CME JOURNAL OF MAGNETIC RESONANCE IMAGING 40:1041–1053 (2014)

Review Article

Diffusion Tensor Imaging and Tractography of the Human Language Pathways: Moving Into the Clinical Realm Prakash Muthusami, MD,* Jija James, PhD, Bejoy Thomas, DNB, T.R. Kapilamoorthy, MD, and Chandrasekharan Kesavadas, MD The functional correlates of anatomical derangements are of interest to the neurological clinician. Diffusion tensor tractography (DTT) is a relatively new tool in the arsenal of functional neuroimaging, by which to assess white matter tracts in the brain. While much import has been given to tracking corticospinal tracts in neurological disease, studying language pathway interconnections using DTT has largely remained in the research realm. Hardware and software advances have allowed this tool to ease into clinical practice, with several radiologists, neurologists, and neurosurgeons now familiar with its applications. DTT images, although visually appealing, are founded in mathematical equations and assumptions, and require a more than basic understanding of principles and limitations before they can be integrated into routine clinical practice. Cognitive pathways like that of language, that are normally hard to assess and especially more so when pathologically affected, have been at the receiving end of several opposing and often controversial hypotheses, and the past decade has seen the clarification, validation or rejection of several of these by the in vivo charting of functional connectivity using DTT. The focus of this review is to illustrate DTT of the language pathways with emphasis on practical considerations, clinical applications, and limitations. Key Words: diffusion tensor imaging; tractography; language pathways; arcuate fasciculus; hemispheric dominance; language plasticity J. Magn. Reson. Imaging 2014;40:1041–1053. C 2013 Wiley Periodicals, Inc. V

THE DIRECTIONAL ANISOTROPY measured by diffusion tensor imaging (DTI) permits the tracking of intact fibers in the living brain (1–3), potentially enaDepartment of Imaging Sciences and Interventional Radiology, Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum. Additional Supporting Information may be found in the online version of this article. *Address reprint requests to: P.M., Department of Imaging Sciences and Interventional Radiology, Sree Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, Kerala, India 695011. E-mail: [email protected] Received May 17, 2013; Accepted November 14, 2013. DOI 10.1002/jmri.24528 View this article online at wileyonlinelibrary.com. C 2013 Wiley Periodicals, Inc. V

bling the characterization of structural connectivity between functional cortical regions (1,4–6). Being a noninvasive imaging method, diffusion tensor tractography (DTT) of white matter tracts to decipher the organization of and interconnections between cognitive functional areas in the brain has recently caught the interest of the research community. One such area of interest is the brain’s language network. Until recently in the research domain, the translation of findings of language mapping into clinical practice is nascent but has exciting potential. One of the oldest and most enduring network models of language organization, propounded by Wernicke in the 19th century consisted of a center for recognizing sound in the posterior temporal lobe (this would later be named the Wernicke’s area) and a center in the inferior frontal lobe which was responsible for the production of sound (later named the Broca’s area) (7–9). Lichtheim later formulated, as an extension of this “classic model,” a three-component interconnected language model that included a hypothetical “concept center” for semantic processing (10,11). More recently, Hickok and Poeppel (12,13) proposed a dual stream model for language processing which, as an analogy of the visual processing model, consisted of ventral and dorsal pathways, the former serving in auditory-motor integration (the so-called “how” function) and the latter in sound-meaning interpretation (the so-called “what” function). There is at present extensive ongoing research into how exactly functional language centers in the brain are interrelated, and endeavors like the Human Connectome Project (HCP) can potentially provide these answers (14). Not surprisingly, white matter DTT forms the basis of projects such as the HCP. In this study, we elucidate the performance and various practical applications of DTT of the language pathways in the clinical setting.

FUNCTIONAL ANATOMY OF BASIS OF NEUROIMAGING

LANGUAGE:

THE

At a very fundamental level, language involves the association of auditory inputs to meaningful thought and speech output, thereby enabling us to interact

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with our environment. While the concept of “input” and “output” centers for language have always been recognized, it is an undeniable fact that at a cognitive level, language encoding necessitates the interplay of memory, attention, auditory, visual, and motor networks (15,16). The popular language models devised in the 19th century were “neurological” models and were largely based on lesional studies (9,17). The most popular of these, reported in 1861, was the brain of Leborgne, one of Broca’s patients, who had developed a motor aphasia from an ischemic insult to the left inferior frontal gyrus. By deduction, this area would represent the area controlling, or at least included in, the circuitry for speech articulation. Approximately a decade after this, Wernicke reported a patient who had speech comprehension difficulty, with damage to the left posterior superior temporal gyrus (10). Yet another decade later, Lichtheim propounded his concept of conduction aphasia, borne from injury to the arcuate fasciculus, which, by then had been established, connected the eponymous Broca’s and Wernicke’s areas (7,18). It is interesting but not wholly surprising that the pathways for processing of language from visual inputs (e.g., when a word is read) are not exactly the same as those involved in processing auditory signals (e.g., when the same word is heard). Dejerine, from his work on alexia syndromes, in 1891 deduced that visual input merges into the language pathways by means of a center in the angular gyrus that traffics signals into the Wernicke’s area (10,18,19). Figure 1a and 1b show the cognitive components of these models. The perceived shortcomings of the lesion deficit model fueled the development of more recent behavioral-based models of language processing, focusing on explaining linguistic functionality rather than the lack of it (18,20– 22). These cognitive models were largely developed by psychologists in the second half of the 20th century. These information processing systems consist of several interacting subcomponents and describe neurofunction in terms of different levels of organization rather than in isolation. These still-evolving concepts form the basis of present neuroimaging-driven language models. With the importance placed on connectionist and/or disconnectionist themes in several of these hypotheses, it behooves us to be familiar with the following white matter tracts in the brain that have an important and often complementary role in language processing. a. Superior Longitudinal Fasciculus (SLF) and Arcuate Fasciculus Previously considered synonymous in humans, these are a group of tracts located lateral to the corona radiata above the insula, connecting portions of frontal lobe to inferior parietal lobule and temporal gyri. In the classical associationist models, the terms superior longitudinal fasciculus (SLF) and arcuate tracts were used interchangeably. Anatomical studies in primates (23), and more recently neuroimaging studies in humans, have shown the subcomponent nature of this bundle (24). It has been shown that the SLF in

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Figure 1. The components of the connectionist model of language which forms the basis of most diffusion tensor tractographic interpretation. a: Pathway for analyzing the spoken word, by means of the auditory lexicon. After auditory input, sounds are processed in Wernicke area, labeled 3. From here, information transfer occurs to 4, Broca’s area, and subsequently a motor plan is formed and sent to the premotor cortex, labeled 5. b: Pathway for analyzing the written word. Note that both these pathways have common integral throughputs from the superior temporal gyrus, labeled 3 in this representation, and share output modules through the inferior frontal gyrus, here labeled 4. Visual processing of language transits through the angular gyrus, labeled 2, which serves as a way-station, so to speak, of the orthographic to auditory lexicon, probably through other components of human cognition. Separate connections from the superior temporal gyrus to the inferior frontal region have been depicted by means of the upwardly convex arrow in (A) and downward convex arrow in (B), to represent that different ventral and dorsal streams exist, although the basis of their functional segregation is yet speculative. c: Schematic diagram depicting the dissociation of the temporofrontal language connections, as elucidated by recent functional neuroimaging studies (See text). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

the nonhuman primate is a four component tract system, connecting the homologue of the human inferior parietal lobule (SLF I, II, and III), and superior temporal gyrus (arcuate fasciculus) to the frontal language areas. The SLF I is the medial and dorsal component, extending to the dorsal premotor and dorsolateral prefrontal cortices (24). The SLF II and arcuate fascicule have largely a similar trajectory above the insula, projecting anteriorly to the dorsolateral frontal cortex (25). The SLF III extends from the supramarginal gyrus to the ventral premotor and prefrontal regions. In a recent q-ball–based interrogation of connections between anterior and posterior language areas in humans, the authors demonstrated a similar dissociation between the trajectory of fiber tracts extending posteriorly from areas 44 compared with those from area 45 of Broca’s area (26). The fibers from area 44, they stated, connect to the inferior parietal lobule while fibers from area 45 connect with a more ventral

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trajectory to the superior and middle temporal gyri. The former of these tracts, corresponding to the aforementioned SLF III, was in turn ventral in its trajectory to the arcuate fasciculus (and theoretically, SLF II) which projected from the traditional location of the Wernicke’s area in the superior temporal gyrus to areas 6 and 8 on the dorsolateral frontal cortex. Although increasing spatial and angular resolution of diffusion imaging studies make the in vivo partitioning of SLF tract components a reality, for clinical purposes it is reasonable to consider this collection of fibers in unison. b. Uncinate Fasciculus (UF) The UF is a ventral associative bundle that connects the anterior temporal lobe with the medial and lateral orbitofrontal cortex. It was initially shown in nonhuman primates as the anterior-most of the temporofrontal projection systems (25), and later shown in humans as a fan-like array of fibers arising from the anterior temporal region and coalescing into a single solid bundle of fibers that runs in the external and extreme capsules deep to the insula before terminating in the inferior frontal regions (27,28). Its functions are far from fully known, but it has been shown to play a role in certain types of learning and memory, and also supposedly mediates social-emotional driven behavior. It is believed to be pathologically involved in several neurological and psychiatric disorders such as schizophrenia, bipolar disorder, and anxiety disorder (29). Its role in the language network has largely been reported to be naming of objects, action, and people (30,31). Recent studies have also shown that the UF is involved in semantic control during word comprehension (32). In one study describing intraoperative subcortical stimulation, the authors found no language perturbations brought about by stimulating the region of the UF (33). They also reported no postoperative language deficits on surgical partial removal of the UF. However, a more recent study showed an impairment in naming objects and famous faces after surgical resection of the UF (31), and another combined functional MRI (fMRI) DTI study suggested that the fibers through the extreme capsule are relevant for comprehension (34). c.

Inferior Longitudinal Fasciculus (ILF)

The ILF is a ventral associative bundle with long and short fibers connecting the occipital and temporal lobes, and for long has been believed to be concerned with the transfer of visual objects to the language areas in the temporal region. Accordingly, several clinical syndromes were attributed to a disconnection in this fiber pathway, including visual agnosia and prosopagnosia (35). Several other neurological disorders have also been correlated with ILF involvement, such as thought disorders, visual emotion, and cognitive impairments (36). In the literature, however, there is no consensus on the role, or, indeed, requirement of the ILF in serving language subcomponents, with opinions varying from its role in object naming (37), language semantics, visual object recognition (38), and

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even no absolute independent function (39). Needless to say, the role of the ILF in language, like the UF, is yet to be fully defined, and functional imaging can potentially provide us with some of the answers. d.

Inferior Fronto Occipito Fasciculus (IFOF)

The IFOF is a ventral associative bundle that connects the ventral occipital lobe to the orbitofrontal cortex by means of the temporal lobe. In the temporal stem, the IFOF runs medial and superior to the UF, and in this region these tracts are in close association with the optic radiations; in the extreme capsule, the IFOF runs superior to the UF. The IFOF is believed to be a direct pathway from the frontal to the occipital lobes (40), the UF and ILF together forming a complementary indirect pathway, and these pathways are linked to the perisylvian network at least in two different regions, posteriorly to the superior temporal language area and anteriorly to the inferior frontal language area. Accordingly, and given the strong correlations between the ILF and IFOF white matter bundles (41), it is likely that these tracts play a similar role in the execution of language processes. ROLE OF FUNCTIONAL NEUROIMAGING The past decade has seen the elucidation as well as alteration of several of the language models by the use of functional neuroimaging (Fig. 1), particularly fMRI and DTT (26,34,42–44). Unlike lesional studies, functional neuroimaging allows probing of function in vivo and has the fundamental advantage of studying the interaction of functional areas. This pertains both to residual function in the setting of structural damage as well as to the loss of function despite structural integrity, thereby not being limited to an assumption of their relation. fMRI maps out the brain areas associated with function by contrasting the blood oxygen level dependent (BOLD) signal on “task” versus “rest” states (45,46). Depicting whether and how these discrete functional areas are structurally related to each other is in the realm of DTT (2,3,47,48). Functional neuroimaging, and in particular DTT, is causing a gradual shift in the classical disconnectionist paradigm of language toward a cognitive model founded on connectivity (1). The 21st century will indubitably witness an increasing interest in, and investigation into, these anatomicofunctional coalitions of assumed neurological prototype using state-of-the-art neuroimaging. DIFFUSION TRACKING

TENSOR

IMAGING

AND

FIBER

DTI is a relatively new imaging technique based on measuring water diffusivity in brain tissue. Water diffusivity is considerably more anisotropic (directional) in white matter than in gray matter, owing to the arrangement of axonal membranes and microskeletal components that necessitate motion parallel to axonal orientation (2,47,49,50). By applying multiple directional motion probing gradients, DTI quantifies this

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Figure 2. The concept of fiber allocation by continuous tracking (FACT) used for deterministic diffusion tensor tractography. a: shows a schematic representation of this line propagation technique. The squares represent voxels, and the oblique lines within them, the direction of the largest eigenvector in that voxel. Discrete co-ordinates are converted to a continuous coordinate which yields a “tract” depicted here by the white line. Interpolation is then performed with distance-averaged vector orientation using a predetermined step size to obtain a continuous smooth tract, depicted here by the curved line. b: FACT performed over several voxels, with predefined track-termination parameters, showing an array of extracted tracts.

anisotropy and provides an assessment of the directionality of white matter within individual voxels. The most widely used DTI parameters are mean diffusivity (MD), as a measure of the average motion of water molecules independent of tissue directionality, and fractional anisotropy (FA), which reflects the directionality of water diffusion within fiber tracts, and thereby the degree of alignment within them and their structural integrity. MD is supposed to be mainly affected by cellular size, integrity, and myelination, whereas FA is indicative of fiber integrity and alignment (51– 53). In normal fiber tracts, water diffusion is directional (high FA), whereas in degenerated or disrupted tracts, FA decreases substantially. DTI parameters are becoming increasingly important in various pathologies of the white matter, including ischemia (54– 57), demyelination (51,55,58,59), as well as in tumor imaging (60–62). Diffusion-sensitive MRI sequences are used to generate virtual two- or three-dimensional representations of the white matter fiber tracts. One can then, with prior anatomical knowledge of white matter tracts, chart out the likely course of particular tracts. These tracts are based on similarities between the diffusion tensor properties of neighboring voxels, and several mathematical algorithms have been devised to translate diffusion properties into putative tracts (3,47,48,63,64). The approaches to reconstructing white matter tracts from vector directionality are roughly divided into two types: line propagation techniques and global energy minimization techniques (47,65–71). As their name suggests, line propagation methods link neighboring voxels that conform to predefined specifications to produce a continuous tract. The fiber allocation by continuous tracking (FACT) algorithm is a popular method used by several tractography software systems. In this technique of deterministic tracking, each voxel is represented by its maximum eigenvector and fiber construction is performed by tracking along consecutive principal eigenvectors such that the resultant fiber at every point

represents the direction of the eigenvector in that voxel. A schematic representation of this method is shown in Figure 2. The global energy minimization methods attempt to find the energetically most favorable path between two predetermined voxels, and represent paths thus delineated as tracts. For example, the “fast marching” method uses likelihood of connectivity of a seed point to another voxel by assessing the arrival times if tracked along different possible paths (47). Similarly, other probability-based algorithms propagate a wavefront of “likely” tracts, that permit analysis of possible diverging or crossing fibers (72). These tracts, being based on the directional movement of water through imaged voxels, are dependent upon, determined by, and thus act as a surrogate for, brain microstructure. It is important to recognize that tract trajectories thus delineated are an instantiation of a conglomerate of individual vector fields. The obvious and significant size disparity between voxels and axons requires that a favorable trade-off exist between spatial resolution and the anisotropy experienced by water molecules due to cytoarchitectural inhomogeneity. While being at present the only noninvasive in vivo method available for mapping white matter fiber tract trajectories in the human brain, this process is technically and mathematically demanding and requires several further advances in the fields of diffusion weighted imaging (DWI) and data processing before a simplistic association between extracted and actual neuronal tracts can be assumed. DISSOCIATING THE LANGUAGE PATHWAYS USING DTT Several tracts pertaining to language networks have been described, and can be described under the following two broad categories (13,34): (A) Dorsal pathways. (B) Ventral pathways. The dorsal stream projects from the temporal cortex toward inferior parietal and posterior frontal cortices

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the SLF. A simpler, but cruder parcellation of the SLF can be performed by DTI for clinical purposes using selective tracking of fibers, for example, to the inferior or middle frontal gyri (see Fig. 5b). The reconstruction protocol (Fig. 4a) is as follows: A single region of interest (ROI) method can be used with a region selected on a coronal section in which the fornix can be identified as a single intense structure. Here the projections are located superior to the sagittal stratum and are seen as green bundles lateral to the blue corona radiata. A two ROI method can also be used where the first ROI is drawn on the inferior and/or middle frontal gyrus on a coronal section and a second ROI is drawn on a region, which includes the posterior superior temporal gyrus on a sagittal slice of the DTI color map. b. Uncinate Fasciculus (UF)

Figure 3. Maps generated from the diffusion tensor images with Neuro 3D software. a: Directional color-coded fractional anisotropy (FA) maps, coded as follows: blue ¼ cephalocaudad, green ¼ anteroposterior, red ¼ left–right. Tensor maps (b), tensor map aligned with anatomical images (c), and tensor map aligned with FA map of the same patient (d). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

and is involved in auditory-motor integration, thus being involved in the control of tasks such as repeating an auditory input. The ventral stream projects from frontal areas to the middle and inferior temporal cortices and occipital cortex, and functions as an “interpreter” for language inputs to abstract thought and thence to formulation of a motor output. The DTI tract correlates of the ventral stream consist of the inferior longitudinal, the inferior fronto-occipital, and the uncinate fasciculi; the correlates of the dorsal pathways consist of the large arcuate and superior longitudinal fasciculi. The process of DTT for the language pathways consist of the following steps: sequence acquisition, postprocessing, region of interest (ROI) placement, and fiber tracking. Our institution protocol for DTI data acquisition is detailed in the online supplement (Supp. Material S1, which is available online). We perform reconstruction of the language white matter pathways as explained below. Figure 3 shows postprocessed DTI maps and Figure 4 shows how ROIs are placed on these maps for generating various language tracts. a. Superior Longitudinal Fasciculus (SLF) and Arcuate Fasciculus Due to the resolution-size mismatch between DTI and nerve bundles, separation of the SLF into its subcomponents is not wholly possible, however, newer techniques like q-ball imaging have been able to dissociate

The most posterior coronal slice in which the temporal lobe is separated from the frontal lobe is selected (Fig. 4b). The first ROI is drawn in the antero-inferior temporal lobe, and the second ROI is drawn in the posterior aspect of the lateral orbitofrontal region on a coronal slice. Alternately, the ROIs can also be conveniently drawn on axial slices that include the inferior temporal and frontal gyri. c.

Inferior Longitudinal Fasciculus (ILF)

A coronal slice is selected that identifies the posterior edge of cingulum, which includes the first ROI in the medial occipital white matter (Fig. 4c). Next, the most posterior coronal slice, which includes the entire temporal lobe, is selected and the second ROI is drawn in the green bundle on the far lateral aspect of the sagittal stratum. Alternately, both ROIs can be drawn on an axial slice of the color DTI map that shows the ILF in its entirety.

Figure 4. Region-of-interest placement for generating the language tracts. Also see text for description. Superior longitudinal fasciculus and arcuate fasciculus (a), uncinate fasciculus (b), inferior longitudinal fasciculus (c), and inferior frontooccipital fasciculus (d). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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individual comparisons or for serial follow-up. Tracing tract anatomy in clinically normal individuals can also provide novel information on the functional neuroanatomy of language. Most of the clinical applications of language DTT, however, are in the setting of a pathological process and especially where a clinical question needs answering (6,56,57,77–79). While the concepts we describe here are also relevant for other functional tracts such as the visual and corticospinal tracts, we shall limit our discussion to the DTT of language tracts. Presurgical Tract Localization in Tumors and Lesional Epilepsy

Figure 5. Parcellation of tracts for clinical demonstration. Color-based tract separation has been performed with overlaying on three-dimensional anatomical images. a: Parcellation of the ventral (uncinate fasciculus in dark blue, inferior longitudinal fasciculus in green, and inferior fronto-occipital fasciculus in red) and dorsal (superior longitudinal and arcuate fascicule in sky blue and yellow) tracts connecting the temporal region with the frontal region. b: Parcellation showing the uncinate fasciculus in green and the arcuate fibers to inferior frontal gyrus in red. Superior longitudinal fibers to the middle frontal gyrus are shown here in yellow, showing the possibility of separation of fibers by tracking to source or destination gyri, a clinically very relevant application. c: Bilateral inferior occipitofrontal fibers. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

d.

Inferior Fronto Occipito Fasciculus (IFOF)

For the first ROI, a coronal slice is selected at the midpoint between the posterior edge of cingulum and posterior edge of parieto-occipital sulcus (Fig. 4d). For the second ROI, a coronal slice is selected at the anterior edge of the genu of corpus callosum. In both these sections, the IFOF can be seen as a green bundle in the medial frontal and occipital regions. Alternately, both ROIs can be conveniently drawn on an axial slice of DTI color map that shows the IFOF in its entirety. Tracts thus generated can be color-parcellated to better depict the different connections. In our experience, this last step allows the surgeon to better appreciate tract orientations and implications before planning treatment. Figure 5 shows various tracts after parcellation.

FROM THE LAB TO THE FIELD: CLINICAL APPLICATIONS OF LANGUAGE TRACTOGRAPHY In the clinical setting, language tractography has a role in both normal subjects as well as in patients. In normal subjects, DTT can be used as a qualitative tool to investigate tract location or presence (73–76). Quantitative parameters such as tract volume, tract density, or mean FA value can be used for accurate inter-

This is at present the area where DTT of the language tracts has the maximum clinical applicability and usefulness. Preservation of eloquent function with elimination of seizures is a priority during tumor resection surgeries. While fMRI localizes functional cortical language areas, it cannot elucidate language tracts in the peritumoral white matter. The ability to overlay in three dimensions information regarding tumor location and extent along with DTT information regarding tract course and orientation enables a detailed understanding of their relations and potential postsurgical deficits (Fig. 6). Notwithstanding brain shift during tumor surgery, DTT delineation provides a good assessment of the actual location of these functional tracts intraoperatively and increases the ability to define a safe margin around the tumor (61,62,80,81). This provides a dual advantage of reduced aggressiveness to preserve function as well as of more precise resections. A few studies have described the usefulness of DTT in preoperative planning with the categorization of tracts into affections such as “disruption”, “displacement,” “displacement with infiltration,” etc. (82–84). Although in routine clinical practice, several factors like tissue-type, tumoral mass effect, perilesional edema, pharmacotherapy, and inherent technical variations lead to significant imprecision in categorically assigning such labels (Fig. 7), this does not preempt the application of DTT information in neurosurgical planning. Similarly, DTT can be useful in the follow-up of the language tracts in low grade lesions (Fig. 8) and postoperatively (Fig. 9). Intraoperative electrophysiological mapping with intracranial electrodes, which requires “awake craniotomy,” has been used for the resection of tumors involving or in proximity to eloquent cortex (62,85–87). Expectedly, this places high technical, cost, and expertise demands. Analyzing the relation of tumor margins to tracts as delineated by DTT can help in planning resections, and a good correlation has been found between intraoperative cortical stimulation and DTT (88,89). Similarly, surgical planning, procedure modification, and prognostication using DTT have been described in lesional epilepsy (90). DTT can also depict the language network reorganization that often accompanies temporal lobe epilepsies (TLE), and can also provide important information before and after anterior temporal lobe resection. Based on DTT data, the cutoff distance for a safe margin of resection has been variously reported to be 5 mm and 10 mm (88–90). In our

Tractography of Language Pathways

Figure 6. Clinical usefulness of three-dimensional anatomical overlay of tractographic data. a: Axial fluid attenuated inversion recovery (FLAIR) image showing a low-grade glioma in the right temporo-insular region. b: Preoperative diffusion tractographic data overlaid on a composite coronal-axial three-dimensional FLAIR image showing the close proximity of arcuate fibers on the right side to the posterior margin of the tumor. c: Preoperative sagittal FLAIR image of a lowgrade glioma in the left inferior temporal gyrus. d: Diffusion tractographic information overlaid on three-dimensional FLAIR image showing close proximity of the ventral tracts (uncinate fasciculus in blue and inferior longitudinal fasciculus in red) to the tumor, while the fibers of the arcuate fasciculus (in yellow) are well away from anatomical tumor margins. Images such as these increase confidence in surgical planning.

practice, we coregister DTI images with a 3D-FLAIR sequence for anatomic information regarding lesion margin, and report distances less than 10 mm to represent increased risk of postoperative neurological deficit (Fig. 10). It has been argued, and with good reason, that fMRI-driven DTT can provide more accurate estimates of the location of white matter tracts related to the lesion of surgical interest (79,91,92). Using fMRI nodes as seed points for tract propagation, tracts in intimate association of the lesion can be determined. A recent study using fMRI-based tractography imported into a neuronavigation system and compared with electrocortical stimulation, showed the location of the stimulus points to be within 6mm of the DTT-predicted arcuate fasciculus (93). While still largely in the research arena, wider routine availability of, and clinician familiarity with functional imaging software will permit its integration into daily practice.

Determining Hemispheric Language Dominance Language lateralization in the human brain was recognized by both Broca and Wernicke. Broca described

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Figure 7. Information regarding tract involvement by diffusion tensor tractography (DTT) including fallacies in interpretation. a: Axial FLAIR image of a high-grade glioma in the left parieto-occipital region. b: DTT showing abrupt cut-off (red arrow) of the left inferior fronto-occipital fasciculus well ahead of the tumor margins. This could be due to several physiological, pathological, and pharmacological factors, as discussed in the text. c: Axial FLAIR image of a high-grade glioma in the left temporo-insular region. d: DTT of the left arcuate fasciculus shows incomplete tracts. This was due to inability of proper ROI placement anteriorly, and significant white matter edema posteriorly.

Figure 8. Diffusion tensor tractography in a case of glioma progression. Upper row, (left to right) shows, in temporal sequence, axial FLAIR images of a left fronto-insular glioma extending into the deep gray structures. Lower row shows the corresponding arcuate fasciculus tractography overlaid on three-dimensional anatomical images. Note the progressive diminution and disarray of left arcuate fibers (red) with increasing grade of the tumor. Also noted is the accompanying increasing volume and density of right arcuate fibers (yellow), possibly denoting plasticity in this patient whose clinical language scores remained preserved over time.

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essing (26,101,102). DTT-based data have shown stronger frontotemporal connections on the left by means of the IFOF and UF and also from language receptive areas to the supramarginal gyrus (101,103). Using DTT, an “indirect” pathway by means of the inferior parietal lobule has been secerned separate from the “direct” arcuate fasciculus (7), suggesting a greater complexity of language connectivity between the frontal and temporal lobes regions than previously supposed. Other authors have, using fMRI-based DTT, reported distinct “ventral” and “dorsal” pathways serving as parallel streams of language processing (34). Whereas a visual assessment is often useful in the clinical setting to show asymmetrical tract patterns, quantitative comparisons can be performed using tract volume, fiber density, and mean FA (Fig. 11). However, given the considerable individual variability in language component processing, establishing the risk of aphasia in surgical therapy of dominant hemisphere using tractography is presently more accurate when preceded by fMRI to localize relevant functional cortex. Figure 9. A middle-aged right-handed man with left temporofronto-insular high grade glioma. a: Initial T2-weighted axial MRI image showing the extent of the lesion. b: Tractography showing a superior longitudinal fasciculus (SLF) between the posterior temporal and middle frontal gyri. Demonstration of this permitted tumor margins to be confidently defined. c: Postoperative T2-weighted axial MRI image showing postoperative defect. There was no postsurgical language deficit. d: Tractography shows maintained volume of SLF, explaining this functional preservation. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

the left-hemispheric language dominance in righthanded patients, and the corollary, that is, the right hemisphere being dominant in left-handed patients was the popular belief (76,94). This conjecture was rendered fallible with the subsequent description of several left-handed patients who suffered language deficits with left hemispheric strokes. Research in the second half of the 20th century, conducted primarily on patients with aphasias and recent-onset epilepsy, had resulted in postulations on the relationship between handedness and lateralization. Nevertheless, deriving hypotheses solely from neurological patients becomes a knotty issue when we factor in shifts in function after a stroke, the possibility of prior contralateral stroke, and the clinical heterogeneity that underlies several presentations. Several recent studies using functional imaging methods have convincingly corroborated these hypotheses (95–98), and provided findings whereon to base new hypotheses. Two fMRI studies demonstrated that 94% (99) and 96% (100) of right-handed subjects had their left hemispheres dominant for language function. Left-handed patients, conversely, showed greater bilateral and right hemispheric patterns of dominance. By providing a noninvasive method to study in vivo connectivity, DTT can provide a structural framework for this functional asymmetry. DTT has also shown several subtler structural hemispheric asymmetries that conform to patterns of variance in semantic proc-

Studying Language Plasticity in the Human Brain The phenomenon of neuroplasticity, the ability of nervous system reorganization in response to

Figure 10. DTT to guide surgical tumor resection. DTT data are coregistered with three-dimensional FLAIR images to assess tract relation to tumor margins. We report distances less than 10mm to represent increased risk of postoperative deficit. a: Preoperative coronal FLAIR image of a medial right temporal dysembroplastic neuroectodermal tumor in a patient with seizures who had right dominant language function. b,c: Arcuate fasciculus overlaid on 3D FLAIR image shows that the fibers are sufficiently far from the tumor margins to allow complete tumor resection without fear of neurological deficit. The patient underwent surgery which was uneventful. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Figure 11. Language asymmetry in health and disease, as illustrated by diffusion tractography. a: Top row shows tractography of the arcuate fasciculus overlaid on anatomical images of a patient with a left parietotemporal high grade glioma. Cutoff of the temporal end of tracts is noted (yellow arrow). fMRI showed a right hemispheric language lateralization. Bottom row shows arcuate fasciculus tractography in another patient with seizures due to focal cortical dysplasia (yellow arrow) and right-lateralized language by fMRI. A visual inspection shows the reduced tract volume ipsilateral to the lesion, and this is useful in the clinical setting. b: Quantitative assessments are more accurate. The upper image shows values of tract number, length, and volume, as well as mean fractional anisotropy (FA) in a healthy volunteer with left-sided language lateralization. The bottom image is of a patient with focal cortical dysplasia (same patient as in Fig. 11a) showing increased right-sided tract volume and mean FA, revealing the basis for the clinical, fMRI, and visual findings of lateralization. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

environmental triggers, has piqued the interest of the research community and has recently been shown to have the potential to translate to effective clinical therapy (104,105). Such plasticity is considered “adaptive” when associated with a gain in function (106) or “maladaptive” when associated with loss of function, as has been illustrated by animal and human studies (107). Understandably, the ability to follow, noninvasively and in vivo, dynamic morphological changes brought about by pathological or physiological processes in the brain will have far-reaching consequences for cognitive neuroscience. Most of our knowledge of neuroplasticity comes from the study of motor recovery after stroke (108– 111). There is less experience with cognitive recovery after stroke, and functional neuroimaging plays a key role in the understanding of the structural processes underlying the functional metaphysis. The functional complexity of language stems from a widely distributed interactive network with task-dependent differential activation. Functional imaging data, largely from positron emission tomography and fMRI studies, suggest that the mechanism for language plasticity is for the most part due to recruitment of previously inhibited transcallosal and collateral secondary cortical modules (112). How these modules interconnect to supplant lost function can potentially be assessed

and followed by DTT (Fig. 12). Such cortical reorganization can be either or both ipsilateral or contralateral. Numerous reports elucidate both perilesional activation and contralateral homotopic activation following injury to language areas, leading to the description of recruited neural circuits as being either “compensatory” (i.e., from contralateral language areas) or “restorative” (i.e., from perilesional language areas) (113,114). Postsurgical language plasticity, while a wellrecognized phenomenon, has little representation in clinical neuroimaging literature. The limited data that exist appear to suggest that postoperative language recovery is dependent on the rate of tumor growth, such that recruitment of distant language networks is more efficient in a slowly growing than a rapidly growing tumor (112,115,116). It has thus been argued that low-grade tumors involving language areas may be surgically resected safely without resultant significant postoperative functional deficits, and also that iterative resection strategies may be considered instead of single definitive resection to reduce the risk and extent of postsurgical deficits. It has also been postulated that unlike ipsilateral recruitment in stroke-related aphasia, in tumors there is a more significant recruitment of contralateral functional networks, but this is not the rule. Whereas fMRI can

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Figure 12. Language connectional plasticity as depicted by tractography. A young right-handed woman with left middle cerebral artery (MCA) stroke 2 years back, had severe initial language affection, and significantly improving language scores over time. a,b: Axial section of T2-weighted MRI shows the chronic left MCA infarct. A voluminous superior longitudinal fasciculus is noted on the right side, yielding a possible explanation. Initial MRI was however not available for comparison. This case denotes recruitment, or activation, as it were, of contralateral connections. c,d: A young male with right-dominant language function, being followed up for right insular cavernoma. Axial T2-weighted image shows the cavernoma with peripheral hemosiderin staining, also extending into the inferior frontal region. Tractography of the right arcuate fasciculus shows a large volume tract, with significant connections to the middle and even superior frontal gyri, suggesting recruitment of perilesional functional cortex. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Muthusami et al.

(i.e., along the principal eigenvector) in a voxel (47,61,74). The complexity of the brain’s neural circuits suggests that this simplistic correlation is not precise and is therefore prone to confounding or altogether overlooking fibers that cross, meet or diverge. Tract information as portrayed by DTT must be interpreted with a prior knowledge of normal anatomy and expected pathological changes. The finesse provided by diffusion spectrum imaging (DSI) and high angular resolution diffusion imaging (HARDI) can potentially resolve a few of these issues and permit a more exact delineation of fiber orientation and relation (26,120,121). It is also important to remember that DTT – derived information (like neuronal density, orientation, or connections) pertaining to hemispheric dominance, plasticity, deficits in stroke etc., are based on factors that are susceptible to several conditions that could provide spurious results. The anisotropy of the diffusion tensor being a function of the intravoxel FA, a change in the latter could result in inconsistent fiber tracking. Edema, for one, is a common confounder while tracking neuronal fibers (Fig. 13) and its presence might cause substantial alteration not only in the process of fiber tracking but also in the finally derived tract. Similarly, posttreatment changes might cause several apparent changes, and deciding the veracity of these is an important clinical consideration. Using DTT information to plan surgical procedures, while providing a roadmap for excision, has the caveat that the surgeon be aware of the inherent limitations of the technique. As seen in Figure 7, when a tract close to a tumor is depicted by DTT to be

reliably illustrate newly functional cortical areas, DTI has an inherent advantage over fMRI in those patients who are unable to follow instructions due to severe pathological cognitive insult. An ideal situation would be to synthesize information from both these modalities in every case.

LIMITATIONS OF APPLYING LANGUAGE TRACTOGRAPHY IN THE CLINICAL CONTEXT DTI and tractography, while a robust and powerful tool capable of providing important information in the clinical setting, are not without limitations. While several excellent expositions are available detailing technical limitations in the performance of DTI and tractography (48,117–119), here we shall discuss these in their practical contexts. The principal limiting factor of DTI is the assumption of a single Gaussian diffusion function within each voxel, which translates to a single fiber direction

Figure 13. Limitation of fiber tracking in the presence of white matter edema. Coronal T2-weighted (a) and axial contrast-enhanced T1-weighted (b) images showing a right temporal meningioma, with severe underlying edema. c,d: Note the “cut-off” appearance of right-sided arcuate fibers, similar to the appearance of infiltrated fibers. This drawback of tractography, due to its dependence on fractional anisotropy (FA) and thus on factors that affect FA at the intravoxel level must be taken into account in tractographic interpretation. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Tractography of Language Pathways

“cut off,” it remains to be answered whether this actually represents tumor infiltration or is an aberration borne from the limitations of the fiber tracking process itself. Increasing familiarity and availability coupled with more reports on clinical applicability will allow these tools to become integrated into routine clinical practice. In this context, it is important that there is increasing use of quantitative DTI data, which would require software standardization across different vendors – the logistic difficulty of this being considerable, parametric maps of relative values (e.g., relative FA) might prove useful. Testing relevance for normal populations and patients against gold standards is necessary before widespread clinical acceptance. Trials with large numbers are required that compare DTI-derived hemispheric dominance against fMRI, DTI-derived plasticity against serial clinical scores and DTI-predicted tracts against intraoperative findings. There could also be a case made for reporting dominance and plasticity as quantitative values, validated against clinical function and outcome. As we have discussed earlier, the addition of functional information from fMRI, can serve to supplement DTT-derived information. THE FUTURE Several newer diffusion models have shown ways to circumvent the limitations of classical tensor-based tractographic models. DSI was one of the first successors to DTI, which allowed the measurement of microscopic diffusion function, thus permitting the resolution of intravoxel fiber crossing. DSI depends on the sampling of the diffusion signal on a threedimensional Cartesian lattice, and this, apart from being time-intensive, also requires large pulsed-field gradients (118,121). An alternative method, based on sampling the diffusion signal from a spherical shell of specified radius, rather than the three-dimensional lattice has also been used, called High angular resolution diffusion imaging (HARDI). Several models for reconstructing HARDI data have been described, as well as model-independent schemes like q-ball imaging (26,122–125). Notwithstanding that these methods pose new challenges and require validation and optimization before they can become clinically viable, it is inevitable that these advances in DTI will eventually spill over into the clinical arena and enable more useful information to be derived for neurological patients. In conclusion, DTT of the language pathways as a clinical tool, although not yet universal in clinical practice, is an area of growing interest. With newer developments in data models and software that push the limits of the yield from tractography, one hopes to eventually achieve a technique of noninvasive, in vivo dissection of white matter tracts. The magnitude of gain that the neurological sciences can expect from this will then be left only to one’s imagination. ACKNOWLEDGMENT Recipient of certificate of honor for Educational Exhibit at RSNA 2011.

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Diffusion tensor imaging and tractography of the human language pathways: moving into the clinical realm.

The functional correlates of anatomical derangements are of interest to the neurological clinician. Diffusion tensor tractography (DTT) is a relativel...
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Quantification of the living human visual system using MRI methods has been challenging, but several applications demand a reliable and time-efficient data acquisition protocol. In this study, we demonstrate the utility of high-spatial-resolution dif

Integrating diffusion tensor imaging-based tractography into deep brain stimulation surgery: a review of the literature.
It has been generally accepted that deep brain stimulation (DBS) not only acts in the nucleus where it is being applied, as initially thought, but that chronic stimulation activates axons located in its scope, and that this activation can exert its e

Magnetic resonance diffusion tensor imaging and fiber-tracking diffusion tensor tractography in the management of spinal astrocytomas.
Some specially imaging of magnetic resonance imaging, the diffusion-weighted imaging (DWI), the diffusion tensor imaging and fractional anisotropy (FA), are useful to described, detect, and map the extent of spinal cord lesions. FA measurements may a

Diffusion Tensor Imaging Tractography in Pure Neuritic Leprosy: First Experience Report and Review of the Literature.
Five years after both right ulnar and median nerve decompression for paraesthesias and palsy, a patient, coming from Nigeria but living in Italy, came to our unit claiming to have persistent pain and combined median and ulnar palsy. Under suspicion o

Diffusion tensor tractography in the presurgical assessment of cerebral gliomas.
Glioma is the most common intra-axial brain tumor characterized by invasion into the surrounding white matter (WM) tracts. These tumors are usually diagnosed by conventional MRI, but this method is unable to describe the relationship between tumor an

New insights into the developing rabbit brain using diffusion tensor tractography and generalized q-sampling MRI.
The use of modern neuroimaging methods to characterize the complex anatomy of brain development at different stages reveals an enormous wealth of information in understanding this highly ordered process and provides clues to detect neurological and n

Tractography of the brainstem in major depressive disorder using diffusion tensor imaging.
The brainstem is the main region that innervates neurotransmitter release to the Hypothalamic-Pituitary Adrenal (HPA) axis and fronto-limbic circuits, two key brain circuits found to be dysfunctional in Major Depressive Disorder (MDD). However, the b

Free-breathing diffusion tensor imaging and tractography of the human heart in healthy volunteers using wavelet-based image fusion.
Free-breathing cardiac diffusion tensor imaging (DTI) is a promising but challenging technique for the study of fiber structures of the human heart in vivo. This work proposes a clinically compatible and robust technique to provide three-dimensional

Segmentation of the canine corpus callosum using diffusion-tensor imaging tractography.
We set out to determine functional white matter (WM) connections passing through the canine corpus callosum; these WM connections would be useful for subsequent studies of canine brains that serve as models for human WM pathway disease. Based on prio

The Safe Area in the Parieto-Occipital Lobe in the Human Brain: Diffusion Tensor Tractography.
A recent study reported on the relatively safe area in the frontal lobe for performance of neurological interventions; however, no study on the posterior safe area has been reported. In this study, using diffusion tensor tractography, we attempted to