Diffusion-tensor imaging of major white matter tracts and their role in language processing in aphasia

Abstract

A growing literature is pointing towards the importance of white matter tracts in understanding the neural mechanisms of language processing, and determining the nature of language deficits and recovery patterns in aphasia. Measurements extracted from diffusion-weighted (DW) images provide comprehensive in vivo measures of local microstructural properties of fiber pathways. In the current study, we compared microstructural properties of major white matter tracts implicated in language processing in each hemisphere (these included arcuate fasciculus (AF), superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), inferior frontal-occipital fasciculus (IFOF), uncinate fasciculus (UF), and corpus callosum (CC), and corticospinal tract (CST) for control purposes) between individuals with aphasia and healthy controls and investigated the relationship between these neural indices and language deficits.

Thirty-seven individuals with aphasia due to left hemisphere stroke and eleven age-matched controls were scanned using DW imaging sequences. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD) values for each major white matter tract were extracted from DW images using tract masks chosen from standardized atlases. Individuals with aphasia were also assessed with a standardized language test in Russian targeting comprehension and production at the word and sentence level.

Individuals with aphasia had significantly lower FA values for left hemisphere tracts and significantly higher values of MD, RD and AD for both left and right hemisphere tracts compared to controls, all indicating profound impairment in tract integrity. Language comprehension was predominantly related to integrity of the left IFOF and left ILF, while language production was mainly related to integrity of the left AF. In addition, individual segments of these three tracts were differentially associated with language production and comprehension in aphasia. Our findings highlight the importance of fiber pathways in supporting different language functions and point to the importance of temporal tracts in language processing, in particular, comprehension.

Introduction

Aphasia is an acquired neurogenic communication disorder leading to deficits in oral and written language comprehension and production (Hallowell & Chapey, 2008). Aphasia in most instances occurs after damage due to stroke or traumatic-brain injury to perisylvian areas in the dominant hemisphere. As early as the 19th century, it was acknowledged that damage to both cortical areas and subcortical fiber pathways (white matter tracts) could lead to language deficits. Carl Wernicke (1874) described a syndrome resulting from a disconnection of Broca's and Wernicke's areas, that would later become known as ‘conduction aphasia’ (Catani & Mesulam, 2008). At the end of the 19th century, Lichtheim (1885), building on Wernicke's work, further extended the descriptions of disconnection syndromes in language and outlined two additional types of aphasia, transcortical sensory and transcortical motor, that resulted from disconnection of the concept center from other language areas, although he did not provide anatomical specifications for these syndromes in his work. Further, contemporary re-examination of classical cortical aphasia cases (e.g., Leborgne patient) using modern neuroimaging techniques have demonstrated extensive white matter involvement (Dronkers et al., 2007, Thiebaut de Schotten et al., 2015). Recent lesion studies repeatedly show that lesions associated with comprehension and production deficits in aphasia can be located in subcortical white matter (Bates et al., 2003, Kümmerer et al., 2013).

Still today, relatively little is known about the functional significance of fiber pathways in language processing, in general, and their contributions to aphasia syndromes, in particular (for review see Bajada et al., 2015, Dick et al., 2014). However, recent advances in diffusion imaging techniques now afford the opportunity to investigate microstructural tissue properties and white matter integrity in vivo in individuals with various brain pathology, including aphasia. Within this novel avenue of research, accumulating evidence shows that differential fiber pathway damage (Hosomi et al., 2009, Kim and Jang, 2013, Kim et al., 2011, Rosso et al., 2015) and premorbid anatomical variations in tract structure (Forkel, Thiebaut de Schotten, Dell'Acqua, et al., 2014) can serve as important prognostic factors for patterns of language recovery following stroke. Measured changes in the macro- and microstructure of fiber pathways have also been used as physiological markers of observed behavioral changes following training (Geva et al., 2011, Scholz et al., 2009). To advance our knowledge of how language is processed in the brain and to gain insights into the neural mechanisms of language recovery in aphasia, further investigation of the functional roles of fiber pathways is required.

Historically, the arcuate fasciculus (AF) has been regarded as the main tract involved in language. The importance of this tract was highlighted in the first network model of language processing by Carl Wernicke (even though initially Wernicke was mistaken regarding its anatomical location) (Catani & Mesulam, 2008). The AF and the superior longitudinal fasciculus (SLF) are fiber bundles that run longitudinally within each cerebral hemisphere and connect frontal cortex with post-rolandic areas, the temporal and inferior parietal lobes, respectively. Once these fibers bundle together to pass over the ventricles, they become difficult to distinguish from one another and have previously been referred to by the same name. However, Petrides and Pandya (1988) – in the rhesus monkey brain using radiographic techniques – and later Makris et al. (2005) – in the human brain using diffusion tensor imaging (DTI) – isolated the two tracts and demonstrated their distinct trajectories. Specifically, Makris et al. (2005) delineated four separate segments of the SLF in the human brain, with the fourth subdivision being the AF. Based on recent neuroimaging techniques and electrostimulation studies, two- and three-pathway models of the AF have been proposed (Brauer et al., 2013, Catani et al., 2005, Glasser and Rilling, 2008). For instance, Catani et al. (2005) demonstrated functional segregation of the AF, with the direct (long) branch presumably supporting phonological processing and indirect (short) branches – lexical-semantic processing. Data no longer unequivocally support the classical depiction of this tract as directly and exclusively connecting Wernicke's with Broca's area. It has been shown that in the frontal lobe the tract actually reaches to the precentral gyrus rather than to the Broca's area (Brown et al., 2014; for review see; Bernal & Ardila, 2009), though the exact terminations of this tract remain to be determined (Makris et al., 2005).

Undoubtedly, the AF in the dominant left hemisphere is important for language, as damage to this tract leads to a broad array of aphasia symptoms (Bates et al., 2003, Dronkers et al., 2000, Dronkers et al., 2015, Dronkers et al., 2007), though its specific functions remain to be established. The integrity of the AF, as indexed via fractional anisotropy (FA), was related to difficulties in repetition and comprehension, however, when damage to cortical language areas was taken into account, only the link with repetition remained significant (Breier, Hasan, Zhang, Men, & Papanicolaou, 2008). In the same study, the SLF was also related to repetition abilities (Breier et al., 2008). Kümmerer et al. (2013), using voxel based lesion-symptom mapping, also showed that a lesion within the posterior temporoparietal periventricular white matter within the projection of the AF and dorsal SLF was associated with repetition deficits. Marchina et al. (2011) demonstrated that AF lesion load significantly predicted impairment in rate, informativeness and overall efficiency of spontaneous speech and naming ability. Lesions to the anterior segment of the AF were related to decreased speech fluency (Fridriksson, Guo, Fillmore, Holland, & Rorden, 2013). Wilson et al. (2011) in a study of primary progressive aphasia reported that decreased integrity of the SLF including its AF component was related to expressive and receptive syntactic processing difficulties. Grossman et al. (2013) also demonstrated that accurate grammatical expression was related to integrity of the SLF (and also the inferior longitudinal fasciculus; ILF) in primary progressive aphasia. During electrostimulation of this tract in awake surgery, speech arrest and naming difficulties, specifically phonemic paraphasias, are observed (Bello et al., 2008, Duffau et al., 2002, Maldonado et al., 2011). Finally, changes in the integrity of the AF both in the dominant (Breier, Juranek, & Papanicolaou, 2011) and non-dominant hemispheres (Schlaug, Marchina, & Norton, 2009) as a result of speech therapy for production deficits in aphasia have been reported. Limited studies have consistently demonstrated a positive relationship between these neural and behavioral changes: with a larger change in FA and tract volume revealed in patients with greater language gains (Schlaug et al., 2009, van Hees et al., 2014). Forkel, Thiebaut de Schotten, Kawadler et al. (2014) showed that the volume of the AF in the right (intact) hemisphere in the acute stage of recovery was predictive of overall language recovery 6-months post-onset. Additionally, the AF also seems to play an important role in language acquisition in children (Bernal and Ardila, 2009, Yeatman et al., 2011), as possibly the ability to learn novel words depends on audio-motor integration that in turn is contingent on efficient connection and communication between pre- and post-rolandic language areas provided by the long branch of the AF (López-Barroso et al., 2013). To date no other fiber pathways have been studied in the search for neural substrate of language improvement or acquisition. In summary, emerging data suggest that the AF is critical for speech fluency, phonological processing and, possibly, syntactic analysis. Further investigation is required to look into its role in language processing in greater detail. Importantly, future studies should be more consistent in spatially distinguishing the AF from the SLF and differentiating their functional roles.

Given the widespread array of areas now known to be involved in language processing, the AF cannot be the only white matter pathway supporting language processing. Still only within the last 10 years have neuroimaging and electrostimulation studies begun to highlight the importance of ventral white matter tracts in language processing (Catani et al., 2005, Dronkers et al., 2015, Duffau et al., 2013, Turken and Dronkers, 2011; see also; Bajada et al., 2015, Dick et al., 2014), such as the ILF, inferior frontal-occipital fasciculus (IFOF), uncinate fasciculus (UF), and middle longitudinal fasciculus (MdLF). Surprisingly, damage to some of these tracts was initially described in 1895 by Dejerine and Dejerine-Klumpke in their post mortem dissections of individuals suffering from aphasia (Krestel, Annoni, & Jagella, 2013): they observed degeneration of the UF, ILF, and IFOF in the autopsy of three patients with aphasia and were the first to describe ventral and dorsal fiber pathways related to language disorders (Dejerine & Dejerine-Klumpke, 1901).

The ILF and IFOF are long intrahemispheric association fibers that run the length of the temporal lobe. The ILF connects the occipital lobe with the anterior portions of the middle and inferior temporal gyri, temporal pole and limbic structures, while the IFOF runs medial to the ILF in the temporal lobe and connects inferior and medial occipital lobe with the inferior orbitofrontal cortex (Catani & Thiebaut de Schotten, 2008). The two pass near each other in the temporal lobe and the extent of their segregation remains unclear (Forkel, Thiebaut de Schotten, Kawadler, et al., 2014). Semantic paraphasic errors were elicited during intraoperative direct electrical stimulation to the IFOF (Bello et al., 2008, Mandonnet et al., 2007), but not the ILF in neurosurgical patients (Mandonnet et al., 2007). Similarly in another study, a double-dissociation was demonstrated for these tracts: stimulation of the ILF lead exclusively to visual object recognition and reading difficulties, whereas stimulation of the IFOF caused anomia, but no visual impairments (Gil-Robles et al., 2013). Other researchers have also pointed to more involvement of the IFOF in language, particularly semantic processing, with the ILF as more related to visual deficits (Fernández-Miranda et al., 2008) and possibly providing an indirect route for semantic processing (Duffau et al., 2013). Further, altered white matter integrity of the ILF (and UF) in patients with semantic dementia (Agosta et al., 2010) and the semantic variant of primary progressive aphasia (Agosta et al., 2013) has also been demonstrated. In primary progressive aphasia, integrity of the ILF was related to accurate grammatical expression, while mean length of utterance was related to the IFOF (Grossman et al., 2013). Voxel-based lesion-symptom mapping has shown that comprehension deficits were associated with lesions to the temporoprefrontal region, particularly the projection of the ventral extreme capsule (Kümmerer et al., 2013). It appears that, in humans, the IFOF passes through a section of the extreme capsule (Catani & Thiebaut de Schotten, 2012), thus providing evidence for its involvement in language comprehension. Previous DTI studies in stroke patients have not explored the specific relationship between the integrity of these temporal tracts and language processing, though subcortical temporal regions are considered important in determining aphasia severity (Rosso et al., 2015), and, in particular, in supporting language comprehension (Dronkers et al., 2004, Turken and Dronkers, 2011).

The functional role of another ventral tract, the UF, in language processing also remains mostly unspecified, with speculations regarding its function being again largely based on its anatomical position, i.e., a direct short connection between anterior temporal and inferior frontal areas that are known to be important for language (Catani & Thiebaut de Schotten, 2008). It has been suggested that the UF may share cortical terminations with the ILF and thus provide an indirect semantic processing route (Duffau et al., 2013) assisting in tasks requiring connections from temporal to frontal regions, such as with lexical retrieval, semantic association, and aspects of naming (Lu et al., 2002). However, the UF terminates in the more ventral and orbital regions of the frontal lobe (Catani & Thiebaut de Schotten, 2012) and evidence supporting a UF role in specific aspects of linguistic processing remains controversial. In primary progressive aphasia and semantic dementia, loss of integrity in the UF has been documented, though its relation to particular aspects of language processing is still to be established (Agosta et al., 2013, Agosta et al., 2010, Catani et al., 2013, Grossman et al., 2013). Further intraoperative subcortical mapping of the UF has led to semantic paraphasias (Bello et al., 2008). DTI and tract-lesion overlap studies in aphasia that considered the integrity of the UF have not been able to detect any specific relationship with language processing (Breier et al., 2008, Marchina et al., 2011), with only one study showing that integrity of the UF (as indexed via tract lesion load) was predictive of both speech fluency and semantic processing (Basilakos et al., 2014).

Another tract that runs within the temporal lobe is the MdLF. This fiber pathway purportedly connects the caudal and inferior parietal lobe with the anterior superior temporal gyrus and sulcus, and potentially the temporal pole (Makris et al., 2013). However, it is problematic to fully differentiate and isolate the MdLF from immediately adjacent fiber tracts, such as the AF and IFOF. To date there is no direct evidence regarding the role of this tract in language and its functional role in humans remains to be ascertained (De Witt Hamer et al., 2011, Duffau et al., 2013, Wang et al., 2013).

In summary, given the existing neuroimaging, electrostimulation, and lesion evidence, of the temporal tracts, the ILF and the IFOF, and possibly the UF, seem to be important for lexical-semantic processing with a specific functional role for each tract yet to be determined.

One more potentially important pathway for language processing is an intralobar tract: the frontal aslant tract, identified by Catani and colleagues (Catani et al., 2012, Catani et al., 2013), that connects Broca's area with the supplementary motor area, pre-supplementary motor area and anterior cingulate. In stroke-induced aphasia, Basilakos et al. (2014) showed that damage to the inferior portion of the aslant tract was most predictive of speech fluency. However, this portion of the aslant tract overlaps with the most anterior segment of the AF thus obfuscating a clear interpretation of the findings. Future investigations will need to further specify the anatomical location of the frontal aslant tract and determine its possible unique contributions to language processing.

In sum, despite recent advances, much remains unknown about the specific functional roles of various fiber pathways. One possible reason is that the aforementioned studies in aphasia investigated the integrity and relationship to language of a limited set of fiber pathways (usually AF, SLF and sometimes UF) within one hemisphere. Another possible reason is that previous approaches have treated fiber pathways as uni-functional entities, whereas white matter tracts in fact consist of both long and short fibers that transmit information between distant and adjacent regions, respectively. As these connect different cortical regions, their functions are also likely to differ. This issue was first highlighted by the fathers of aphasiology: in describing disconnection syndromes in aphasia, Carl Wernicke wrote that ‘aphasia may be caused by any disruption of this pathway, the clinical picture, however, may vary considerably and is related to the specific segment of the pathway involved’ (as cited in Catani & Mesulam, 2008). For instance, the differential role of long- versus short-range connections in the ventral visual stream has already been proposed (Rudrauf et al., 2008). In the language system this has not been systematically attempted; existing studies aim to determine the functional role of the whole tract, rather than its subsections. Another reason why the linguistic roles of fiber pathways have yet to be elucidated is that few indices of microstructural tissue properties are usually taken into account, with FA and possibly mean diffusivity (MD) considered. While FA reflects the magnitude of directional diffusivity and thus is potentially indicative of overall tract integrity in cases of brain disorders explicitly impacting white matter, other indices, such as axial diffusivity (AD; the 1st largest eigenvalue) and radial diffusivity (RD; average of the 2nd and 3rd eigenvalues) should be considered (Alexander, Lee, Lazar, & Field, 2008). Song et al., 2002, Song, 2003) proposed that these indices reflect different neural mechanisms: an increase in RD is indicative of demyelination, while an increased AD reflects axonal degeneration. These metrics are used extensively in other areas, for instance in research on healthy aging (Bennett & Madden, 2014) and motor outcome following stroke (Auriat et al., 2015, Lindenberg et al., 2012), but so far have been predominantly excluded from DTI studies of language.

The current study strives to overcome these limitations and provide a first comprehensive investigation of the functional roles of major fiber pathways in relation to language in aphasia. The integrity of the AF, SLF, IFOF, ILF, and UF were explored as their contribution to language processing has been previously established, though their exact roles remain to be ascertained. The MdLF and the frontal aslant tract were not considered in the present study as they are not currently included in standardized atlases of white matter tracts (Eickhoff et al., 2005; Mori, Wakana, Nagae-Poetscher, & van Zijl, 2005; Natbrainlab tractography based atlas (accessed 12.20.2015)–http://www.natbrainlab.co.uk/#!atlas-maps/ch5f), perhaps because their potential role in language and their exact anatomy await further specification. We did, however, consider the corpus callosum (CC), as it supports communication between the two hemispheres and might play an important role in compensatory recruitment or secondary degeneration of the contralateral regions. To control for the possible confounding influence of lesion load, we decided to additionally consider one other tract that is often directly damaged in stroke or has secondary axonal degeneration but is not considered part of the language connectome: the corticospinal tract (CST). We explored the integrity of the selected white matter tracts in both hemispheres to determine the contribution of fiber pathways in the left lesioned hemisphere to aphasic language deficits and possible changes of fiber pathways in the right, intact hemisphere.

The first aim of the study was to examine the microstructural properties of selected major white matter tracts bilaterally in individuals with aphasia as compared to a control group with four main DTI indices: FA, MD, AD and RD – extracted from diffusion-weighted (DW) images. These metrics together provide comprehensive in vivo measures of microstructural properties of white matter tracts (Alexander et al., 2008). We anticipated that for all left hemisphere tracts including the CC there would be significant pathological reduction in FA and increases in MD, RD, AD compared to the control group. We did not expect to see differences in DTI indices of the right hemisphere tracts between groups.

The second aim was to relate the integrity of these tracts to language processing at the word and sentence level. At this level of analysis we expected to find a pattern that would be consistent with dorsal–ventral models of language processing (Bornkessel-Schlesewsky et al., 2015, Poeppel et al., 2012, Saur et al., 2008), i.e., dorsal tracts would be more associated with production deficits, while ventral tracts – with comprehension. Naturally, the control fiber pathway – CST – was not expected to be related to language abilities.

The third aim was to subdivide tracts that demonstrated a significant relationship with language measures, into smaller segments and correlate our DTI metrics for these segments with language measures. Here, in contrast to the whole-tract analysis above, we envisaged that a more complex picture would emerge, with specific segments of both ventral and dorsal tracts contributing simultaneously to expressive and receptive language processing.

The current study provides the first comprehensive investigation of all major fiber pathways in a large group of individuals with post-stroke aphasia and is the first one to consider the differential role of small tract segments.