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1.  What do brain lesions tell us about theories of embodied semantics and the human mirror neuron system? 
Recent work has been mixed with respect to the notion of embodied semantics, which suggests that processing linguistic stimuli referring to motor-related concepts recruits the same sensorimotor regions of cortex involved in the execution and observation of motor acts or the objects associated with those acts. In this study, we asked whether lesions to key sensorimotor regions would preferentially impact the comprehension of stimuli associated with the use of the hand, mouth or foot. Twenty-seven patients with left-hemisphere strokes and 10 age- and education-matched controls were presented with pictures and words representing objects and actions typically associated with the use of the hand, mouth, foot or no body part at all (i.e., neutral). Picture/sound pairs were presented simultaneously, and participants were required to press a space bar only when the item pairs matched (i.e., congruent trials). We conducted two different analyses: 1) we compared task performance of patients with and without lesions in several key areas previously implicated in the putative human mirror neuron system (i.e., Brodmann areas 4/6, 1/2/3, 21 and 44/45), and 2) we conducted Voxel-based Lesion-Symptom Mapping analyses (VLSM; Bates et al., 2003) to identify additional regions associated with the processing of effector-related versus neutral stimuli. Processing of effector-related stimuli was associated with several regions across the left hemisphere, and not solely with premotor/motor or somatosensory regions. We also did not find support for a somatotopically-organized distribution of effector-specific regions. We suggest that, rather than following the strict interpretation of homuncular somatotopy for embodied semantics, these findings support theories proposing the presence of a greater motor-language network which is associated with, but not restricted to, the network responsible for action execution and observation.
doi:10.1016/j.cortex.2010.06.001
PMCID: PMC3615255  PMID: 20621292
Embodiment; Mirror neurons; VLSM; Stroke; Embodied semantics
2.  Grey and white matter correlates of picture naming: Evidence from a voxel-based lesion analysis of the Boston Naming Test 
A number of recent studies utilizing both functional neuroimaging and lesion analysis techniques in neurologic patients have produced conflicting results with respect to the neural correlates of picture naming. Picture naming involves a number of cognitive processes, from visual perception/recognition to lexical-semantic retrieval to articulation. This middle process, the ability to retrieve a name associated with an object, has been attributed in some cases to posterior portions of the left lateral temporal lobe and in other cases, to anterior temporal cortex. In the current study, we used voxel-based lesion symptom mapping (VLSM) to identify neural correlates of picture naming in a large sample of well-characterized left hemisphere (LH) patients suffering from a range of naming deficits. We tested patients on the Boston Naming Test (BNT), a clinical, standardized measure of picture naming that is widely used in both clinical and research settings. We found that overall performance on the BNT was associated with a network of LH regions that included significant portions of the left anterior to posterior middle temporal gyrus (MTG) and superior temporal gyrus (STG) and underlying white matter, and extended into left inferior parietal cortex. However, when we added covariates to this analysis that controlled for deficits in visual recognition and motor speech in order to isolate brain regions specific to lexical-semantic retrieval, the significant regions that remained were confined almost exclusively to the left mid-posterior MTG and underlying white matter. These findings support the notion that a large network in left peri-Sylvian cortex supports picture naming, but that the left mid-posterior MTG and underlying white matter play a critical role in the core ability to retrieve a name associated with an object or picture.
doi:10.1016/j.cortex.2012.03.001
PMCID: PMC3613759  PMID: 22482693
Picture naming; Word production; Temporal cortex; Wernicke’s aphasia; Aphasia; Middle temporal gyrus; Lexical-semantics
3.  Role of the lateral prefrontal cortex in speech monitoring 
The role of lateral prefrontal cortex (LPFC) in speech monitoring has not been delineated. Recent work suggests that medial frontal cortex (MFC) is involved in overt speech monitoring initiated before auditory feedback. This mechanism is reflected in an event-related potential (ERP), the error negativity (Ne), peaking within 100 ms after vocal-onset. Critically, in healthy individuals the Ne is sensitive to the accuracy of the response; it is larger for error than correct trials. By contrast, patients with LPFC damage are impaired in non-verbal monitoring tasks showing no amplitude difference between the Ne measured in correct vs. error trials. Interactions between the LPFC and the MFC are assumed to play a necessary role for normal action monitoring. We investigated whether the LPFC was involved in speech monitoring to the same extent as in non-linguistic actions by comparing performance and EEG activity in patients with LPFC damage and in aged-matched controls performing linguistic (Picture Naming) and non-linguistic (Simon) tasks. Controls did not produce enough errors to allow the comparison of the Ne or other ERP in error vs. correct trials. PFC patients had worse performance than controls in both tasks, but their Ne was larger for error than correct trials only in Naming. This task-dependent pattern can be explained by LPFC-dependent working-memory requirements present in non-linguistic tasks used to study action monitoring but absent in picture naming. This suggests that LPFC may not be necessary for speech monitoring as assessed by simple picture naming. In addition, bilateral temporal cortex activity starting before and peaking around vocal-onset was observed in LPFC and control groups in both tasks but was larger for error than correct trials only in Naming, suggesting the temporal cortex is associated with on-line monitoring of speech specifically when access to lexical representations is necessary.
doi:10.3389/fnhum.2013.00703
PMCID: PMC3810824  PMID: 24194708
on-line speech monitoring; prefrontal lesions; error negativity; electroencephalography; brain networks; overt picture-naming
4.  White matter damage in primary progressive aphasias: a diffusion tensor tractography study 
Brain  2011;134(10):3011-3029.
Primary progressive aphasia is a clinical syndrome that encompasses three major phenotypes: non-fluent/agrammatic, semantic and logopenic. These clinical entities have been associated with characteristic patterns of focal grey matter atrophy in left posterior frontoinsular, anterior temporal and left temporoparietal regions, respectively. Recently, network-level dysfunction has been hypothesized but research to date has focused largely on studying grey matter damage. The aim of this study was to assess the integrity of white matter tracts in the different primary progressive aphasia subtypes. We used diffusion tensor imaging in 48 individuals: nine non-fluent, nine semantic, nine logopenic and 21 age-matched controls. Probabilistic tractography was used to identify bilateral inferior longitudinal (anterior, middle, posterior) and uncinate fasciculi (referred to as the ventral pathway); and the superior longitudinal fasciculus segmented into its frontosupramarginal, frontoangular, frontotemporal and temporoparietal components, (referred to as the dorsal pathway). We compared the tracts’ mean fractional anisotropy, axial, radial and mean diffusivities for each tract in the different diagnostic categories. The most prominent white matter changes were found in the dorsal pathways in non-fluent patients, in the two ventral pathways and the temporal components of the dorsal pathways in semantic variant, and in the temporoparietal component of the dorsal bundles in logopenic patients. Each of the primary progressive aphasia variants showed different patterns of diffusion tensor metrics alterations: non-fluent patients showed the greatest changes in fractional anisotropy and radial and mean diffusivities; semantic variant patients had severe changes in all metrics; and logopenic patients had the least white matter damage, mainly involving diffusivity, with fractional anisotropy altered only in the temporoparietal component of the dorsal pathway. This study demonstrates that both careful dissection of the main language tracts and consideration of all diffusion tensor metrics are necessary to characterize the white matter changes that occur in the variants of primary progressive aphasia. These results highlight the potential value of diffusion tensor imaging as a new tool in the multimodal diagnostic evaluation of primary progressive aphasia.
doi:10.1093/brain/awr099
PMCID: PMC3187537  PMID: 21666264
primary progressive aphasia; progressive non-fluent aphasia; semantic dementia; logopenic progressive aphasia; diffusion tensor imaging
5.  Aphasic Patients Exhibit a Reversal of Hemispheric Asymmetries in Categorical Color Discrimination 
Brain and language  2011;116(3):151-156.
Patients with left hemisphere (LH) or right hemisphere (RH) brain injury due to stroke were tested on a speeded, color discrimination task in which two factors were manipulated: 1) the categorical relationship between the target and the distracters and 2) the visual field in which the target was presented. Similar to controls, the RH patients were faster in detecting targets in the right visual field when the target and distracters had different color names compared to when their names were the same. This effect was absent in the LH patients, consistent with the hypothesis that injury to the left hemisphere handicaps the automatic activation of lexical codes. Moreover, the LH patients showed a reversed effect, such that the advantage of different target-distracter names was now evident for targets in the left visual field. This reversal may suggest a reorganization of the color lexicon in the right hemisphere following left hemisphere brain injury and/or the unmasking of a heightened right hemisphere sensitivity to color categories.
doi:10.1016/j.bandl.2010.11.005
PMCID: PMC3051014  PMID: 21216454
aphasia; categorical perception; color; hemispheric laterality; linguistic relativity
6.  Connected speech production in three variants of primary progressive aphasia 
Brain  2010;133(7):2069-2088.
Primary progressive aphasia is a clinical syndrome defined by progressive deficits isolated to speech and/or language, and can be classified into non-fluent, semantic and logopenic variants based on motor speech, linguistic and cognitive features. The connected speech of patients with primary progressive aphasia has often been dichotomized simply as ‘fluent’ or ‘non-fluent’, however fluency is a multidimensional construct that encompasses features such as speech rate, phrase length, articulatory agility and syntactic structure, which are not always impacted in parallel. In this study, our first objective was to improve the characterization of connected speech production in each variant of primary progressive aphasia, by quantifying speech output along a number of motor speech and linguistic dimensions simultaneously. Secondly, we aimed to determine the neuroanatomical correlates of changes along these different dimensions. We recorded, transcribed and analysed speech samples for 50 patients with primary progressive aphasia, along with neurodegenerative and normal control groups. Patients were scanned with magnetic resonance imaging, and voxel-based morphometry was used to identify regions where atrophy correlated significantly with motor speech and linguistic features. Speech samples in patients with the non-fluent variant were characterized by slow rate, distortions, syntactic errors and reduced complexity. In contrast, patients with the semantic variant exhibited normal rate and very few speech or syntactic errors, but showed increased proportions of closed class words, pronouns and verbs, and higher frequency nouns, reflecting lexical retrieval deficits. In patients with the logopenic variant, speech rate (a common proxy for fluency) was intermediate between the other two variants, but distortions and syntactic errors were less common than in the non-fluent variant, while lexical access was less impaired than in the semantic variant. Reduced speech rate was linked with atrophy to a wide range of both anterior and posterior language regions, but specific deficits had more circumscribed anatomical correlates. Frontal regions were associated with motor speech and syntactic processes, anterior and inferior temporal regions with lexical retrieval, and posterior temporal regions with phonological errors and several other types of disruptions to fluency. These findings demonstrate that a multidimensional quantification of connected speech production is necessary to characterize the differences between the speech patterns of each primary progressive aphasic variant adequately, and to reveal associations between particular aspects of connected speech and specific components of the neural network for speech production.
doi:10.1093/brain/awq129
PMCID: PMC2892940  PMID: 20542982
primary progressive aphasia; progressive non-fluent aphasia; semantic dementia; logopenic progressive aphasia; speech production
7.  Neural correlates of syntactic processing in the non-fluent variant of primary progressive aphasia 
The left posterior inferior frontal cortex (IFC) is important for syntactic processing, and has been shown in many functional imaging studies to be differentially recruited for the processing of syntactically complex sentences relative to simpler ones. In the non-fluent variant of primary progressive aphasia (PPA), degeneration of the posterior IFC is associated with expressive and receptive agrammatism, however the functional status of this region in non-fluent PPA is not well understood. Our objective was to determine whether the atrophic posterior IFC is differentially recruited for the processing of syntactically complex sentences in non-fluent PPA. Using structural and functional magnetic resonance imaging, we quantified tissue volumes and functional responses to a syntactic comprehension task in eight patients with non-fluent PPA, compared to healthy age-matched controls. In controls, the posterior IFC showed more activity for syntactically complex sentences than simpler ones, as expected. In non-fluent PPA patients, the posterior IFC was atrophic and, unlike controls, showed an equivalent level of functional activity for syntactically complex and simpler sentences. This abnormal pattern of functional activity was specific to the posterior IFC: the mid superior temporal sulcus, another region modulated by syntactic complexity in controls, showed normal modulation by complexity in patients. A more anterior inferior frontal region was recruited by patients, but did not support successful syntactic processing. We conclude that in non-fluent PPA, the posterior IFC is not only structurally damaged, but is also functionally abnormal, suggesting a critical role for this region in the breakdown of syntactic processing in this syndrome.
doi:10.1523/JNEUROSCI.2547-10.2010
PMCID: PMC3024013  PMID: 21159955
syntactic processing; primary progressive aphasia; progressive non-fluent aphasia; inferior frontal gyrus; superior temporal sulcus; functional magnetic resonance imaging
8.  Is Relational Reasoning Dependent on Language? A Voxel-Based Lesion Symptom Mapping Study 
Brain and language  2010;113(2):59-64.
Previous studies with brain-injured patients have suggested that language abilities are necessary for complex problem solving, even when tasks are non-verbal. In the current study, we tested this notion by analyzing behavioral and neuroimaging data from a large group of left-hemisphere stroke patients (n = 107) suffering from a range of language impairment from none to severe. Patients were tested on the Raven’s Colored Progressive Matrices (RCPM), a non-verbal test of reasoning that requires participants to complete a visual pattern or sequence with one of six possible choices. For some items, the solution could be determined by visual pattern-matching, but other items required more complex, relational reasoning. As predicted, performance on the relational-reasoning items was disproportionately affected in language-impaired patients with aphasia, relative to non-aphasic, left-hemisphere patients. A voxel-based lesion symptom mapping (VLSM) procedure was used to relate patients’ RCPM performance with areas of damage in the brain. Results showed that deficits on the relational reasoning problems were associated with lesions in the left middle and superior temporal gyri, regions essential for language processing, as well as in the left inferior parietal lobule. In contrast, the visual pattern-matching condition was associated with lesions in posterior portions of the left hemisphere that subserve visual processing, namely, occipital and inferotemporal cortex. These findings provide compelling support for the idea that language is critical for higher-level reasoning and problem-solving.
doi:10.1016/j.bandl.2010.01.004
PMCID: PMC2994599  PMID: 20206985
9.  Language networks in semantic dementia 
Brain  2009;133(1):286-299.
Cognitive deficits in semantic dementia have been attributed to anterior temporal lobe grey matter damage; however, key aspects of the syndrome could be due to altered anatomical connectivity between language pathways involving the temporal lobe. The aim of this study was to investigate the left language-related cerebral pathways in semantic dementia using diffusion tensor imaging-based tractography and to combine the findings with cortical anatomical and functional magnetic resonance imaging data obtained during a reading activation task. The left inferior longitudinal fasciculus, arcuate fasciculus and fronto-parietal superior longitudinal fasciculus were tracked in five semantic dementia patients and eight healthy controls. The left uncinate fasciculus and the genu and splenium of the corpus callosum were also obtained for comparison with previous studies. From each tract, mean diffusivity, fractional anisotropy, as well as parallel and transverse diffusivities were obtained. Diffusion tensor imaging results were related to grey and white matter atrophy volume assessed by voxel-based morphometry and functional magnetic resonance imaging activations during a reading task. Semantic dementia patients had significantly higher mean diffusivity, parallel and transverse in the inferior longitudinal fasciculus. The arcuate and uncinate fasciculi demonstrated significantly higher mean diffusivity, parallel and transverse and significantly lower fractional anisotropy. The fronto-parietal superior longitudinal fasciculus was relatively spared, with a significant difference observed for transverse diffusivity and fractional anisotropy, only. In the corpus callosum, the genu showed lower fractional anisotropy compared with controls, while no difference was found in the splenium. The left parietal cortex did not show significant volume changes on voxel-based morphometry and demonstrated normal functional magnetic resonance imaging activation in response to reading items that stress sublexical phonological processing. This study shows that semantic dementia is associated with anatomical damage to the major superior and inferior temporal white matter connections of the left hemisphere likely involved in semantic and lexical processes, with relative sparing of the fronto-parietal superior longitudinal fasciculus. Fronto-parietal regions connected by this tract were activated normally in the same patients during sublexical reading. These findings contribute to our understanding of the anatomical changes that occur in semantic dementia, and may further help to explain the dissociation between marked single-word and object knowledge deficits, but sparing of phonology and fluency in semantic dementia.
doi:10.1093/brain/awp233
PMCID: PMC2801321  PMID: 19759202
semantic dementia; semantic knowledge; diffusion tensor-based tractography; functional MRI; voxel-based morphometry
10.  The Neural Architecture of the Language Comprehension Network: Converging Evidence from Lesion and Connectivity Analyses 
While traditional models of language comprehension have focused on the left posterior temporal cortex as the neurological basis for language comprehension, lesion and functional imaging studies indicate the involvement of an extensive network of cortical regions. However, the full extent of this network and the white matter pathways that contribute to it remain to be characterized. In an earlier voxel-based lesion-symptom mapping analysis of data from aphasic patients (Dronkers et al., 2004), several brain regions in the left hemisphere were found to be critical for language comprehension: the left posterior middle temporal gyrus, the anterior part of Brodmann's area 22 in the superior temporal gyrus (anterior STG/BA22), the posterior superior temporal sulcus (STS) extending into Brodmann's area 39 (STS/BA39), the orbital part of the inferior frontal gyrus (BA47), and the middle frontal gyrus (BA46). Here, we investigated the white matter pathways associated with these regions using diffusion tensor imaging from healthy subjects. We also used resting-state functional magnetic resonance imaging data to assess the functional connectivity profiles of these regions. Fiber tractography and functional connectivity analyses indicated that the left MTG, anterior STG/BA22, STS/BA39, and BA47 are part of a richly interconnected network that extends to additional frontal, parietal, and temporal regions in the two hemispheres. The inferior occipito-frontal fasciculus, the arcuate fasciculus, and the middle and inferior longitudinal fasciculi, as well as transcallosal projections via the tapetum were found to be the most prominent white matter pathways bridging the regions important for language comprehension. The left MTG showed a particularly extensive structural and functional connectivity pattern which is consistent with the severity of the impairments associated with MTG lesions and which suggests a central role for this region in language comprehension.
doi:10.3389/fnsys.2011.00001
PMCID: PMC3039157  PMID: 21347218
aphasia; language comprehension; language network; structural connectivity; fiber tracts; resting-state functional connectivity; disconnection; middle temporal gyrus
11.  COGNITIVE PROCESSING SPEED AND THE STRUCTURE OF WHITE MATTER PATHWAYS: CONVERGENT EVIDENCE FROM NORMAL VARIATION AND LESION STUDIES 
NeuroImage  2008;42(2):1032-1044.
We investigated the relation between cognitive processing speed and structural properties of white matter pathways via convergent imaging studies in healthy and brain-injured groups. Voxel-based morphometry (VBM) was applied to diffusion tensor imaging data from thirty-nine young healthy subjects in order to investigate the relation between processing speed, as assessed with the Digit-Symbol subtest from WAIS-III, and fractional anisotropy, an index of microstructural organization of white matter. Digit-Symbol performance was positively correlated with fractional anisotropy of white matter in the parietal and temporal lobes bilaterally and in the left middle frontal gyrus. Fiber tractography indicated that these regions are consistent with the trajectories of the superior and inferior longitudinal fasciculi. In a second investigation, we assessed the effect of white matter damage on processing speed using voxel-based lesion symptom mapping (VLSM) analysis of data from seventy-two patients with left hemisphere strokes. Lesions in left parietal white matter, together with cortical lesions in supramarginal and angular gyri were associated with impaired performance. These findings suggest that cognitive processing speed, as assessed by the Digit-Symbol test, is closely related to the structural integrity of white matter tracts associated with parietal and temporal cortices and left middle frontal gyrus. Further, fiber tractography applied to VBM results and the patient findings suggest that the superior longitudinal fasciculus, a major tract subserving fronto-parietal integration, makes a prominent contribution to processing speed.
doi:10.1016/j.neuroimage.2008.03.057
PMCID: PMC2630965  PMID: 18602840
Cognitive processing speed; diffusion tensor imaging; individual differences; magnetic resonance imaging; neural pathways; neuropsychology
12.  Cognition and Anatomy in Three Variants of Primary Progressive Aphasia 
Annals of neurology  2004;55(3):335-346.
We performed a comprehensive cognitive, neuroimaging, and genetic study of 31 patients with primary progressive aphasia (PPA), a decline in language functions that remains isolated for at least 2 years. Detailed speech and language evaluation was used to identify three different clinical variants: nonfluent progressive aphasia (NFPA; n = 11), semantic dementia (SD; n = 10), and a third variant termed logopenic progressive aphasia (LPA; n = 10). Voxel-based morphometry (VBM) on MRIs showed that, when all 31 PPA patients were analyzed together, the left perisylvian region and the anterior temporal lobes were atrophied. However, when each clinical variant was considered separately, distinctive patterns emerged: (1) NFPA, characterized by apraxia of speech and deficits in processing complex syntax, was associated with left inferior frontal and insular atrophy; (2) SD, characterized by fluent speech and semantic memory deficits, was associated with anterior temporal damage; and (3) LPA, characterized by slow speech and impaired syntactic comprehension and naming, showed atrophy in the left posterior temporal cortex and inferior parietal lobule. Apolipoprotein E ε4 haplotype frequency was 20% in NFPA, 0% in SD, and 67% in LPA. Cognitive, genetic, and anatomical features indicate that different PPA clinical variants may correspond to different underlying pathological processes.
doi:10.1002/ana.10825
PMCID: PMC2362399  PMID: 14991811
13.  Spatiotemporal Dynamics of Word Processing in the Human Brain 
Frontiers in Neuroscience  2007;1(1):185-196.
We examined the spatiotemporal dynamics of word processing by recording the electrocorticogram (ECoG) from the lateral frontotemporal cortex of neurosurgical patients chronically implanted with subdural electrode grids. Subjects engaged in a target detection task where proper names served as infrequent targets embedded in a stream of task-irrelevant verbs and nonwords. Verbs described actions related to the hand (e.g, throw) or mouth (e.g., blow), while unintelligible nonwords were sounds which matched the verbs in duration, intensity, temporal modulation, and power spectrum. Complex oscillatory dynamics were observed in the delta, theta, alpha, beta, low, and high gamma (HG) bands in response to presentation of all stimulus types. HG activity (80–200 Hz) in the ECoG tracked the spatiotemporal dynamics of word processing and identified a network of cortical structures involved in early word processing. HG was used to determine the relative onset, peak, and offset times of local cortical activation during word processing. Listening to verbs compared to nonwords sequentially activates first the posterior superior temporal gyrus (post-STG), then the middle superior temporal gyrus (mid-STG), followed by the superior temporal sulcus (STS). We also observed strong phase-locking between pairs of electrodes in the theta band, with weaker phase-locking occurring in the delta, alpha, and beta frequency ranges. These results provide details on the first few hundred milliseconds of the spatiotemporal evolution of cortical activity during word processing and provide evidence consistent with the hypothesis that an oscillatory hierarchy coordinates the flow of information between distinct cortical regions during goal-directed behavior.
doi:10.3389/neuro.01.1.1.014.2007
PMCID: PMC2518055  PMID: 18982128
electrocorticogram; oscillations; gamma; verbs; word processing; target detection; superior temporal gyrus; superior temporal sulcus

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