Neural basis of speech and grammar symptoms in non-fluent variant primary progressive aphasia spectrum.

The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) is a neurodegenerative syndrome primarily defined by the presence of apraxia of speech (AoS) and/or expressive agrammatism. In addition, many patients exhibit dysarthria and/or receptive agrammatism. This leads to substantial phenotypic variation within the speech-language domain across individuals and time, in terms of both the specific combination of symptoms as well as their severity. How to resolve such phenotypic heterogeneity in nfvPPA is a matter of debate. 'Splitting' views propose separate clinical entities: 'primary progressive apraxia of speech' when AoS occurs in the absence of expressive agrammatism, 'progressive agrammatic aphasia' (PAA) in the opposite case, and 'AOS + PAA' when mixed motor speech and language symptoms are clearly present. While therapeutic interventions typically vary depending on the predominant symptom (e.g. AoS versus expressive agrammatism), the existence of behavioural, anatomical and pathological overlap across these phenotypes argues against drawing such clear-cut boundaries. In the current study, we contribute to this debate by mapping behaviour to brain in a large, prospective cohort of well characterized patients with nfvPPA (n = 104). We sought to advance scientific understanding of nfvPPA and the neural basis of speech-language by uncovering where in the brain the degree of MRI-based atrophy is associated with inter-patient variability in the presence and severity of AoS, dysarthria, expressive agrammatism or receptive agrammatism. Our cross-sectional examination of brain-behaviour relationships revealed three main observations. First, we found that the neural correlates of AoS and expressive agrammatism in nfvPPA lie side by side in the left posterior inferior frontal lobe, explaining their behavioural dissociation/association in previous reports. Second, we identified a 'left-right' and 'ventral-dorsal' neuroanatomical distinction between AoS versus dysarthria, highlighting (i) that dysarthria, but not AoS, is significantly influenced by tissue loss in right-hemisphere motor-speech regions; and (ii) that, within the left hemisphere, dysarthria and AoS map onto dorsally versus ventrally located motor-speech regions, respectively. Third, we confirmed that, within the large-scale grammar network, left frontal tissue loss is preferentially involved in expressive agrammatism and left temporal tissue loss in receptive agrammatism. Our findings thus contribute to define the function and location of the epicentres within the large-scale neural networks vulnerable to neurodegenerative changes in nfvPPA. We propose that nfvPPA be redefined as an umbrella term subsuming a spectrum of speech and/or language phenotypes that are closely linked by the underlying neuroanatomy and neuropathology.

An empirical comparison of univariate versus multivariate methods for the analysis of brain-behavior mapping.

Lesion symptom mapping (LSM) tools are used on brain injury data to identify the neural structures critical for a given behavior or symptom. Univariate lesion symptom mapping (ULSM) methods provide statistical comparisons of behavioral test scores in patients with and without a lesion on a voxel by voxel basis. More recently, multivariate lesion symptom mapping (MLSM) methods have been developed that consider the effects of all lesioned voxels in one model simultaneously. In the current study, we provide a much-needed systematic comparison of several ULSM and MLSM methods, using both synthetic and real data to identify the potential strengths and weaknesses of both approaches. We tested the spatial precision of each LSM method for both single and dual (network type) anatomical target simulations across anatomical target location, sample size, noise level, and lesion smoothing. Additionally, we performed false positive simulations to identify the characteristics associated with each method's spurious findings. Simulations showed no clear superiority of either ULSM or MLSM methods overall, but rather highlighted specific advantages of different methods. No single method produced a thresholded LSM map that exclusively delineated brain regions associated with the target behavior. Thus, different LSM methods are indicated, depending on the particular study design, specific hypotheses, and sample size. Overall, we recommend the use of both ULSM and MLSM methods in tandem to enhance confidence in the results: Brain foci identified as significant across both types of methods are unlikely to be spurious and can be confidently reported as robust results.

Spatiotemporal dynamics of word retrieval in speech production revealed by cortical high-frequency band activity.

Word retrieval is core to language production and relies on complementary processes: the rapid activation of lexical and conceptual representations and word selection, which chooses the correct word among semantically related competitors. Lexical and conceptual activation is measured by semantic priming. In contrast, word selection is indexed by semantic interference and is hampered in semantically homogeneous (HOM) contexts. We examined the spatiotemporal dynamics of these complementary processes in a picture naming task with blocks of semantically heterogeneous (HET) or HOM stimuli. We used electrocorticography data obtained from frontal and temporal cortices, permitting detailed spatiotemporal analysis of word retrieval processes. A semantic interference effect was observed with naming latencies longer in HOM versus HET blocks. Cortical response strength as indexed by high-frequency band (HFB) activity (70-150 Hz) amplitude revealed effects linked to lexical-semantic activation and word selection observed in widespread regions of the cortical mantle. Depending on the subsecond timing and cortical region, HFB indexed semantic interference (i.e., more activity in HOM than HET blocks) or semantic priming effects (i.e., more activity in HET than HOM blocks). These effects overlapped in time and space in the left posterior inferior temporal gyrus and the left prefrontal cortex. The data do not support a modular view of word retrieval in speech production but rather support substantial overlap of lexical-semantic activation and word selection mechanisms in the brain.

Direct brain recordings reveal hippocampal rhythm underpinnings of language processing.

Language is classically thought to be supported by perisylvian cortical regions. Here we provide intracranial evidence linking the hippocampal complex to linguistic processing. We used direct recordings from the hippocampal structures to investigate whether theta oscillations, pivotal in memory function, track the amount of contextual linguistic information provided in sentences. Twelve participants heard sentences that were either constrained ("She locked the door with the") or unconstrained ("She walked in here with the") before presentation of the final word ("key"), shown as a picture that participants had to name. Hippocampal theta power increased for constrained relative to unconstrained contexts during sentence processing, preceding picture presentation. Our study implicates hippocampal theta oscillations in a language task using natural language associations that do not require memorization. These findings reveal that the hippocampal complex contributes to language in an active fashion, relating incoming words to stored semantic knowledge, a necessary process in the generation of sentence meaning.

Role of the left hemisphere in visuospatial working memory.

Visuospatial processing deficits are typically associated with damage to the right hemisphere. However, deficits on spatial working memory have been reported among some individuals with focal left hemisphere damage (LHD). It has been suggested that the left hemisphere may play a role in such non-verbal working memory tasks due to the use of subvocal, verbally-mediated strategies. The current study investigated the role of the left hemisphere in spatial working memory by testing spatial span performance, both forward and backward, in a large group of individuals with a history of left hemisphere stroke. Our first aim was to establish whether individuals with LHD are indeed impaired on spatial span tasks using standardized span tasks with published normative data. Our second aim was to identify the role that language plays in supporting spatial working memory by comparing LHD individuals with and without aphasia, and by relating spatial span performance to performance on a series of language measures. Our third aim was to identify left hemisphere brain regions that contribute to spatial working memory using voxel-based lesion symptom mapping (VLSM), a whole-brain statistical approach that identifies regions critical to a particular behavior on a voxel-by-voxel basis. We found that 28% of individuals with LHD performed in the clinically-impaired range on forward spatial span and 16% performed in the clinically-impaired range on backward spatial span. There were no significant differences in performance between individuals with and without aphasia, and there were no correlations between spatial span performance and language functions such as repetition and comprehension. The VLSM analysis showed that backward spatial span was associated with a left fronto-parietal network consisting of somatosensory cortex, the supramarginal gyrus, lateral prefrontal cortex, and the frontal eye fields. Regions identified in the VLSM analysis of forward spatial span did not reach the conservative statistical threshold for significance. Overall, these results suggest that spatial working memory, as measured by spatial span, can be significantly disrupted in a subset of individuals with LHD whose lesions infringe on a network of regions in the left hemisphere that have been implicated in domain-general working memory and attentional control mechanisms.

Redefining the role of Broca's area in speech.

For over a century neuroscientists have debated the dynamics by which human cortical language networks allow words to be spoken. Although it is widely accepted that Broca's area in the left inferior frontal gyrus plays an important role in this process, it was not possible, until recently, to detail the timing of its recruitment relative to other language areas, nor how it interacts with these areas during word production. Using direct cortical surface recordings in neurosurgical patients, we studied the evolution of activity in cortical neuronal populations, as well as the Granger causal interactions between them. We found that, during the cued production of words, a temporal cascade of neural activity proceeds from sensory representations of words in temporal cortex to their corresponding articulatory gestures in motor cortex. Broca's area mediates this cascade through reciprocal interactions with temporal and frontal motor regions. Contrary to classic notions of the role of Broca's area in speech, while motor cortex is activated during spoken responses, Broca's area is surprisingly silent. Moreover, when novel strings of articulatory gestures must be produced in response to nonword stimuli, neural activity is enhanced in Broca's area, but not in motor cortex. These unique data provide evidence that Broca's area coordinates the transformation of information across large-scale cortical networks involved in spoken word production. In this role, Broca's area formulates an appropriate articulatory code to be implemented by motor cortex.

Neuroplasticity of language in left-hemisphere stroke: Evidence linking subsecond electrophysiology and structural connections.

The understanding of neuroplasticity following stroke is predominantly based on neuroimaging measures that cannot address the subsecond neurodynamics of impaired language processing. We combined behavioral and electrophysiological measures and structural-connectivity estimates to characterize neuroplasticity underlying successful compensation of language abilities after left-hemispheric stroke. We recorded the electroencephalogram from patients with stroke lesions to the left temporal lobe and from matched controls during context-driven word retrieval. Participants heard lead-in sentences that either constrained the final word ("He locked the door with the") or not ("She walked in here with the"). The last word was shown as a picture to be named. Individual-participant analyses were conducted, focusing on oscillatory power as a subsecond indicator of a brain region's functional neurophysiological computations. All participants named pictures faster following constrained than unconstrained sentences, except for two patients, who had extensive damage to the left temporal lobe. Left-lateralized alpha-beta oscillatory power decreased in controls pre-picture presentation for constrained relative to unconstrained contexts. In patients, the alpha-beta power decreases were observed with the same time course as in controls but were lateralized to the intact right hemisphere. The right lateralization depended on the probability of white-matter connections between the bilateral temporal lobes. The two patients who performed poorly behaviorally showed no alpha-beta power decreases. Our findings suggest that incorporating direct measures of neural activity into investigations of neuroplasticity can provide important neural markers to help predict language recovery, assess the progress of neurorehabilitation, and delineate targets for therapeutic neuromodulation. Hum Brain Mapp 38:3151-3162, 2017. © 2017 Wiley Periodicals, Inc.

What Do Language Disorders Reveal about Brain-Language Relationships? From Classic Models to Network Approaches.

Studies of language disorders have shaped our understanding of brain-language relationships over the last two centuries. This article provides a review of this research and how our thinking has changed over the years regarding how the brain processes language. In the 19th century, a series of famous case studies linked distinct speech and language functions to specific portions of the left hemisphere of the brain, regions that later came to be known as Broca's and Wernicke's areas. One hundred years later, the emergence of new brain imaging tools allowed for the visualization of brain injuries in vivo that ushered in a new era of brain-behavior research and greatly expanded our understanding of the neural processes of language. Toward the end of the 20th century, sophisticated neuroimaging approaches allowed for the visualization of both structural and functional brain activity associated with language processing in both healthy individuals and in those with language disturbance. More recently, language is thought to be mediated by a much broader expanse of neural networks that covers a large number of cortical and subcortical regions and their interconnecting fiber pathways. Injury to both grey and white matter has been seen to affect the complexities of language in unique ways that have altered how we think about brain-language relationships. The findings that support this paradigm shift are described here along with the methodologies that helped to discover them, with some final thoughts on future directions, techniques, and treatment interventions for those with communication impairments. (JINS, 2017, 23, 741-754).

Not Just Language: Persisting Lateralized Visuospatial Impairment after Left Hemisphere Stroke.

OBJECTIVES: Imbalances in spatial attention are most often associated with right hemisphere brain injury. This report assessed 25 chronic left hemisphere stroke patients for attentional bias. METHODS: Participants were evaluated with a computerized visual search task and a standardized neuropsychological assessment known as the Behavioral Inattention Test (BITC). Twenty age-matched controls were also tested. RESULTS: Although little to no attentional impairment was observed on the BITC, the computerized visual search task revealed statistically significant contralesional attentional impairment in the left hemisphere stroke group. Specifically, these participants required 208 ms more viewing time, on average, to reliably detect visual targets on the right side of the display compared to detection on the left side, while controls showed a difference of only 8 ms between the two sides. CONCLUSIONS: The observation of significant leftward visuospatial bias in this chronic stroke group provides further evidence that the left hemisphere also plays a role in the balance of visual attention across space. These results have implications for left hemisphere patients who are often not screened for visuospatial problems, as well as for theories of visual attention which have primarily emphasized the role of the right hemisphere. (JINS, 2016, 22, 695-704).

Cerebral perfusion in post-stroke aphasia and its relationship to residual language abilities.

Stroke alters blood flow to the brain resulting in damaged tissue and cell death. Moreover, the disruption of cerebral blood flow (perfusion) can be observed in areas surrounding and distal to the lesion. These structurally preserved but suboptimally perfused regions may also affect recovery. Thus, to better understand aphasia recovery, the relationship between cerebral perfusion and language needs to be systematically examined. In the current study, we aimed to evaluate (i) how stroke affects perfusion outside of lesioned areas in chronic aphasia and (ii) how perfusion in specific cortical areas and perilesional tissue relates to language outcomes in aphasia. We analysed perfusion data from a large sample of participants with chronic aphasia due to left hemisphere stroke (n = 43) and age-matched healthy controls (n = 25). We used anatomically defined regions of interest that covered the frontal, parietal, and temporal areas of the perisylvian cortex in both hemispheres, areas typically known to support language, along with several control regions not implicated in language processing. For the aphasia group, we also looked at three regions of interest in the perilesional tissue. We compared perfusion levels between the two groups and investigated the relationship between perfusion levels and language subtest scores while controlling for demographic and lesion variables. First, we observed that perfusion levels outside the lesioned areas were significantly reduced in frontal and parietal regions in the left hemisphere in people with aphasia compared to the control group, while no differences were observed for the right hemisphere regions. Second, we found that perfusion in the left temporal lobe (and most strongly in the posterior part of both superior and middle temporal gyri) and inferior parietal areas (supramarginal gyrus) was significantly related to residual expressive and receptive language abilities. In contrast, perfusion in the frontal regions did not show such a relationship; no relationship with language was also observed for perfusion levels in control areas and all right hemisphere regions. Third, perilesional perfusion was only marginally related to language production abilities. Cumulatively, the current findings demonstrate that blood flow is reduced beyond the lesion site in chronic aphasia and that hypoperfused neural tissue in critical temporoparietal language areas has a negative impact on behavioural outcomes. These results, using perfusion imaging, underscore the critical and general role that left hemisphere posterior temporal regions play in various expressive and receptive language abilities. Overall, the study highlights the importance of exploring perfusion measures in stroke.

A case of pure apraxia of speech after left hemisphere stroke: behavioral findings and neural correlates.

Introduction: Apraxia of speech (AOS) is a motor speech disorder impairing the coordination of complex articulatory movements needed to produce speech. AOS typically co-occurs with a non-fluent aphasia, or language disorder, making it challenging to determine the specific brain structures that cause AOS. Cases of pure AOS without aphasia are rare but offer the best window into the neural correlates that support articulatory planning. The goal of the current study was to explore patterns of apraxic speech errors and their underlying neural correlates in a case of pure AOS. Methods: A 67-year-old right-handed man presented with severe AOS resulting from a fronto-insular lesion caused by an ischemic stroke. The participant's speech and language were evaluated at 1-, 3- and 12-months post-onset. High resolution structural MRI, including diffusion weighted imaging, was acquired at 12 months post-onset. Results: At the first assessment, the participant made minor errors on the Comprehensive Aphasia Test, demonstrating mild deficits in writing, auditory comprehension, and repetition. By the second assessment, he no longer had aphasia. On the Motor Speech Evaluation, the severity of his AOS was initially rated as 5 (out of 7) and improved to a score of 4 by the second visit, likely due to training by his SLP at the time to slow his speech. Structural MRI data showed a fronto-insular lesion encompassing the superior precentral gyrus of the insula and portions of the inferior and middle frontal gyri and precentral gyrus. Tractography derived from diffusion MRI showed partial damage to the frontal aslant tract and arcuate fasciculus along the white matter projections to the insula. Discussion: This pure case of severe AOS without aphasia affords a unique window into the behavioral and neural mechanisms of this motor speech disorder. The current findings support previous observations that AOS and aphasia are dissociable and confirm a role for the precentral gyrus of the insula and BA44, as well as underlying white matter in supporting the coordination of complex articulatory movements. Additionally, other regions including the precentral gyrus, Broca's area, and Area 55b are discussed regarding their potential role in successful speech production.

Design and Implementation of a Clinical Science Specialty Clinic for Adults with Neurological Disorders and Their Caregivers.

Mental health problems are common for persons with neurological disorders (PWNDs) and their caregivers (CGs) but often are not adequately treated. Despite this growing need, the training of clinical psychologists typically does not include coursework or practicum experience working with these populations. To address this, a team of faculty, supervisors, and doctoral students in UC Berkeley's Clinical Science program undertook a year-long process that consisted of building a training curriculum that integrated coursework and consultation with visiting experts; providing supervised practicum training with PWNDs and CGs and evaluating training and clinical outcomes. We hoped to prepare students to train other mental health professionals to work with these populations in the future. In this article, we describe the Specialty Clinic with special attention given to the training provided, challenges faced and solutions found, clinic operations and logistics, and lessons learned. We also review key clinical issues and report key indicators of client outcomes. Finally, we evaluate the success of the Specialty Clinic and offer recommendations for others interested in providing these kinds of much needed training and clinical services in this important area.

White matter damage in primary progressive aphasias: a diffusion tensor tractography study.

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.

APHASIA: HOW OUR LANGUAGE SYSTEM CAN "BREAK".

Our brains enable us to learn language. We develop it early on in life and use it effortlessly every day. It is only when the language system breaks down that we fully realize how complicated it is to speak and understand. In this article, we will explore what happens when brain damage leads to a language disorder called aphasia. About 15 million people worldwide and about 2 million in the U.S. alone are affected by aphasia. Sadly, many people still do not know what aphasia is. Here, we will explain different types of aphasia, tell you about the language difficulties people with this disorder encounter, and provide information about how language is processed in the brain.

The unique role of the frontal aslant tract in speech and language processing.

The frontal aslant tract (FAT) is a recently described intralobar tract that connects the superior and inferior frontal gyri. The FAT has been implicated in various speech and language processes and disorders, including motor speech impairments, stuttering disorders, opercular syndrome, and verbal fluency, but the specific function(s) of the FAT have yet to be elucidated. In the current study, we aimed to address this knowledge gap by investigating the underlying role that the FAT plays in motor aspects of speech and language abilities in post-stroke aphasia. Our goals were three-fold: 1) To identify which specific motor speech or language abilities are impacted by FAT damage by utilizing a powerful imaging analysis method, High Angular Resolution Diffusion Imaging (HARDI) tractography; 2) To determine whether damage to the FAT is associated with functional deficits on a range of motor speech and language tasks even when accounting for cortical damage to adjacent cortical regions; and 3) To explore whether subsections of the FAT (lateral and medial segments) play distinct roles in motor speech performance. We hypothesized that damage to the FAT would be most strongly associated with motor speech performance in comparison to language tasks. We analyzed HARDI data from thirty-three people with aphasia (PWA) with a history of chronic left hemisphere stroke. FAT metrics were related to scores on several speech and language tests: the Motor Speech Evaluation (MSE), the Western Aphasia Battery (WAB) aphasia quotient and subtests, and the Boston Naming Test (BNT). Our results indicated that the integrity of the FAT was strongly associated with the MSE as predicted, and weakly negatively associated with WAB subtest scores including Naming, Comprehension, and Repetition, likely reflecting the fact that performance on these WAB subtests is associated with damage to posterior areas of the brain that are unlikely to be damaged with a frontal lesion. We also performed hierarchical stepwise regressions to predict language function based on FAT properties and lesion load to surrounding cortical areas. After accounting for the contributions of the inferior frontal gyrus, the ventral precentral gyrus, and the superior precentral gyrus of the insula, the FAT still remained a significant predictor of MSE apraxia scores. Our results further showed that the medial and lateral subsections of the FAT did not appear to play distinct roles but rather may indicate normal anatomical variations of the FAT. Overall, current results indicate that the FAT plays a specific and unique role in motor speech. These results further our understanding of the role that white matter tracts play in speech and language.

Dysgraphia Phenotypes in Native Chinese Speakers With Primary Progressive Aphasia.

BACKGROUND AND OBJECTIVES: Most primary progressive aphasia (PPA) literature is based on English language users. Linguistic features that vary from English, such as logographic writing systems, are underinvestigated. The current study characterized the dysgraphia phenotypes of patients with PPA who write in Chinese and investigated their diagnostic utility in classifying PPA variants. METHODS: This study recruited 40 participants with PPA and 20 cognitively normal participants from San Francisco, Hong Kong, and Taiwan. We measured dictation accuracy using the Chinese Language Assessment for PPA (CLAP) 60-character orthographic dictation test and examined the occurrence of various writing errors across the study groups. We also performed voxel-based morphometry analysis to identify the gray matter regions correlated with dictation accuracy and prevalence of writing errors. RESULTS: All PPA groups produced significantly less accurate writing responses than the control group and no significant differences in dictation accuracy were noted among the PPA variants. With a cut score of 36 out of 60 in the CLAP orthographic dictation task, the test achieved sensitivity and specificity of 90% and 95% in identifying Chinese participants with PPA vs controls. In addition to a character frequency effect, dictation accuracy was affected by homophone density and the number of strokes in semantic variant PPA and logopenic variant PPA groups. Dictation accuracy was correlated with volumetric changes over left ventral temporal cortices, regions known to be critical for orthographic long-term memory. Individuals with semantic variant PPA frequently presented with phonologically plausible errors at lexical level, patients with logopenic variant PPA showed higher preponderance towards visual and stroke errors, and patients with nonfluent/agrammatic variant PPA commonly exhibited compound word and radical errors. The prevalence of phonologically plausible, visual, and compound word errors was negatively correlated with cortical volume over the bilateral temporal regions, left temporo-occipital area, and bilateral orbitofrontal gyri, respectively. DISCUSSION: The findings demonstrate the potential role of the orthographic dictation task as a screening tool and PPA classification indicator in Chinese language users. Each PPA variant had specific Chinese dysgraphia phenotypes that vary from those previously reported in English-speaking patients with PPA, highlighting the importance of language diversity in PPA.

Neural correlates of syntactic processing in the nonfluent 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 nonfluent 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 nonfluent 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 nonfluent PPA. Using structural and functional magnetic resonance imaging, we quantified tissue volumes and functional responses to a syntactic comprehension task in eight patients with nonfluent 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 nonfluent 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 nonfluent PPA, the posterior IFC is not only structurally damaged, but also functionally abnormal, suggesting a critical role for this region in the breakdown of syntactic processing in this syndrome.

Language networks in semantic dementia.

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.

Connected speech production in three variants of primary progressive aphasia.

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.

Case study: A selective tactile naming deficit for letters and numbers due to interhemispheric disconnection.

The role of white matter pathways in cognition is a topic of active investigation that is vital to both the fields of clinical neurology and cognitive neuroscience. White matter pathways provide critical connectivity amongst numerous specialized brain regions thereby enabling higher level cognition. While the effects of dissections and lesions of the corpus callosum have been reported, it is less understood how unilateral focal white matter lesions may impact cognitive processes. Here, we report a unique case study in which a small left lateralized stroke in the white matter adjacent to the body of the corpus callosum selectively impaired the ability to name letters and numbers presented to the ipsilesional, left hand. Naming of letters, numbers and objects was tested in both the visual and tactile modalities in both hands. Diffusion-weighted imaging showed a marked reduction in white matter pathway integrity through the body of the corpus callosum. Clinically, this case highlights the significant impact that a focal white matter lesion can have on higher-level cognition, specifically the integration of verbal and tactile information. Moreover, this case adds to prior reports on tactile agnosia by including DTI imaging data and emphasizing the role that white matter pathways through the body of the corpus callosum play in integrating tactile input from the right hemisphere with verbal naming capabilities of the left hemisphere. Finally, the findings also provoke fresh insight into alternative strategies for rehabilitating cognitive functioning when structural connectivity may be compromised.