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1.  What role does the anterior temporal lobe play in sentence-level processing? Neural correlates of syntactic processing in semantic PPA 
Journal of cognitive neuroscience  2013;26(5):970-985.
Neuroimaging and neuropsychological studies have implicated the anterior temporal lobe (ATL) in sentence-level processing, with syntactic structure-building and/or combinatorial semantic processing suggested as possible roles. A potential challenge to the view that the ATL is involved in syntactic aspects of sentence processing comes from the clinical syndrome of semantic variant primary progressive aphasia (semantic PPA, also known as semantic dementia). In semantic PPA, bilateral neurodegeneration of the anterior temporal lobes is associated with profound lexical semantic deficits, yet syntax is strikingly spared. The goal of this study was to investigate the neural correlates of syntactic processing in semantic PPA, in order to determine which regions normally involved in syntactic processing are damaged in semantic PPA, and whether spared syntactic processing depends on preserved functionality of intact regions, preserved functionality of atrophic regions, or compensatory functional reorganization. We scanned 20 individuals with semantic PPA and 24 age-matched controls using structural and functional MRI. Participants performed a sentence comprehension task that emphasized syntactic processing and minimized lexical semantic demands. We found that in controls, left inferior frontal and left posterior temporal regions were modulated by syntactic processing, while anterior temporal regions were not significantly modulated. In the semantic PPA group, atrophy was most severe in the anterior temporal lobes, but extended to the posterior temporal regions involved in syntactic processing. Functional activity for syntactic processing was broadly similar in patients and controls; in particular, whole-brain analyses revealed no significant differences between patients and controls in the regions modulated by syntactic processing. The atrophic left anterior temporal lobe did show abnormal functionality in semantic PPA patients, however this took the unexpected form of a failure to deactivate. Taken together, our findings indicate that spared syntactic processing in semantic PPA depends on preserved functionality of structurally intact left frontal regions and moderately atrophic left posterior temporal regions, but no functional reorganization was apparent as a consequence of anterior temporal atrophy and dysfunction. These results suggest that the role of the anterior temporal lobe in sentence processing is less likely to relate to syntactic structure-building, and more likely to relate to higher level processes such as combinatorial semantic processing.
PMCID: PMC4006153  PMID: 24345172
2.  Dysfunctional visual word form processing in progressive alexia 
Brain  2013;136(4):1260-1273.
Progressive alexia is an acquired reading deficit caused by degeneration of brain regions that are essential for written word processing. Functional imaging studies have shown that early processing of the visual word form depends on a hierarchical posterior-to-anterior processing stream in occipito-temporal cortex, whereby successive areas code increasingly larger and more complex perceptual attributes of the letter string. A region located in the left lateral occipito-temporal sulcus and adjacent fusiform gyrus shows maximal selectivity for words and has been dubbed the ‘visual word form area’. We studied two patients with progressive alexia in order to determine whether their reading deficits were associated with structural and/or functional abnormalities in this visual word form system. Voxel-based morphometry showed left-lateralized occipito-temporal atrophy in both patients, very mild in one, but moderate to severe in the other. The two patients, along with 10 control subjects, were scanned with functional magnetic resonance imaging as they viewed rapidly presented words, false font strings, or a fixation crosshair. This paradigm was optimized to reliably map brain regions involved in orthographic processing in individual subjects. All 10 control subjects showed a posterior-to-anterior gradient of selectivity for words, and all 10 showed a functionally defined visual word form area in the left hemisphere that was activated for words relative to false font strings. In contrast, neither of the two patients with progressive alexia showed any evidence for a selectivity gradient or for word-specific activation of the visual word form area. The patient with mild atrophy showed normal responses to both words and false font strings in the posterior part of the visual word form system, but a failure to develop selectivity for words in the more anterior part of the system. In contrast, the patient with moderate to severe atrophy showed minimal activation of any part of the visual word form system for either words or false font strings. Our results suggest that progressive alexia is associated with a dysfunctional visual word form system, with or without substantial cortical atrophy. Furthermore, these findings demonstrate that functional MRI has the potential to reveal the neural bases of cognitive deficits in neurodegenerative patients at very early stages, in some cases before the development of extensive atrophy.
PMCID: PMC3613714  PMID: 23471694
progressive alexia; letter-by-letter reading; posterior cortical atrophy; logopenic primary progressive aphasia; visual word form system
3.  Treating apraxia of speech with an implicit protocol that activates speech motor areas via inner speech 
Aphasiology  2014;28(5):515-532.
Treatments of apraxia of speech (AOS) have traditionally relied on overt practice. One alternative to this method is implicit phoneme manipulation which was derived from early models on inner speech. Implicit phoneme manipulation requires the participant to covertly move and combine phonemes to form a new word. This process engages a system of self-monitoring which is referred to as fully conscious inner speech.
The present study aims to advance the understanding and validity of a new treatment for AOS, implicit phoneme manipulation. Tasks were designed to answer the following questions. 1. Would the practice of implicit phoneme manipulation improve the overt production of complex consonant blends in words? 2. Would this improvement generalize to untrained complex and simpler consonant blends in words? 3. Would these treatment tasks activate regions known to support motor planning and programming as verified by fMRI?
Method & Procedures
The participant was asked to covertly manipulate phonemes to create a new word and to associate this newly formed word to a target picture among 4 phonologically-related choices. To avoid overt practice, probes were collected only after each block of training was completed. Probe sessions assessed the effects of implicit practice on the overt production of simple and complex consonant blends in words. An imaging protocol compared semantic baseline tasks to treatment tasks to verify that implicit phoneme manipulation activated brain regions of interest.
Outcomes & Results
Behavioral: Response to implicit training of complex consonant blends resulted in improvements which were maintained 6 weeks after treatment. Further, this treatment generalized to simpler consonant blends in words. Imaging: Functional imaging during implicit phoneme manipulation showed significant activation in brain regions responsible for phonological processing when compared to the baseline semantic task.
Implicit phoneme manipulation offers an alternative to traditional methods that require overt production for treatment of AOS. Additionally, this implicit treatment method was shown to activate neural areas known to be involved in phonological processing, motor planning and programming.
PMCID: PMC4136530  PMID: 25147422
4.  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.
PMCID: PMC2892940  PMID: 20542982
primary progressive aphasia; progressive non-fluent aphasia; semantic dementia; logopenic progressive aphasia; speech production
5.  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.
PMCID: PMC3024013  PMID: 21159955
syntactic processing; primary progressive aphasia; progressive non-fluent aphasia; inferior frontal gyrus; superior temporal sulcus; functional magnetic resonance imaging
6.  Neural correlates of word production stages delineated by parametric modulation of psycholinguistic variables 
Human brain mapping  2009;30(11):3596-3608.
Word production is a complex multi-stage process linking conceptual representations, lexical entries, phonological forms and articulation. Previous studies have revealed a network of predominantly left-lateralized brain regions supporting this process, but many details regarding the precise functions of different nodes in this network remain unclear. In order to better delineate the functions of regions involved in word production, we used event-related functional magnetic resonance imaging (fMRI) to identify brain areas where blood oxygen level-dependent (BOLD) responses to overt picture naming were modulated by three psycholinguistic variables: concept familiarity, word frequency, and word length, and one behavioral variable: reaction time. Each of these variables has been suggested by prior studies to be associated with different aspects of word production. Processing of less familiar concepts was associated with greater BOLD responses in bilateral occipito-temporal regions, reflecting visual processing and conceptual preparation. Lower frequency words produced greater BOLD signal in left inferior temporal cortex and the left temporo-parietal junction, suggesting involvement of these regions in lexical selection and retrieval and encoding of phonological codes. Word length was positively correlated with signal intensity in Heschl's gyrus bilaterally, extending into the mid superior temporal gyrus (STG) and sulcus (STS) in the left hemisphere. The left mid STS site was also modulated by reaction time, suggesting a role in the storage of lexical phonological codes.
PMCID: PMC2767422  PMID: 19365800
functional MRI; event-related; lexical access
7.  The salience network causally influences default mode network activity during moral reasoning 
Brain  2013;136(6):1929-1941.
Large-scale brain networks are integral to the coordination of human behaviour, and their anatomy provides insights into the clinical presentation and progression of neurodegenerative illnesses such as Alzheimer’s disease, which targets the default mode network, and behavioural variant frontotemporal dementia, which targets a more anterior salience network. Although the default mode network is recruited when healthy subjects deliberate about ‘personal’ moral dilemmas, patients with Alzheimer’s disease give normal responses to these dilemmas whereas patients with behavioural variant frontotemporal dementia give abnormal responses to these dilemmas. We hypothesized that this apparent discrepancy between activation- and patient-based studies of moral reasoning might reflect a modulatory role for the salience network in regulating default mode network activation. Using functional magnetic resonance imaging to characterize network activity of patients with behavioural variant frontotemporal dementia and healthy control subjects, we present four converging lines of evidence supporting a causal influence from the salience network to the default mode network during moral reasoning. First, as previously reported, the default mode network is recruited when healthy subjects deliberate about ‘personal’ moral dilemmas, but patients with behavioural variant frontotemporal dementia producing atrophy in the salience network give abnormally utilitarian responses to these dilemmas. Second, patients with behavioural variant frontotemporal dementia have reduced recruitment of the default mode network compared with healthy control subjects when deliberating about these dilemmas. Third, a Granger causality analysis of functional neuroimaging data from healthy control subjects demonstrates directed functional connectivity from nodes of the salience network to nodes of the default mode network during moral reasoning. Fourth, this Granger causal influence is diminished in patients with behavioural variant frontotemporal dementia. These findings are consistent with a broader model in which the salience network modulates the activity of other large-scale networks, and suggest a revision to a previously proposed ‘dual-process’ account of moral reasoning. These findings also characterize network interactions underlying abnormal moral reasoning in frontotemporal dementia, which may serve as a model for the aberrant judgement and interpersonal behaviour observed in this disease and in other disorders of social function. More broadly, these findings link recent work on the dynamic interrelationships between large-scale brain networks to observable impairments in dementia syndromes, which may shed light on how diseases that target one network also alter the function of interrelated networks.
PMCID: PMC3673466  PMID: 23576128
moral reasoning; frontotemporal dementia; salience network; default mode network; functional neuroimaging
8.  Neural substrates of socioemotional self-awareness in neurodegenerative disease 
Brain and Behavior  2014;4(2):201-214.
Neuroimaging studies examining neural substrates of impaired self-awareness in patients with neurodegenerative diseases have shown divergent results depending on the modality (cognitive, emotional, behavioral) of awareness. Evidence is accumulating to suggest that self-awareness arises from a combination of modality-specific and large-scale supramodal neural networks.
We investigated the structural substrates of patients' tendency to overestimate or underestimate their own capacity to demonstrate empathic concern for others. Subjects' level of empathic concern was measured using the Interpersonal Reactivity Index, and subject-informant discrepancy scores were used to predict regional atrophy pattern, using voxel-based morphometry analysis. Of the 102 subjects, 83 were patients with neurodegenerative diseases such as behavioral variant frontotemporal dementia (bvFTD) or semantic variant primary progressive aphasia (svPPA); the other 19 were healthy older adults.
bvFTD and svPPA patients typically overestimated their level of empathic concern compared to controls, and overestimating one's empathic concern predicted damage to predominantly right-hemispheric anterior infero-lateral temporal regions, whereas underestimating one's empathic concern showed no neuroanatomical basis.
These findings suggest that overestimation and underestimation of one's capacity for empathic concern cannot be interpreted as varying degrees of the same phenomenon, but may arise from different pathophysiological processes. Damage to anterior infero-lateral temporal regions has been associated with semantic self-knowledge, emotion processing, and social perspective taking; neuropsychological functions partly associated with empathic concern itself. These findings support the hypothesis that—at least in the socioemotional domain—neural substrates of self-awareness are partly modality-specific.
PMCID: PMC3967536  PMID: 24683513
Affective perspective taking; dementia; empathy; infero-lateral temporal cortex; neurodegeneration; semantic self-knowledge; unawareness; voxel-based morphometry
9.  Elicitation of specific syntactic structures in primary progressive aphasia 
Brain and language  2012;123(3):183-190.
Many patients with primary progressive aphasia (PPA) are impaired in syntactic production. Because most previous studies of expressive syntax in PPA have relied on quantitative analysis of connected speech samples, which is a relatively unconstrained task, it is not well understood which specific syntactic structures are most challenging for these patients. We used an elicited syntactic production task to identify which syntactic structures pose difficulties for 31 patients with three variants of PPA: non-fluent/agrammatic, semantic and logopenic. Neurodegenerative and healthy age-matched participants were included as controls. As expected, non-fluent/agrammatic patients made the most syntactic errors. The structures that resulted in the most errors were constructions involving third person singular present agreement, and constructions involving embedded clauses. Deficits on this elicited production task were associated with atrophy of the left posterior inferior frontal gyrus.
PMCID: PMC3502680  PMID: 23046707
syntax; production; primary progressive aphasia; voxel-based morphometry
10.  Distinct Neural Substrates for Semantic Knowledge and Naming in the Temporoparietal Network 
Cerebral Cortex (New York, NY)  2011;22(10):2217-2226.
Patients with anterior temporal lobe (ATL) lesions show semantic and lexical retrieval deficits, and the differential role of this area in the 2 processes is debated. Functional neuroimaging in healthy individuals has not clarified the matter because semantic and lexical processes usually occur simultaneously and automatically. Furthermore, the ATL is a region challenging for functional magnetic resonance imaging (fMRI) due to susceptibility artifacts, especially at high fields. In this study, we established an optimized ATL-sensitive fMRI acquisition protocol at 4 T and applied an event-related paradigm to study the identification (i.e., association of semantic biographical information) of celebrities, with and without the ability to retrieve their proper names. While semantic processing reliably activated the ATL, only more posterior areas in the left temporal and temporal–parietal junction were significantly modulated by covert lexical retrieval. These results suggest that within a temporoparietal network, the ATL is relatively more important for semantic processing, and posterior language regions are relatively more important for lexical retrieval.
PMCID: PMC3895951  PMID: 22047967
EPI optimization; famous faces; lexical retrieval; MRI; susceptibility artifacts
11.  The neural basis of syntactic deficits in primary progressive aphasia 
Brain and language  2012;122(3):190-198.
Patients with primary progressive aphasia (PPA) vary considerably in terms of which brain regions are impacted, as well as in the extent to which syntactic processing is impaired. Here we review the literature on the neural basis of syntactic deficits in PPA. Structural and functional imaging studies have most consistently associated syntactic deficits with damage to left inferior frontal cortex. Posterior perisylvian regions have been implicated in some studies. Damage to the superior longitudinal fasciculus, including its arcuate component, has been linked with syntactic deficits, even after gray matter atrophy is taken into account. These findings suggest that syntactic processing depends on left frontal and posterior perisylvian regions, as well as intact connectivity between them. In contrast, anterior temporal regions, and the ventral tracts that link frontal and temporal language regions, appear to be less important for syntax, since they are damaged in many PPA patients with spared syntactic processing.
PMCID: PMC3418470  PMID: 22546214
syntax; primary progressive aphasia; voxel-based morphometry; functional MRI; diffusion tensor imaging
12.  Syntactic processing depends on dorsal language tracts 
Neuron  2011;72(2):397-403.
Frontal and temporal language areas involved in syntactic processing are connected by several dorsal and ventral tracts, but the functional roles of the different tracts are not well understood. To identify which white matter tract(s) are important for syntactic processing, we examined the relationship between white matter damage and syntactic deficits in patients with primary progressive aphasia, using multimodal neuroimaging and neurolinguistic assessment. Diffusion tensor imaging showed that microstructural damage to left hemisphere dorsal tracts—the superior longitudinal fasciculus including its arcuate component—was strongly associated with deficits in comprehension and production of syntax. Damage to these dorsal tracts predicted syntactic deficits after gray matter atrophy was taken into account, and fMRI confirmed that these tracts connect regions modulated by syntactic processing. In contrast, damage to ventral tracts—the extreme capsule fiber system or the uncinate fasciculus—was not associated with syntactic deficits. Our findings show that syntactic processing depends primarily on dorsal language tracts.
PMCID: PMC3201770  PMID: 22017996
13.  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.
PMCID: PMC3187537  PMID: 21666264
primary progressive aphasia; progressive non-fluent aphasia; semantic dementia; logopenic progressive aphasia; diffusion tensor imaging
14.  Clinicopathological correlations in corticobasal degeneration 
Annals of neurology  2011;70(2):327-340.
To characterize cognitive and behavioral features, physical findings and brain atrophy patterns in pathology-proven corticobasal degeneration (CBD) and corticobasal syndrome (CBS) with known histopathology.
We reviewed clinical and MRI data in all patients evaluated at our center with either an autopsy diagnosis of CBD (n=18) or clinical CBS at first presentation with known histopathology (n=40). Atrophy patterns were compared using voxel-based morphometry.
CBD was associated with four clinical syndromes: progressive nonfluent aphasia (5), behavioral variant frontotemporal dementia (5), executive-motor (7), and posterior cortical atrophy (1). Behavioral or cognitive problems were the initial symptoms in 15/18 patients; less than half exhibited early motor findings. Compared to controls, CBD patients showed atrophy in dorsal prefrontal and peri-rolandic cortex, striatum and brainstem (p<0.001 uncorrected). The most common pathologic substrates for clinical CBS were CBD (35%), Alzheimer’s disease (AD, 23%), progressive supranuclear palsy (13%), and frontotemporal lobar degeneration (FTLD) with TDP inclusions (13%). CBS was associated with perirolandic atrophy irrespective of underlying pathology. In CBS due to FTLD (tau or TDP), atrophy extended into prefrontal cortex, striatum and brainstem, while in CBS due to AD, atrophy extended into temporoparietal cortex and precuneus (p<0.001 uncorrected).
Frontal lobe involvement is characteristic of CBD, and in many patients frontal, not parietal or basal ganglia symptoms, dominate early-stage disease. CBS is driven by medial peri-rolandic dysfunction, but this anatomy is not specific to one single underlying histopathology. Antemortem prediction of CBD will remain challenging until clinical features of CBD are redefined, and sensitive, specific biomarkers are identified.
PMCID: PMC3154081  PMID: 21823158
15.  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.
PMCID: PMC2994599  PMID: 20206985
16.  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.
PMCID: PMC2801321  PMID: 19759202
semantic dementia; semantic knowledge; diffusion tensor-based tractography; functional MRI; voxel-based morphometry
17.  Automated MRI-based classification of primary progressive aphasia variants 
NeuroImage  2009;47(4):1558-1567.
Degeneration of language regions in the dominant hemisphere can result in primary progressive aphasia (PPA), a clinical syndrome characterized by progressive deficits in speech and/or language function. Recent studies have identified three variants of PPA: progressive non-fluent aphasia (PNFA), semantic dementia (SD) and logopenic progressive aphasia (LPA). Each variant is associated with characteristic linguistic features, distinct patterns of brain atrophy, and different likelihoods of particular underlying pathogenic processes, which makes correct differential diagnosis highly clinically relevant. Evaluation of linguistic behavior can be challenging for non-specialists, and neuroimaging findings in single subjects are often difficult to evaluate by eye. We investigated the utility of automated structural MR image analysis to discriminate PPA variants (N=86) from each other and from normal controls (N=115). T1 images were preprocessed to obtain modulated grey matter (GM) images. Feature selection was performed with principal components analysis (PCA) on GM images as well as images of lateralized atrophy. PC coefficients were classified with linear support vector machines, and a cross-validation scheme was used to obtain accuracy rates for generalization to novel cases. The overall mean accuracy in discriminating between pairs of groups was 92.2%. For one pair of groups, PNFA and SD, we also investigated the utility of including several linguistic variables as features. Models with both imaging and linguistic features performed better than models with only imaging or only linguistic features. These results suggest that automated methods could assist in the differential diagnosis of PPA variants, enabling therapies to be targeted to likely underlying etiologies.
PMCID: PMC2719687  PMID: 19501654
18.  Detecting Sarcasm from Paralinguistic Cues: Anatomic and Cognitive Correlates in Neurodegenerative Disease 
NeuroImage  2009;47(4):2005-2015.
While sarcasm can be conveyed solely through contextual cues such as counterfactual or echoic statements, face-to-face sarcastic speech may be characterized by specific paralinguistic features that alert the listener to interpret the utterance as ironic or critical, even in the absence of contextual information. We investigated the neuroanatomy underlying failure to understand sarcasm from dynamic vocal and facial paralinguistic cues. Ninety subjects (20 frontotemporal dementia, 11 semantic dementia [SemD], 4 progressive nonfluent aphasia, 27 Alzheimer’s disease, 6 corticobasal degeneration, 9 progressive supranuclear palsy, 13 healthy older controls) were tested using the Social Inference – Minimal subtest of The Awareness of Social Inference Test (TASIT). Subjects watched brief videos depicting sincere or sarcastic communication and answered yes-no questions about the speaker’s intended meaning. All groups interpreted Sincere (SIN) items normally, and only the SemD group was impaired on the Simple Sarcasm (SSR) condition. Patients failing the SSR performed more poorly on dynamic emotion recognition tasks and had more neuropsychiatric disturbances, but had better verbal and visuospatial working memory than patients who comprehended sarcasm. Voxel-based morphometry analysis of SSR scores in SPM5 demonstrated that poorer sarcasm comprehension was predicted by smaller volume in bilateral posterior parahippocampii (PHc), temporal poles, and R medial frontal pole (pFWE<0.05). This study provides lesion data suggesting that the PHc may be involved in recognizing a paralinguistic speech profile as abnormal, leading to interpretive processing by the temporal poles and right medial frontal pole that identifies the social context as sarcastic, and recognizes the speaker’s paradoxical intentions.
PMCID: PMC2720152  PMID: 19501175
19.  Gray matter correlates of set-shifting among neurodegenerative disease, mild cognitive impairment, and healthy older adults 
There is increasing recognition that set-shifting, a form of cognitive control, is mediated by different neural structures. However, these regions have not yet been carefully identified as many studies do not account for the influence of component processes (e.g., motor speed). We investigated gray matter correlates of set-shifting while controlling for component processes. Using the Design Fluency (DF), Trail Making Test (TMT), and Color Word Interference (CWI) subtests from the Delis-Kaplan Executive Function System (D-KEFS), we investigated the correlation between set-shifting performance and gray matter volume in 160 subjects with neurodegenerative disease, mild cognitive impairment, and healthy older adults using voxel-based morphometry. All three set-shifting tasks correlated with multiple, widespread gray matter regions. After controlling for the component processes, set-shifting performance correlated with focal regions in prefrontal and posterior parietal cortices. We also identified bilateral prefrontal cortex and the right posterior parietal lobe as common sites for set-shifting across the three tasks. There was a high degree of multicollinearity between the set-shifting conditions and the component processes of TMT and CWI, suggesting DF may better isolate set-shifting regions. Overall, these findings highlight the neuroanatomical correlates of set-shifting and the importance of controlling for component processes when investigating complex cognitive tasks.
PMCID: PMC2891121  PMID: 20374676
D-KEFS; Design fluency; Trail making test; Color word interference; Executive function; Voxel-based morphometry
20.  The neural basis of surface dyslexia in semantic dementia 
Brain  2008;132(1):71-86.
Semantic dementia (SD) is a neurodegenerative disease characterized by atrophy of anterior temporal regions and progressive loss of semantic memory. SD patients often present with surface dyslexia, a relatively selective impairment in reading low-frequency words with exceptional or atypical spelling-to-sound correspondences. Exception words are typically ‘over-regularized’ in SD and pronounced as they are spelled (e.g. ‘sew’ is pronounced as ‘sue’). This suggests that in the absence of sufficient item-specific knowledge, exception words are read by relying mainly on subword processes for regular mapping of orthography to phonology. In this study, we investigated the functional anatomy of surface dyslexia in SD using functional magnetic resonance imaging (fMRI) and studied its relationship to structural damage with voxel-based morphometry (VBM). Five SD patients and nine healthy age-matched controls were scanned while they read regular words, exception words and pseudowords in an event-related design. Vocal responses were recorded and revealed that all patients were impaired in reading low-frequency exception words, and made frequent over-regularization errors. Consistent with prior studies, fMRI data revealed that both groups activated a similar basic network of bilateral occipital, motor and premotor regions for reading single words. VBM showed that these regions were not significantly atrophied in SD. In control subjects, a region in the left intraparietal sulcus was activated for reading pseudowords and low-frequency regular words but not exception words, suggesting a role for this area in subword mapping from orthographic to phonological representations. In SD patients only, this inferior parietal region, which was not atrophied, was also activated by reading low-frequency exception words, especially on trials where over-regularization errors occurred. These results suggest that the left intraparietal sulcus is involved in subword reading processes that are differentially recruited in SD when word-specific information is lost. This loss is likely related to degeneration of the anterior temporal lobe, which was severely atrophied in SD. Consistent with this, left mid-fusiform and superior temporal regions that showed reading-related activations in controls were not activated in SD. Taken together, these results suggest that the left inferior parietal region subserves subword orthographic-to-phonological processes that are recruited for exception word reading when retrieval of exceptional, item-specific word forms is impaired by degeneration of the anterior temporal lobe.
PMCID: PMC2638692  PMID: 19022856
semantic dementia; dyslexia; parietal lobe; voxel-based morphometry; functional MRI
21.  Neural Basis of Interpersonal Traits in Neurodegenerative Diseases 
Neuropsychologia  2009;47(13):2812-2827.
Several functional and structural imaging studies have investigated the neural basis of personality in healthy adults, but human lesions studies are scarce. Personality changes are a common symptom in patients with neurodegenerative diseases like frontotemporal dementia (FTD) and semantic dementia (SD), allowing a unique window into the neural basis of personality. In this study, we used the Interpersonal Adjective Scales to investigate the structural basis of eight interpersonal traits (dominance, arrogance, coldness, introversion, submissiveness, ingenuousness, warmth, and extraversion) in 257 subjects: 214 patients with neurodegenerative diseases such as FTD, SD, progressive non-fluent aphasia, Alzheimer’s disease, amnestic mild cognitive impairment, corticobasal degeneration, and progressive supranuclear palsy and 43 healthy elderly people. Measures of interpersonal traits were correlated with regional atrophy pattern using voxel-based morphometry (VBM) analysis of structural MR images. Interpersonal traits mapped onto distinct brain regions depending on the degree to which they involved agency and affiliation. Interpersonal traits high in agency related to left dorsolateral prefrontal and left lateral frontopolar regions, whereas interpersonal traits high in affiliation related to right ventromedial prefrontal and right anteromedial temporal regions. Consistent with the existing literature on neural networks underlying social cognition, these results indicate that brain regions related to externally-focused, executive control-related processes underlie agentic interpersonal traits such as dominance, whereas brain regions related to internally-focused, emotion- and reward-related processes underlie affiliative interpersonal traits such as warmth. In addition, these findings indicate that interpersonal traits are subserved by complex neural networks rather than discrete anatomic areas.
PMCID: PMC2765796  PMID: 19540253
neurodegenerative disease; personality; affiliation; agency; voxel-based morphometry
22.  Neural Organization of Linguistic Short-Term Memory is Sensory Modality-Dependent 
Journal of cognitive neuroscience  2008;20(12):2198-2210.
Despite decades of research, there is still disagreement regarding the nature of the information that is maintained in linguistic short-term memory (STM). Some authors argue for abstract phonological codes, whereas others argue for more general sensory traces. We assess these possibilities by investigating linguistic STM in two distinct sensory-motor modalities, spoken and signed language. Hearing bilingual participants (native in English and American Sign Language) performed equivalent STM tasks in both languages during fMRI scanning. Distinct, sensory-specific activations were seen during the maintenance phase of the task for spoken versus signed language. These regions have been previously shown to respond to non-linguistic sensory stimulation, suggesting that linguistic STM tasks recruit sensory-specific networks. However, maintenance-phase activations common to the two languages were also observed, implying some form of common process. We conclude that linguistic STM involves sensory-dependent neural networks, but suggest that sensory-independent neural networks may also exist.
PMCID: PMC2727636  PMID: 18457510
speech; sign; language; fMRI; short-term memory
23.  Giving Speech a Hand: Gesture Modulates Activity in Auditory Cortex During Speech Perception 
Human brain mapping  2009;30(3):1028-1037.
Viewing hand gestures during face-to-face communication affects speech perception and comprehension. Despite the visible role played by gesture in social interactions, relatively little is known about how the brain integrates hand gestures with co-occurring speech. Here we used functional magnetic resonance imaging (fMRI) and an ecologically valid paradigm to investigate how beat gesture – a fundamental type of hand gesture that marks speech prosody – might impact speech perception at the neural level. Subjects underwent fMRI while listening to spontaneously-produced speech accompanied by beat gesture, nonsense hand movement, or a still body; as additional control conditions, subjects also viewed beat gesture, nonsense hand movement, or a still body all presented without speech. Validating behavioral evidence that gesture affects speech perception, bilateral nonprimary auditory cortex showed greater activity when speech was accompanied by beat gesture than when speech was presented alone. Further, the left superior temporal gyrus/sulcus showed stronger activity when speech was accompanied by beat gesture than when speech was accompanied by nonsense hand movement. Finally, the right planum temporale was identified as a putative multisensory integration site for beat gesture and speech (i.e., here activity in response to speech accompanied by beat gesture was greater than the summed responses to speech alone and beat gesture alone), indicating that this area may be pivotally involved in synthesizing the rhythmic aspects of both speech and gesture. Taken together, these findings suggest a common neural substrate for processing speech and gesture, likely reflecting their joint communicative role in social interactions.
PMCID: PMC2644740  PMID: 18412134
gestures; speech perception; auditory cortex; magnetic resonance imaging; nonverbal communication
24.  First Insights into the Evolution of Streptococcus uberis: a Multilocus Sequence Typing Scheme That Enables Investigation of Its Population Biology 
Intramammary infection with Streptococcus uberis is a common cause of bovine mastitis throughout the world. Several procedures to differentiate S. uberis isolates have been proposed. However, all are prone to interlaboratory variation, and none is suitable for the description of the population structure. We describe here the development of a multilocus sequence typing (MLST) scheme for S. uberis to help address these issues. The sequences of seven housekeeping gene fragments from each of 160 United Kingdom milk isolates of S. uberis were determined. Between 5 and 17 alleles were obtained per locus, giving the potential to discriminate between 1.3 × 107 sequence types. In this study, 57 sequence types (STs) were identified. Statistical comparisons between the maximum-likelihood trees constructed by using the seven housekeeping gene fragments showed that the congruence was no better than that between each tree and trees of random topology, indicating there had been significant recombination within these loci. The population contained one major lineage (designated the ST-5 complex). This dominated the population, containing 24 STs and representing 112 isolates. The other 33 STs were not assigned to any clonal complex. All of the isolates in the ST-5 lineage carried hasA, a gene that is essential for capsule production. There was no clear association between ST or clonal complex and disease. The S. uberis MLST system offers researchers a valuable tool that allows further investigation of the population biology of this organism and insights into the epidemiology of this disease on a global scale.
PMCID: PMC1392973  PMID: 16461695

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