Repetition-imitation and aphasia: Neural Basis and treatment

Study 2: a single-case study was developed. Repetition performance was widely assessed in a patient with crossed conduction aphasia and striatal/capsular vascular lesions encompassing the right arcuate fasciculus (AF) and inferior frontal-occipital fasciculus (IFOF), the temporal stem and the white matter underneath the supramarginal gyrus. He showed lexicality effects repeating better words than non-words, but manipulation of other lexical-semantic variables exerted less influence on repetition performance. Imageability and frequency effects, production of meaning-based paraphrases during sentence repetition, or better performance on repeating novel sentences than overlearned clichés were hardly ever observed in this patient. Diffusion tensor imaging disclosed damage to the right long direct segment of the AF and IFOF with relative sparing of the anterior indirect and posterior segments of the AF, together with fully developed left perisylvian white matter pathways. These findings suggest that striatal/capsular lesions extending into the right AF and IFOF in some individuals with right hemisphere language dominance are associated with atypical repetition patterns which might reflect reduced interactions between phonological and lexical-semantic processes. Study 3: A within-patient design, with multiple assessments, was developed with the same patient as in Study 2A. The initial dose of Donepezil (5 mg/day) was titulated up to 10 mg/day and administered alone (without aphasia therapy) during 3 months (Endpoint 1). Then, the drug was combined with a verbal repetition-imitation therapy (Look-Listen and Repeat - LLR) (1 hour/day) during 2 months (Endpoint 2). Language evaluations, diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) were performed at baseline and at both endpoints. Donepezil alone and combined with LLR induced marked improvement in measures of speech production (Correct Information Units/minute during picture description, and repetition of word lists, idiomatic-novel phrases and sentences). Greater benefits were observed after combined therapy and the obtained gains in speech production remained well-above baseline scores even four months after combined therapy interruption. Longitudinal DTI showed structural plasticity in the right frontal aslant tract (FAT) with both interventions and VBM additionally revealed increased grey matter density in cortical areas connected through the FAT. Donepezil alone and combined with LLR improved speech production deficits by inducing structural plastic changes in white matter tracts and grey matter areas spared by the lesion in the injured hemisphere. Conclusions: Cholinergic modulation and intensive verbal repetition-imitation therapy improve speech production deficits in crossed conduction aphasia by inducing right hemisphere structural plasticity. Conclusions: MSRT become a simultaneous training of attention, auditory and visual input processing with the activation of different semantic fields, STM, executive processing, and language production. Treatment with donepezil has a positive effect in communication skills of CA patient. We observe a summative effect between donepezil and MSRT. The improvement associates neuroplasticity changes in neuroimaging.In the past two decades, single-case studies evaluated the effect of massed repetition training to improve speech production and short-term memory deficits in conduction aphasia (CA). Improvements were reported in treated language and memory domains with modest generalisation of gains to spontaneous speech or auditory comprehension. Although these results are encouraging, sentence repetition training has not been compared with distributed speech-language therapy, and no studies have examined the role of pharmacological interventions to enhance gains promoted by these behavioural interventions in CA. To explore repetition and imitation in the context of neural basis and treatment of aphasia, we developed three studies (STUDY 1, 2 & 3). Study 1: The effects of massed sentence repetition therapy (MSRT) were compared to those of distributed speech-language therapy (DSLT) in measures of verbal output, short-term memory and repetition in patients with chronic post-stroke CA receiving treatment with the cholinesterase inhibitor donepezil (DP). Both interventions improved performance in speech production tasks, but better improvements were found with DP-MSRT than with DP-DSLT. Larger treatment effects were found for DP-MSRT in comparison with baselines and DP-DSLT in repetition of word pairs and triplets, and novel and experimental sentences with generalisation of gains to aphasia severity, connected speech and non-treated control sentences

Resting-state language network neuroplasticity in post-stroke music listening: A randomized controlled trial

Recent evidence suggests that post-stroke vocal music listening can aid language recovery, but the network-level functional neuroplasticity mechanisms of this effect are unknown. Here, we sought to determine if improved language recovery observed after post-stroke listening to vocal music is driven by changes in longitudinal resting-state functional connectivity within the language network. Using data from a single-blind randomized controlled trial on stroke patients (N = 38), we compared the effects of daily listening to self-selected vocal music, instrumental music and audio books on changes of the resting-state functional connectivity within the language network and their correlation to improved language skills and verbal memory during the first 3 months post-stroke. From acute to 3-month stage, the vocal music and instrumental music groups increased functional connectivity between a cluster comprising the left inferior parietal areas and the language network more than the audio book group. However, the functional connectivity increase correlated with improved verbal memory only in the vocal music group cluster. This study shows that listening to vocal music post-stroke promotes recovery of verbal memory by inducing changes in longitudinal functional connectivity in the language network. Our results conform to the variable neurodisplacement theory underpinning aphasia recovery.Peer reviewe

Brain structural and functional correlates of the heterogenous progression of mixed transcortical aphasia

Mixed transcortical aphasia (MTCA) is characterized by non-fluent speech and comprehension deficits coexisting with preserved repetition. MTCA may evolve to less severe variants of aphasias or even to full language recovery. Mechanistically, MCTA has traditionally been attributed to a disconnection between the spared left perisylvian language network (PSLN) responsible for preserved verbal repetition, and damaged left extrasylvian networks, which are responsible for language production and comprehension impairments. However, despite significant advances in in vivo neuroimaging, the structural and functional status of the PSLN network in MTCA and its evolution has not been investigated. Thus, the aim of the present study is to examine the status of the PSLN, both in terms of its functional activity and structural integrity, in four cases who developed acute post-stroke MTCA and progressed to different types of aphasia. For it, we conducted a neuroimaging- behavioral study performed in the chronic stage of four patients. The behavioral profile of MTCA persisted in one patient, whereas the other three patients progressed to less severe types of aphasias. Neuroimaging findings suggest that preserved verbal repetition in MTCA does not always depend on the optimal status of the PSLN and its dorsal connections. Instead, the right hemisphere or the left ventral pathway may also play a role in supporting verbal repetition. The variability in the clinical evolution of MTCA may be explained by the varying degree of PSLN alteration and individual premorbid neuroanatomical language substrates. This study offers a fresh perspective of MTCA through the lens of modern neuroscience and unveils novel insights into the neural underpinnings of repetition.Funding for open access publishing: Universidad Málaga/CBUA. This work was supported by the Spanish Ministry of Economy, Industry and Competitiveness, Instituto de Salud Carlos III under Grant: PI16/01514 (MLB and GD) and by the Junta de Andalucía under Grant: P20_00501 (GD). MLB was funded by the European Social Fund (FEDER). DL-B was supported by the Ayuda RYC2020-029495-I Ramón y Cajal funded by the MCIN/AEI/10.13039/501100011033 and by El FSE invierte en tu futuro; and by the Grant PID2021-127617NA-I00 Proyecto de Generación de Conocimiento 2021 funded by MCIN/AEI /10.13039/501100011033/ and FEDER Una manera de hacer Europa. JP-P was funded by a PhD scholarship (FPU16/05198) from the Spanish Ministry of Education, Culture and Sport under the FPU program. MJT-P was supported by a Margarita Salas postdoctoral fellowship by the University of Malaga, funded by the European Union– NextGenerationEU – and the Spanish Ministerio de Universidades, and by a mobility grant from the Spanish Ministry of Universities under the José Castillejo program

Neurobiological signatures of L2 proficiency: Evidence from a bi-directional cross-linguistic study

Available online 12 November 2018Recent evidence has shown that convergence of print and speech processing across a network of primarily left-hemisphere regions of the brain is a predictor of future reading skills in children, and a marker of fluent reading ability in adults. The present study extends these findings into the domain of second-language (L2) literacy, through brain imaging data of English and Hebrew L2 learners. Participants received an fMRI brain scan, while performing a semantic judgement task on spoken and written words and pseudowords in both their L1 and L2, alongside a battery of L1 and L2 behavioural measures. Imaging results show, overall, a similar network of activation for reading across the two languages, alongside significant convergence of print and speech processing across a network of left-hemisphere regions in both L1 and L2 and in both cohorts. Importantly, convergence is greater for L1 in occipito-temporal regions tied to automatic skilled reading processes including the visual word-form area, but greater for L2 in frontal regions of the reading network, tied to more effortful, active processing. The main groupwise brain effects tell a similar story, with greater L2 than L1 activation across frontal, temporal and parietal regions, but greater L1 than L2 activation in parieto-occipital regions tied to automatic mapping processes in skilled reading. These results provide evidence for the shifting of the reading networks towards more automatic processing as reading proficiency rises and the mappings and statistics of the new orthography are learned and incorporated into the reading system.This paper was supported by the ERC Advanced grant awarded to Ram Frost (project 692502), the Israel Science Foundation (Grant 217/14 awarded to Ram Frost), and by the National Institute of Child Health and Human Development at the National Institutes of Health (RO1 HD 067364 awarded to Ken Pugh and Ram Frost, and PO1 HD 01994 awarded to Jay Rueckl)

Using fMRI and Behavioural Measures to Investigate Rehabilitation in Post-Stroke Aphasic Deficits

In this thesis I investigated whether an intensive computerised, home-based therapy programme could improve phonological discrimination ability in 19 patients with chronic post-stroke aphasia. One skill specifically targeted by the treatment demonstrated an improvement due to the therapy. However, this improvement did not generalise to untreated items, and was only effective for participants without a lesion involving the frontal lobe, indicating a potentially important role for this region in determining outcome of aphasia therapy. Complementary functional imaging studies investigated activity in domain-general and domain-specific networks in both patients and healthy volunteers during listening and repeating simple sentences. One important consideration when comparing a patient group with a healthy population is the difference in task difficulty encountered by the two groups. Increased cognitive effort can be expected to increase activity in domain-general networks. I minimised the effect of this confound by manipulating task difficulty for the healthy volunteers to reduce their behavioural performance so that it was comparable to that of the patients. By this means I demonstrated that the activation patterns in domain-general regions were very similar in the two groups. Region-of-interest analysis demonstrated that activity within a domain-general network, the salience network, predicted residual language function in the patients with aphasia, even after accounting for lesion volume and their chronological age. I drew two broad conclusions from these studies. First, that computer-based rehabilitation can improve disordered phonological discrimination in chronic aphasia, but that lesion distribution may influence the response to this training. Second, that the ability to activate domain-general cognitive control regions influences outcome in aphasia. This allows me to propose that in future work, therapeutic strategies, pharmacological or behavioural, targeting domain-general brain systems, may benefit aphasic stroke rehabilitation.Open Acces

Treatment of non-fluent aphasia through melody, rhythm and formulaic language

Left-hemisphere stroke patients often suffer a profound loss of spontaneous speech — known as non-fluent aphasia. Yet, many patients are still able to sing entire pieces of text fluently. This striking finding has inspired mainly two research questions. If the experimental design focuses on one point in time (cross section), one may ask whether or not singing facilitates speech production in aphasic patients. If the design focuses on changes over several points in time (longitudinal section), one may ask whether or not singing qualifies as a therapy to aid recovery from aphasia. The present work addresses both of these questions based on two separate experiments. A cross-sectional experiment investigated the relative effects of melody, rhythm, and lyric type on speech production in seventeen patients with non-fluent aphasia. The experiment controlled for vocal frequency variability, pitch accuracy, rhythmicity, syllable duration, phonetic complexity and other influences, such as learning effects and the acoustic setting. Contrary to earlier reports, the cross-sectional results suggest that singing may not benefit speech production in non-fluent aphasic patients over and above rhythmic speech. Previous divergent findings could very likely be due to affects from the acoustic setting, insufficient control for syllable duration, and language-specific stress patterns. However, the data reported here indicate that rhythmic pacing may be crucial, particularly for patients with lesions including the basal ganglia. Overall, basal ganglia lesions accounted for more than fifty percent of the variance related to rhythmicity. The findings suggest that benefits typically attributed to singing in the past may actually have their roots in rhythm. Moreover, the results demonstrate that lyric type may have a profound impact on speech production in non-fluent aphasic patients. Among the studied patients, lyric familiarity and formulaic language appeared to strongly mediate speech production, regardless of whether patients were singing or speaking rhythmically. Lyric familiarity and formulaic language may therefore help to explain effects that have, up until now, been presumed to result from singing. A longitudinal experiment investigated the relative long-term effects of melody and rhythm on the recovery of formulaic and non-formulaic speech. Fifteen patients with chronic non-fluent aphasia underwent either singing therapy, rhythmic therapy, or standard speech therapy. The experiment controlled for vocal frequency variability, phonatory quality, pitch accuracy, syllable duration, phonetic complexity and other influences, such as the acoustic setting and learning effects induced by the testing itself. The longitudinal results suggest that singing and rhythmic speech may be similarly effective in the treatment of non-fluent aphasia. Both singing and rhythmic therapy patients made good progress in the production of common, formulaic phrases — known to be supported by right corticostriatal brain areas. This progress occurred at an early stage of both therapies and was stable over time. Moreover, relatives of the patients reported that they were using a fixed number of formulaic phrases successfully in communicative contexts. Independent of whether patients had received singing or rhythmic therapy, they were able to easily switch between singing and rhythmic speech at any time. Conversely, patients receiving standard speech therapy made less progress in the production of formulaic phrases. They did, however, improve their production of unrehearsed, non-formulaic utterances, in contrast to singing and rhythmic therapy patients, who did not. In light of these results, it may be worth considering the combined use of standard speech therapy and the training of formulaic phrases, whether sung or rhythmically spoken. This combination may yield better results for speech recovery than either therapy alone. Overall, treatment and lyric type accounted for about ninety percent of the variance related to speech recovery in the data reported here. The present work delivers three main results. First, it may not be singing itself that aids speech production and speech recovery in non-fluent aphasic patients, but rhythm and lyric type. Second, the findings may challenge the view that singing causes a transfer of language function from the left to the right hemisphere. Moving beyond this left-right hemisphere dichotomy, the current results are consistent with the idea that rhythmic pacing may partly bypass corticostriatal damage. Third, the data support the claim that non-formulaic utterances and formulaic phrases rely on different neural mechanisms, suggesting a two-path model of speech recovery. Standard speech therapy focusing on non-formulaic, propositional utterances may engage, in particular, left perilesional brain regions, while training of formulaic phrases may open new ways of tapping into right-hemisphere language resources — even without singing

From dysfunctional to extraordinary verbal repetition abilities: clinical implications and neural features

Three cases are presented to index the hypothesis that mitigated echolalia emerges from overreliance on the dorsal language stream, through the arcuate fasciculus, when the ventral stream is damaged; whereas conduite d’approche ensues when the ventral stream attempts to compensate a dorsal damage. The role of the right hemisphere and other alternative pathways in both cerebral hemispheres in the successful compensation of brain injury is also discussed. Further, Study 2 reconceptualizes different types of echolalia within a continuous of severity and communication capacity. To accomplish this new instantiation, it is proposed that different types of echolalia may be associated to failure in distinctive linguistic and non-linguistic cognitive functions. Recommendations for its evaluation and treatment are provided, suggesting that echolalia interfering with functional communication should be treated. Further, complementing the previous one, Study 3 reports a comprehensive single case study exploring response to treatment, and behavioral and neuroimaging features of a person with mitigated echolalia associated to a chronic fluent aphasia. Findings from such case include a reduction of mitigated echolalia after two weeks of intensive aphasia therapy as well as the maintenance of these gains with memantine alone for at least 6 months. Importantly, reduction of mitigated echolalia instances in response to treatment speeded up the time needed to complete comprehension tasks. Neuroimaging results, although indirectly, suggested that mitigated echolalia may be supported by the activity of the remaining components of the left dorsal stream and compensatory right hemisphere recruitment. Additionally, to further explore the neural and cognitive mechanisms involved in verbal repetition in a model of language expertise, Study 4 tackles cognitive features and neural correlates of verbal expertise in two healthy adult subjects displaying an extraordinary ability to orally reverse language, a condition referred to as backward speech. Results suggest that phonological expertise, as shown in backward speech, involves reshaping (or pre-existent differences) of cortical areas and tracts relevant for auditory-motor integration and semantic processing. Greater functional coupling between critical language areas and domain-general and high-order visual areas may further support reversing processes. Lastly, Study 5 presents a systematic review of the literature aimed to examine sex differences in the prevalence of repetition deficits in persons with post-stroke aphasia. Results show that the proportion of females in the group of aphasia characterized by repetition deficits (i.e., conduction aphasia) is lower than the expected by the prevalence of stroke among them. It is suggested that sex-related differences in the volume of areas of the right hemisphere homologues to the ones subserving repetition in the left hemisphere may be at the base of this difference. This finding poses sex as a relevant variable to account for variance in repetition abilities, and as a relevant factor to consider in future studies of language acquisition, maturation, and relearning promoted by aphasia therapy. Fecha de lectura de Tesis Doctoral: 16 de diciembre 2019Verbal repetition and audio-visual imitation stand as crucial functions for the acquisition and maturation of language in childhood, language learning in adulthood, and a major resource for language recovery after brain damage. Although modern neuroimaging techniques have allowed the identification of the brain areas involved in repetition tasks in healthy subjects, many clinical and neural aspects of this linguistic function are still overlooked in persons with aphasia and in emerging models of language expertise. Therefore, the present dissertation aims to explore cognitive correlates and neural features of verbal repetition from different perspectives including models of dysfunctional repetition (i.e., people with aphasia) and language expertise (i.e., healthy backward speakers). Generally, this thesis explores the potential of the dorsal and ventral components of the neural network supporting verbal repetition to assume, under certain circumstances (e.g., brain damage or extraordinary abilities), non-canonical functions. Further, this dissertation addresses clinical issues of some aphasic symptoms characterized by uncontrolled repetition (i.e., echolalia), as well as reviews sex as a source of variability in verbal repetition outcomes after brain damage. This dissertation includes five studies that are part of this dissertation. First, it reviews the mechanisms involved in dysfunctional repetition, especially in two repetitive verbal behaviors named conduite d’approche and mitigated echolalia (Study 1) and addresses clinical issues of the last one (Study 2 and 3). In this regard, Study 1 proposes that in the context of aphasia these symptoms (i.e., conduite d’approche and mitigated echolalia) may represent active attempts of verbal communication, rather than inconsequential repetitive verbal behaviors resulting from maladaptive neural changes