Efficacy of spoken word comprehension therapy in patients with chronic aphasia: a cross-over randomised controlled trial with structural imaging.

OBJECTIVE: The efficacy of spoken language comprehension therapies for persons with aphasia remains equivocal. We investigated the efficacy of a self-led therapy app, 'Listen-In', and examined the relation between brain structure and therapy response. METHODS: A cross-over randomised repeated measures trial with five testing time points (12-week intervals), conducted at the university or participants' homes, captured baseline (T1), therapy (T2-T4) and maintenance (T5) effects. Participants with chronic poststroke aphasia and spoken language comprehension impairments completed consecutive Listen-In and standard care blocks (both 12 weeks with order randomised). Repeated measures analyses of variance compared change in spoken language comprehension on two co-primary outcomes over therapy versus standard care. Three structural MRI scans (T2-T4) for each participant (subgroup, n=25) were analysed using cross-sectional and longitudinal voxel-based morphometry. RESULTS: Thirty-five participants completed, on average, 85 hours (IQR=70-100) of Listen-In (therapy first, n=18). The first study-specific co-primary outcome (Auditory Comprehension Test (ACT)) showed large and significant improvements for trained spoken words over therapy versus standard care (11%, Cohen's d=1.12). Gains were largely maintained at 12 and 24 weeks. There were no therapy effects on the second standardised co-primary outcome (Comprehensive Aphasia Test: Spoken Words and Sentences). Change on ACT trained words was associated with volume of pretherapy right hemisphere white matter and post-therapy grey matter tissue density changes in bilateral temporal lobes. CONCLUSIONS: Individuals with chronic aphasia can improve their spoken word comprehension many years after stroke. Results contribute to hemispheric debates implicating the right hemisphere in therapy-driven language recovery. Listen-In will soon be available on GooglePlay. TRIAL REGISTRATION NUMBER: NCT02540889.

Right hemisphere structural adaptation and changing language skills years after left hemisphere stroke.

Stroke survivors with acquired language deficits are commonly thought to reach a 'plateau' within a year of stroke onset, after which their residual language skills will remain stable. Nevertheless, there have been reports of patients who appear to recover over years. Here, we analysed longitudinal change in 28 left-hemisphere stroke patients, each more than a year post-stroke when first assessed-testing each patient's spoken object naming skills and acquiring structural brain scans twice. Some of the patients appeared to improve over time while others declined; both directions of change were associated with, and predictable given, structural adaptation in the intact right hemisphere of the brain. Contrary to the prevailing view that these patients' language skills are stable, these results imply that real change continues over years. The strongest brain-behaviour associations (the 'peak clusters') were in the anterior temporal lobe and the precentral gyrus. Using functional magnetic resonance imaging, we confirmed that both regions are actively involved when neurologically normal control subjects name visually presented objects, but neither appeared to be involved when the same participants used a finger press to make semantic association decisions on the same stimuli. This suggests that these regions serve word-retrieval or articulatory functions in the undamaged brain. We teased these interpretations apart by reference to change in other tasks. Consistent with the claim that the real change is occurring here, change in spoken object naming was correlated with change in two other similar tasks, spoken action naming and written object naming, each of which was independently associated with structural adaptation in similar (overlapping) right hemisphere regions. Change in written object naming, which requires word-retrieval but not articulation, was also significantly more correlated with both (i) change in spoken object naming; and (ii) structural adaptation in the two peak clusters, than was change in another task-auditory word repetition-which requires articulation but not word retrieval. This suggests that the changes in spoken object naming reflected variation at the level of word-retrieval processes. Surprisingly, given their qualitatively similar activation profiles, hypertrophy in the anterior temporal region was associated with improving behaviour, while hypertrophy in the precentral gyrus was associated with declining behaviour. We predict that either or both of these regions might be fruitful targets for neural stimulation studies (suppressing the precentral region and/or enhancing the anterior temporal region), aiming to encourage recovery or arrest decline even years after stroke occurs.

Modulation of frontal effective connectivity during speech.

Noninvasive neurostimulation methods such as transcranial direct current stimulation (tDCS) can elicit long-lasting, polarity-dependent changes in neocortical excitability. In a previous concurrent tDCS-fMRI study of overt picture naming, we reported significant behavioural and regionally specific neural facilitation effects in left inferior frontal cortex (IFC) with anodal tDCS applied to left frontal cortex (Holland et al., 2011). Although distributed connectivity effects of anodal tDCS have been modelled at rest, the mechanism by which 'on-line' tDCS may modulate neuronal connectivity during a task-state remains unclear. Here, we used Dynamic Causal Modelling (DCM) to determine: (i) how neural connectivity within the frontal speech network is modulated during anodal tDCS; and, (ii) how individual variability in behavioural response to anodal tDCS relates to changes in effective connectivity strength. Results showed that compared to sham, anodal tDCS elicited stronger feedback from inferior frontal sulcus (IFS) to ventral premotor (VPM) accompanied by weaker self-connections within VPM, consistent with processes of neuronal adaptation. During anodal tDCS individual variability in the feedforward connection strength from IFS to VPM positively correlated with the degree of facilitation in naming behaviour. These results provide an essential step towards understanding the mechanism of 'online' tDCS paired with a cognitive task. They also identify left IFS as a 'top-down' hub and driver for speech change.

Comparing language outcomes in monolingual and bilingual stroke patients.

Post-stroke prognoses are usually inductive, generalizing trends learned from one group of patients, whose outcomes are known, to make predictions for new patients. Research into the recovery of language function is almost exclusively focused on monolingual stroke patients, but bilingualism is the norm in many parts of the world. If bilingual language recruits qualitatively different networks in the brain, prognostic models developed for monolinguals might not generalize well to bilingual stroke patients. Here, we sought to establish how applicable post-stroke prognostic models, trained with monolingual patient data, are to bilingual stroke patients who had been ordinarily resident in the UK for many years. We used an algorithm to extract binary lesion images for each stroke patient, and assessed their language with a standard tool. We used feature selection and cross-validation to find 'good' prognostic models for each of 22 different language skills, using monolingual data only (174 patients; 112 males and 62 females; age at stroke: mean = 53.0 years, standard deviation = 12.2 years, range = 17.2-80.1 years; time post-stroke: mean = 55.6 months, standard deviation = 62.6 months, range = 3.1-431.9 months), then made predictions for both monolinguals and bilinguals (33 patients; 18 males and 15 females; age at stroke: mean = 49.0 years, standard deviation = 13.2 years, range = 23.1-77.0 years; time post-stroke: mean = 49.2 months, standard deviation = 55.8 months, range = 3.9-219.9 months) separately, after training with monolingual data only. We measured group differences by comparing prediction error distributions, and used a Bayesian test to search for group differences in terms of lesion-deficit associations in the brain. Our models distinguish better outcomes from worse outcomes equally well within each group, but tended to be over-optimistic when predicting bilingual language outcomes: our bilingual patients tended to have poorer language skills than expected, based on trends learned from monolingual data alone, and this was significant (P < 0.05, corrected for multiple comparisons) in 13/22 language tasks. Both patient groups appeared to be sensitive to damage in the same sets of regions, though the bilinguals were more sensitive than the monolinguals. media-1vid1 10.1093/brain/awv020_video_abstract awv020_video_abstract.

Neuroimaging in aphasia treatment research: quantifying brain lesions after stroke.

New structural and functional neuroimaging methods continue to rapidly develop, offering promising tools for cognitive neuroscientists. In the last 20 years, advanced magnetic resonance imaging (MRI) techniques have provided invaluable insights into how language is represented and processed in the brain and how it can be disrupted by damage to, or dysfunction of, various parts of the brain. Current functional MRI (fMRI) approaches have also allowed researchers to purposefully investigate how individuals recover language after stroke. This paper presents recommendations for quantification of brain lesions derived from discussions among international researchers at the Neuroimaging in Aphasia Treatment Research Workshop held at Northwestern University (Evanston, Illinois, USA). Methods for detailing and characterizing the brain damage that can influence results of fMRI studies in chronic aphasic stroke patients are discussed. Moreover, we aimed to provide the reader with a set of general practical guidelines and references to facilitate choosing adequate structural imaging strategies that facilitate fMRI studies in aphasia treatment research.

Neuroimaging in aphasia treatment research: consensus and practical guidelines for data analysis.

Functional magnetic resonance imaging is the most widely used imaging technique to study treatment-induced recovery in post-stroke aphasia. The longitudinal design of such studies adds to the challenges researchers face when studying patient populations with brain damage in cross-sectional settings. The present review focuses on issues specifically relevant to neuroimaging data analysis in aphasia treatment research identified in discussions among international researchers at the Neuroimaging in Aphasia Treatment Research Workshop held at Northwestern University (Evanston, Illinois, USA). In particular, we aim to provide the reader with a critical review of unique problems related to the pre-processing, statistical modeling and interpretation of such data sets. Despite the fact that data analysis procedures critically depend on specific design features of a given study, we aim to discuss and communicate a basic set of practical guidelines that should be applicable to a wide range of studies and useful as a reference for researchers pursuing this line of research.

Mapping spoken language and cognitive deficits in post-stroke aphasia.

Aphasia is an acquired disorder caused by damage, most commonly due to stroke, to brain regions involved in speech and language. While language impairment is the defining symptom of aphasia, the co-occurrence of non-language cognitive deficits and their importance in predicting rehabilitation and recovery outcomes is well documented. However, people with aphasia (PWA) are rarely tested on higher-order cognitive functions, making it difficult for studies to associate these functions with a consistent lesion correlate. Broca's area is a particular brain region of interest that has long been implicated in speech and language production. Contrary to classic models of speech and language, cumulative evidence shows that Broca's area and surrounding regions in the left inferior frontal cortex (LIFC) are involved in, but not specific to, speech production. In this study we aimed to explore the brain-behaviour relationships between tests of cognitive skill and language abilities in thirty-six adults with long-term speech production deficits caused by post-stroke aphasia. Our findings suggest that non-linguistic cognitive functions, namely executive functions and verbal working memory, explain more of the behavioural variance in PWA than classical language models imply. Additionally, lesions to the LIFC, including Broca's area, were associated with non-linguistic executive (dys)function, suggesting that lesions to this area are associated with non-language-specific higher-order cognitive deficits in aphasia. Whether executive (dys)function - and its neural correlate in Broca's area - contributes directly to PWA's language production deficits or simply co-occurs with it, adding to communication difficulties, remains unclear. These findings support contemporary models of speech production that place language processing within the context of domain-general perception, action and conceptual knowledge. An understanding of the covariance between language and non-language deficits and their underlying neural correlates will inform better targeted aphasia treatment and outcomes.

The effect of aging on the neural correlates of phonological word retrieval.

Age has a differential effect on cognition, with word retrieval being one of the cognitive domains most affected by aging. This study examined the functional and structural neural correlates of phonological word retrieval in younger and older adults using word and picture rhyme judgment tasks. Although the behavioral performance in the fMRI task was similar for the two age groups, the older adults had increased activation in the right pars triangularis across tasks and in the right pars orbitalis for the word task only. Increased activation together with preserved performance in the older participants would suggest that increased activation was related to compensatory processing. We validated this hypothesis by showing that right pars triangularis activation during correct rhyme judgments was highest in participants who made overall more errors, therefore being most error-prone. Our findings demonstrate that the effect of aging differ in adjacent but distinct right inferior frontal regions. The differential effect of age on word and picture tasks also provides new clues to the level of processing that is most affected by age in speech production tasks. Specifically, we suggest that right inferior frontal activation in older participants is needed to inhibit errors.

The neural correlates of inner speech defined by voxel-based lesion-symptom mapping.

The neural correlates of inner speech have been investigated previously using functional imaging. However, methodological and other limitations have so far precluded a clear description of the neural anatomy of inner speech and its relation to overt speech. Specifically, studies that examine only inner speech often fail to control for subjects' behaviour in the scanner and therefore cannot determine the relation between inner and overt speech. Functional imaging studies comparing inner and overt speech have not produced replicable results and some have similar methodological caveats as studies looking only at inner speech. Lesion analysis can avoid the methodological pitfalls associated with using inner and overt speech in functional imaging studies, while at the same time providing important data about the neural correlates essential for the specific function. Despite its advantages, a study of the neural correlates of inner speech using lesion analysis has not been carried out before. In this study, 17 patients with chronic post-stroke aphasia performed inner speech tasks (rhyme and homophone judgements), and overt speech tasks (reading aloud). The relationship between brain structure and language ability was studied using voxel-based lesion-symptom mapping. This showed that inner speech abilities were affected by lesions to the left pars opercularis in the inferior frontal gyrus and to the white matter adjacent to the left supramarginal gyrus, over and above overt speech production and working memory. These results suggest that inner speech cannot be assumed to be simply overt speech without a motor component. It also suggests that the use of overt speech to understand inner speech and vice versa might result in misleading conclusions, both in imaging studies and clinical practice.

A checklist for assessing the methodological quality of concurrent tES-fMRI studies (ContES checklist): a consensus study and statement.

Low-intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation, applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional MRI (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. The objective of this work was to develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency and reproducibility (ContES checklist). A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists through the International Network of the tES-fMRI Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC on the basis of a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed by using the checklist. Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (i) technological factors, (ii) safety and noise tests and (iii) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. In conclusion, use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies and increase methodological transparency and reproducibility.

Parallel recovery in a trilingual speaker: the use of the Bilingual Aphasia Test as a diagnostic complement to the Comprehensive Aphasia Test.

We illustrate the value of the Bilingual Aphasia Test in the diagnostic assessment of a trilingual speaker post-stroke living in England for whom English was a non-native language. The Comprehensive Aphasia Test is routinely used to assess patients in English, but only in combination with the Bilingual Aphasia Test is it possible and practical to provide a full picture of the language impairment. We describe our test selection and the assessment it allows us to make.

Lesion site and therapy time predict responses to a therapy for anomia after stroke: a prognostic model development study.

Stroke is a leading cause of disability, and language impairments (aphasia) after stroke are both common and particularly feared. Most stroke survivors with aphasia exhibit anomia (difficulties with naming common objects), but while many therapeutic interventions for anomia have been proposed, treatment effects are typically much larger in some patients than others. Here, we asked whether that variation might be more systematic, and even predictable, than previously thought. 18 patients, each at least 6 months after left hemisphere stroke, engaged in a computerised treatment for their anomia over a 6-week period. Using only: (a) the patients' initial accuracy when naming (to-be) trained items; (b) the hours of therapy that they devoted to the therapy; and (c) whole-brain lesion location data, derived from structural MRI; we developed Partial Least Squares regression models to predict the patients' improvements on treated items, and tested them in cross-validation. Somewhat surprisingly, the best model included only lesion location data and the hours of therapy undertaken. In cross-validation, this model significantly out-performed the null model, in which the prediction for each patient was simply the mean treatment effect of the group. This model also made promisingly accurate predictions in absolute terms: the correlation between empirical and predicted treatment response was 0.62 (95% CI 0.27, 0.95). Our results indicate that individuals' variation in response to anomia treatment are, at least somewhat, systematic and predictable, from the interaction between where and how much lesion damage they have suffered, and the time they devoted to the therapy.

Transcranial direct current stimulation with functional magnetic resonance imaging: a detailed validation and operational guide.

Introduction: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique used to modulate human brain and behavioural function in both research and clinical interventions. The combination of functional magnetic resonance imaging (fMRI) with tDCS enables researchers to directly test causal contributions of stimulated brain regions, answering questions about the physiology and neural mechanisms underlying behaviour. Despite the promise of the technique, advances have been hampered by technical challenges and methodological variability between studies, confounding comparability/replicability. Methods: Here tDCS-fMRI at 3T was developed for a series of experiments investigating language recovery after stroke. To validate the method, one healthy volunteer completed an fMRI paradigm with three conditions: (i) No-tDCS, (ii) Sham-tDCS, (iii) 2mA Anodal-tDCS. MR data were analysed in SPM12 with region-of-interest (ROI) analyses of the two electrodes and reference sites. Results: Quality assessment indicated no visible signal dropouts or distortions introduced by the tDCS equipment. After modelling scanner drift, motion-related variance, and temporal autocorrelation, we found no field inhomogeneity in functional sensitivity metrics across conditions in grey matter and in the three ROIs. Discussion: Key safety factors and risk mitigation strategies that must be taken into consideration when integrating tDCS into an fMRI environment are outlined. To obtain reliable results, we provide practical solutions to technical challenges and complications of the method. It is hoped that sharing these data and SOP will promote methodological replication in future studies, enhancing the quality of tDCS-fMRI application, and improve the reliability of scientific results in this field. Conclusions: The method and data provided here provide a technically safe, reliable tDCS-fMRI procedure to obtain high quality MR data. The detailed framework of the Standard Operation Procedure SOP ( https://doi.org/10.5281/zenodo.4606564) systematically reports the technical and procedural elements of our tDCS-fMRI approach, which we hope can be adopted and prove useful in future studies.

NUVA: A Naming Utterance Verifier for Aphasia Treatment.

Anomia (word-finding difficulties) is the hallmark of aphasia, an acquired language disorder most commonly caused by stroke. Assessment of speech performance using picture naming tasks is a key method for both diagnosis and monitoring of responses to treatment interventions by people with aphasia (PWA). Currently, this assessment is conducted manually by speech and language therapists (SLT). Surprisingly, despite advancements in automatic speech recognition (ASR) and artificial intelligence with technologies like deep learning, research on developing automated systems for this task has been scarce. Here we present NUVA, an utterance verification system incorporating a deep learning element that classifies 'correct' versus' incorrect' naming attempts from aphasic stroke patients. When tested on eight native British-English speaking PWA the system's performance accuracy ranged between 83.6% to 93.6%, with a 10-fold cross-validation mean of 89.5%. This performance was not only significantly better than a baseline created for this study using one of the leading commercially available ASRs (Google speech-to-text service) but also comparable in some instances with two independent SLT ratings for the same dataset.

Neurolinguistics: structural plasticity in the bilingual brain.

Humans have a unique ability to learn more than one language--a skill that is thought to be mediated by functional (rather than structural) plastic changes in the brain. Here we show that learning a second language increases the density of grey matter in the left inferior parietal cortex and that the degree of structural reorganization in this region is modulated by the proficiency attained and the age at acquisition. This relation between grey-matter density and performance may represent a general principle of brain organization.

Structural correlates of semantic and phonemic fluency ability in first and second languages.

Category and letter fluency tasks are commonly used clinically to investigate the semantic and phonological processes central to speech production, but the neural correlates of these processes are difficult to establish with functional neuroimaging because of the relatively unconstrained nature of the tasks. This study investigated whether differential performance on semantic (category) and phonemic (letter) fluency in neurologically normal participants was reflected in regional gray matter density. The participants were 59 highly proficient speakers of 2 languages. Our findings corroborate the importance of the left inferior temporal cortex in semantic relative to phonemic fluency and show this effect to be the same in a first language (L1) and second language (L2). Additionally, we show that the pre-supplementary motor area (pre-SMA) and head of caudate bilaterally are associated with phonemic more than semantic fluency, and this effect is stronger for L2 than L1 in the caudate nuclei. To further validate these structural results, we reanalyzed previously reported functional data and found that pre-SMA and left caudate activation was higher for phonemic than semantic fluency. On the basis of our findings, we also predict that lesions to the pre-SMA and caudate nuclei may have a greater impact on phonemic than semantic fluency, particularly in L2 speakers.

Neuroanatomical markers of speaking Chinese.

The aim of this study was to identify regional structural differences in the brains of native speakers of a tonal language (Chinese) compared to nontonal (European) language speakers. Our expectation was that there would be differences in regions implicated in pitch perception and production. We therefore compared structural brain images in three groups of participants: 31 who were native Chinese speakers; 7 who were native English speakers who had learnt Chinese in adulthood; and 21 European multilinguals who did not speak Chinese. The results identified two brain regions in the vicinity of the right anterior temporal lobe and the left insula where speakers of Chinese had significantly greater gray and white matter density compared with those who did not speak Chinese. Importantly, the effects were found in both native Chinese speakers and European subjects who learnt Chinese as a non-native language, illustrating that they were language related and not ethnicity effects. On the basis of prior studies, we suggest that the locations of these gray and white matter changes in speakers of a tonal language are consistent with a role in linking the pitch of words to their meaning.

Anatomical traces of vocabulary acquisition in the adolescent brain.

A surprising discovery in recent years is that the structure of the adult human brain changes when a new cognitive or motor skill is learned. This effect is seen as a change in local gray or white matter density that correlates with behavioral measures. Critically, however, the cognitive and anatomical mechanisms underlying these learning-related structural brain changes remain unknown. Here, we combined brain imaging, detailed behavioral analyses, and white matter tractography in English-speaking monolingual adolescents to show that a critical linguistic prerequisite (namely, knowledge of vocabulary) is proportionately related to relative gray matter density in bilateral posterior supramarginal gyri. The effect was specific to the number of words learned, regardless of verbal fluency or other cognitive abilities. The identified region was found to have direct connections to other inferior parietal areas that separately process either the sounds of words or their meanings, suggesting that the posterior supramarginal gyrus plays a role in linking the basic components of vocabulary knowledge. Together, these analyses highlight the cognitive and anatomical mechanisms that mediate an essential language skill.