuroimage 17(1):77–94.

Catani M, Jones DK, Donato R, Ffytche DH (2003a) Occipito-temporal connections in the human brain. Brain 126(Pt 9):2093–2107.

Catani M, Jones DK, Ffytche DH (2005) Perisylvian language net-works of the human brain. Ann Neurol 57(1):8–16.

Catani M, Mesulam M (2008) The arcuate fasciculus and the dis-connection theme in language and aphasia: history and current state. Cortex 44(8): 953–961.

Catani M, Piccirilli M, Cherubini A, Tarducci R, Sciarma T, Gobbi G, Pelliccioli G, Petrillo SM, Senin U, Mecocci P (2003b) Axonal injury within language network in primary progressive aphasia. Ann Neurol 53(2):242–247.

Catani M, Pugliese L, Kanaan R, Picchioni M, Toulopoulou T, Shergill S, Williams S, Murphy D, McGuire P. (2007) Altered temporal auditory connections in schizophrenia. ISMRM May 19–25, Berlin.

Deacon TW (1992) Cortical connections of the inferior arcuate sul-cus cortex in the macaque brain. Brain Res 573(1):8–26.

De Fossé L, Hodge SM, Makris N, Kennedy DN, Caviness VS Jr., McGrath L, Steele S, Ziegler DA, Herbert MR, Frazier JA, Tager-Flusberg H, Harris GJ (2004) Language-association cortex asym-metry in autism and specific language impairment. Ann Neurol 56(6):757–766.

Dejerine J (1895) Anatomie des Centres Nerveux. Paris: Rueff et Cie. Doricchi F, Thiebaut de Schotten M, Tomaiuolo F, Bartolomeo

P (2008) White matter (dis)connections and gray matter (dys)functions in visual neglect: gaining insight into the brain networks of spatial awareness. Cortex 44(8):983–995.

Dronkers NF, Plaisant O, Iba-Zizen MT, Cabanis EA (2007) Paul Broca’s historic cases: high resolution MR imaging of the brains of Leborgne and Lelong. Brain 130(5):1432–1441.

Dubois J, Hertz-Pannier L, Cachia A, Mangin JF, Le Bihan D, Dehaene-Lambertz G (2009) Structural asymmetries in the infant language and sensori-motor networks. Cerebral Cortex 19(2):414–423.

Eluvathingal TJ, Hasan KM, Kramer L, Fletcher JM, Ewing-Cobbs L (2007) Quantitative diffusion tensor tractography of association and projection fibers in normally developing children and ado-lescents. Cerebral Cortex 17(12):2760–2768.

Ferro JM, Mariano G, Madureira S (1999) Recovery from aphasia and neglect. Cerebrovasc Dis 9(Suppl 5):6–22.

Ford JM, Mathalon DH, Whitfield S, Faustman WO, Roth WT (2002) Reduced communication between frontal and temporal lobes during talking in schizophrenia. Biol Psychiatry 51(6):485–492.

Friston KJ, Frith CD (1995) Schizophrenia: a disconnection syn-drome? Clin Neurosci 3(2):89–97.

Galuske RA, Schlote W, Bratzke H, Singer W (2000) Interhemispheric asymmetries of the modular structure in human temporal cor-tex. Science 289(5486):1946–1949.

Geschwind N (1965) Disconnexion syndromes in animals and man. I. Brain 88(2):237–294.

Geschwind N (1967) Wernicke’s contribution to the study of aphasia. Cortex 3:449–463.

Geschwind N (1970) The organization of language and the brain. Science 170(961):940–944.

Geschwind N, Levitsky W (1968) Human brain: left–right asym-metries in temporal speech region. Science 161(837):186–187.

Grossman M, McMillan C, Moore P, Ding L, Glosser G, Work M, Gee J (2004) What’s in a name: voxel-based morphometric analyses of MRI and naming difficulty in Alzheimer’s disease, frontotem-poral dementia and corticobasal degeneration. Brain 127(Pt 3): 628–649.

Hagmann P, Cammoun L, Martuzzi R, Maeder P, Clarke S, Thiran JP, Meuli R (2006) Hand preference and sex shape the architecture of language networks. Hum Brain Mapp 27(10):828–835.

Herbert MR, Ziegler DA, Makris N, Filipek PA, Kemper TL, Normandin JJ, Sanders HA, Kennedy DN, Caviness VS (2004) Localization of white matter volume increase in autism and developmental language disorder. Ann Neurol 55(4):530–540.

Jacquemot C, Scott SK (2006) What is the relationship between pho-nological short-term memory and speech processing? Trends Cogn Sci 10(11):480–486.

Jardri R, Pins D, Bubrovszky M, Despretz P, Pruvo JP, Steinling M, Thomas P (2007) Self awareness and speech processing: an fMRI study. Neuroimage 35(4):1645–1653.

Jones DK, Catani M, Pierpaoli C, Reeves SJ, Shergill SS, O’Sullivan M, Golesworthy P, McGuire P, Horsfield MA, Simmons A, et al. (2006) Age effects on diffusion tensor magnetic resonance imag-ing tractography measures of frontal cortex connections in schiz-ophrenia. Hum Brain Mapp 27(3):230–238.

Jung-Beeman M (2005) Bilateral brain processes for comprehending natural language. Trends Cogn Sci 9(11):512–518.


413

Kertesz A, McCabe P (1977) Recovery patterns and prognosis in aphasia. Brain 100(1):1–18.

Kraepelin E (1919) Dementia Praecox and Paraphrenia. Huntington, NY.Langton Hewer R (1993) The epidemiology of disabling neurologi-

cal disorders, In Neurological Rehabilitation (Greenwood RBM, McMillian TM, Ward CD, eds), pp. 3–12. Edinburgh: Churchill Livingstone.

Lawes IN, Barrick TR, Murugam V, Spierings N, Evans DR, Song M, Clark CA (2008) Atlas-based segmentation of white matter tracts of the human brain using diffusion tensor tractography and comparison with classical dissection. Neuroimage 39(1):62–79.

Lawrie SM, Buechel C, Whalley HC, Frith CD, Friston KJ, Johnstone EC (2002) Reduced frontotemporal functional connectivity in schizo-phrenia associated with auditory hallucinations. Biol Psychiatry 51(12):1008–1011.

Le Bihan D (2003) Looking into the functional architecture of the brain with diffusion MRI. Nat Rev Neurosci 4(6):469–480.

Lennox BR, Park SB, Medley I, Morris PG, Jones PB (2000) The functional anatomy of auditory hallucinations in schizophrenia. Psychiatry Res 100(1):13–20.

Lu LH, Crosson B, Nadeau SE, Heilman KM, Gonzalez- Rothi LJ, Raymer A, Gilmore RL, Bauer RM, Roper SN (2002) Category-specific naming deficits for objects and actions: seman-tic attribute and grammatical role hypotheses. Neuropsychologia 40(9):1608–1621.

Mandonnet E, Nouet A, Gatignol P, Capelle L, Duffau H (2007) Does the left inferior longitudinal fasciculus play a role in lan-guage? A brain stimulation study. Brain 130(Pt 3):623–629.

Martin-Loeches M, Casado P, Hernandez-Tamames JA, Alvarez-Linera J (2008) Brain activation in discourse comprehension: a 3t fMRI study. Neuroimage 41(2):614–622.

Matsumoto R, Nair DR, LaPresto E, Najm I, Bingaman W, Shibasaki H, Luders HO (2004) Functional connectivity in the human language system: a cortico-cortical evoked potential study. Brain 127(10):2316–2330.

Mesulam MM (1990) Large-scale neurocognitive networks and dis-tributed processing for attention, language, and memory. Ann Neurol 28(5):597–613.

Mesulam MM (2003) Primary progressive aphasia – a language-based dementia. N Engl J Med 349(16):1535–1542.

Mummery CJ, Patterson K, Wise RJ, Vandenberghe R, Price CJ, Hodges JR (1999) Disrupted temporal lobe connections in semantic dementia. Brain 122(Pt 1):61–73.

Nucifora PG, Verma R, Melhem ER, Gur RE, Gur RC (2005) Leftward asymmetry in relative fiber density of the arcuate fas-ciculus. Neuroreport 16(8):791–794.

Parker GJ, Luzzi S, Alexander DC, Wheeler-Kingshott CA, Ciccarelli O, Lambon Ralph MA (2005) Lateralization of ventral and dorsal auditory-language pathways in the human brain. Neuroimage 24(3):656–666.

Paus T, Zijdenbos A, Worsley K, Collins DL, Blumenthal J, Giedd JN, Rapoport JL, Evans AC (1999) Structural maturation of neural pathways in children and adolescents: in vivo study. Science 283(5409):1908–1911.

Pedersen PM, Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS (1995) Aphasia in acute stroke: incidence, determinants, and recovery. Ann Neurol 38(4):659–666.

Petrides M, Pandya DN (1988) Association fiber pathways to the frontal cortex from the superior temporal region in the rhesus monkey. J Comp Neurol 273(1):52–66.

Petrides M, Pandya DN (2002) Comparative cytoarchitectonic anal-ysis of the human and the macaque ventrolateral prefrontal cor-tex and corticocortical connection patterns in the monkey. Eur J Neurosci 16(2):291–310.

Powell HW, Parker GJ, Alexander DC, Symms MR, Boulby PA, Wheeler-Kingshott CA, Barker GJ, Noppeney U, Koepp MJ, Duncan JS (2006) Hemispheric asymmetries in language-related pathways: a combined functional MRI and tractography study. Neuroimage 32(1):388–399.

Pugliese L, Thomson A, Daly E, Catani M, Murphy D (2008) Lateralization of perisylvian pathways with age in Asperger’s syndrome – a cross sectional DTI study; May 15–17, London, 325 pp.

Reil J (1809) Die Sylvische Grube oder das Thal, das gestreifte grobe hirnganglium, dessen kapsel und die seitentheile des grobn gehirns. Archiv für die Physiologie 9:195–208.

Reil J (1812) Die vördere commissur im groben gehirn. Archiv für die Physiologie 11:89–100.

Rilling JK, Glasser MF, Preuss TM, Ma X, Zhao T, Hu X, Behrens TE (2008) The evolution of the arcuate fasciculus revealed with comparative DTI. Nat Neurosci 11(4):426–428.

Rodrigo S, Oppenheim C, Chassoux F, Hodel J, de Vanssay A, Baudoin-Chial S, Devaux B, Meder JF (2008) Language laterali-zation in temporal lobe epilepsy using functional MRI and prob-abilistic tractography. Epilepsia 49(8):1367–1376.

Rudrauf D, Mehta S, Grabowski T (2008) Disconnection’s renais-sance takes shape: formal incorporation in group-level lesion studies. Cortex 44(8):1084–1096.

Sabsevitz DS, Medler DA, Seidenberg M, Binder JR (2005) Modulation of the semantic system by word imageability. Neuroimage 27(1):188–200.

Sakai KL (2005) Language acquisition and brain development. Science 310(5749):815–819.

Schmahmann J, Pandya DN (2006). Fiber Pathways of the Brain. New York: Oxford University Press.

Schmithorst VJ, Holland SK (2007) Sex differences in the devel-opment of neuroanatomical functional connectivity underly-ing intelligence found using Bayesian connectivity analysis. Neuroimage 35(1):406–419.

Sharp DJ, Scott SK, Wise RJ (2004) Retrieving meaning after tem-poral lobe infarction: the role of the basal language area. Ann Neurol 56(6):836–846.

Stephan KE, Baldeweg T, Friston KJ (2006) Synaptic plasticity and dysconnection in schizophrenia. Biol Psychiatry 59(10):929–939.

Stephan KE, Marshall JC, Friston KJ, Rowe JB, Ritzl A, Zilles K, Fink GR (2003) Lateralized cognitive processes and lateralized task control in the human brain. Science 301(5631):384–386.

Striedter G (2005) Principles of Brain Evolution. Sunderland: Sinauer. Sundaram SK, Sivaswamy L, Makki MI, Behen ME, Chugani HT

(2008) Absence of arcuate fasciculus in children with global developmental delay of unknown etiology: a diffusion tensor imaging study. J Pediatr 152(2):250–255.

Thiebaut de Schotten M, Kinkingnéhun S, Delmaire C, Lehéricy S, Duffau H, Thivard L, Volle E, Levy R, Dubois B, Bartolomeo P (2008) Visualization of disconnection syndromes in humans. Cortex 44(8):1097–1103.

Vernooij MW, Smits M, Wielopolski PA, Houston GC, Krestin GP, Van der Lugt A (2007) Fiber density asymmetry of the arcuate fasciculus in relation to functional hemispheric language later-alization in both right- and left-handed healthy subjects: a com-bined fMRI and DTI study. Neuroimage 35(3):1064–1076.

Vilberg KL, Rugg MD (2008) Memory retrieval and the parietal cortex: a review of evidence from a dual-process perspective. Neuropsychologia 46(7):1787–1799.

Wernicke C (1874) Der Aphasische Symptomencomplex. Ein psychologische Studie auf anatomischer Basis. Eggert G, translator. Breslau: Cohn & Weigert.

Wernicke C (1906). Grundrisse der Psychiatrie. Leipzig: Thieme.

REfEREnCEs

diffusion mri || the connectional anatomy of language

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