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Children with developmental language disorder (DLD) struggle to learn their native language for no apparent reason. While research on the neurobiological underpinnings of the disorder has focused on the role of corticostriatal systems, little is known about the role of the cerebellum in DLD. Corticocerebellar circuits might be involved in the disorder as they contribute to complex sensorimotor skill learning, including the acquisition of spoken language. Here, we used diffusion-weighted imaging data from 77 typically developing and 54 children with DLD and performed probabilistic tractography to identify the cerebellum's white matter tracts: the inferior, middle, and superior cerebellar peduncles. Children with DLD showed lower fractional anisotropy (FA) in the inferior cerebellar peduncles (ICP), fiber tracts that carry motor and sensory input via the inferior olive to the cerebellum. Lower FA in DLD was driven by lower axial diffusivity. Probing this further with more sophisticated modeling of diffusion data, we found higher orientation dispersion but no difference in neurite density in the ICP of children with DLD. Reduced FA is therefore unlikely to be reflecting microstructural differences in myelination, rather the organization of axons in these pathways is disrupted. ICP microstructure was not associated with language or motor coordination performance in our sample. We also found no differences in the middle and superior peduncles, the main pathways connecting the cerebellum with the cortex. To conclude, it is not corticocerebellar but atypical olivocerebellar white matter connections that characterize DLD and suggest the involvement of the olivocerebellar system in speech and language acquisition and development.
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In this exploratory study we compare and contrast two methods for deriving a laterality index (LI) from functional magnetic resonance imaging (fMRI) data: the weighted bootstrapped mean from the LI Toolbox (toolbox method), and a novel method that uses subtraction of activations from homologous regions in left and right hemispheres to give an array of difference scores (mirror method). Data came from 31 individuals who had been selected to include a high proportion of people with atypical laterality when tested with functional transcranial Doppler ultrasound (fTCD). On two tasks, word generation and semantic matching, the mirror method generally gave better agreement with fTCD laterality than the toolbox method, both for individual regions of interest, and for a large region corresponding to the middle cerebral artery. LI estimates from this method had much smaller confidence intervals (CIs) than those from the toolbox method; with the mirror method, most participants were reliably lateralised to left or right, whereas with the toolbox method, a higher proportion were categorised as bilateral (i.e., the CI for the LI spanned zero). Reasons for discrepancies between fMRI methods are discussed: one issue is that the toolbox method averages the LI across a wide range of thresholds. Furthermore, examination of task-related t-statistic maps from the two hemispheres showed that language lateralisation is evident in regions characterised by deactivation, and so key information may be lost by ignoring voxel activations below zero, as is done with conventional estimates of the LI.
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Approximately 7% of children have developmental language disorder (DLD), a neurodevelopmental condition associated with persistent language learning difficulties without a known cause. Our understanding of the neurobiological basis of DLD is limited. Here, we used FreeSurfer to investigate cortical surface area and thickness in a large cohort of 156 children and adolescents aged 10-16 years with a range of language abilities, including 54 with DLD, 28 with a history of speech-language difficulties who did not meet criteria for DLD, and 74 age-matched controls with typical language development (TD). We also examined cortical asymmetries in DLD using an automated surface-based technique. Relative to the TD group, those with DLD showed smaller surface area bilaterally in the inferior frontal gyrus extending to the anterior insula, in the posterior temporal and ventral occipito-temporal cortex, and in portions of the anterior cingulate and superior frontal cortex. Analysis of the whole cohort using a language proficiency factor revealed that language ability correlated positively with surface area in similar regions. There were no differences in cortical thickness, nor in asymmetry of these cortical metrics between TD and DLD. This study highlights the importance of distinguishing between surface area and cortical thickness in investigating the brain basis of neurodevelopmental disorders and suggests the development of cortical surface area to be of importance to DLD. Future longitudinal studies are required to understand the developmental trajectory of these cortical differences in DLD and how they relate to language maturation.
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BACKGROUND: Damage to the primary visual cortex following an occipital stroke causes loss of conscious vision in the contralateral hemifield. Yet, some patients retain the ability to detect moving visual stimuli within their blind field. The present study asked whether such individual differences in blind field perception following loss of primary visual cortex could be explained by the concentration of neurotransmitters γ-aminobutyric acid (GABA) and glutamate or activity of the visual motion processing, human middle temporal complex (hMT+). METHODS: We used magnetic resonance imaging in 19 patients with chronic occipital stroke to measure the concentration of neurotransmitters GABA and glutamate (proton magnetic resonance spectroscopy) and functional activity in hMT+ (functional magnetic resonance imaging). We also tested each participant on a 2-interval forced choice detection task using high-contrast, moving Gabor patches. We then measured and assessed the strength of relationships between participants' residual vision in their blind field and in vivo neurotransmitter concentrations, as well as visually evoked functional magnetic resonance imaging activity in their hMT+. Levels of GABA and glutamate were also measured in a sensorimotor region, which served as a control. RESULTS: Magnetic resonance spectroscopy-derived GABA and glutamate concentrations in hMT+ (but not sensorimotor cortex) strongly predicted blind-field visual detection abilities. Performance was inversely related to levels of both inhibitory and excitatory neurotransmitters in hMT+ but, surprisingly, did not correlate with visually evoked blood oxygenation level-dependent signal change in this motion-sensitive region. CONCLUSIONS: Levels of GABA and glutamate in hMT+ appear to provide superior information about motion detection capabilities inside perimetrically defined blind fields compared to blood oxygenation level-dependent signal changes-in essence, serving as biomarkers for the quality of residual visual processing in the blind-field. Whether they also reflect a potential for successful rehabilitation of visual function remains to be determined.
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Acidente Vascular Cerebral , Córtex Visual , Humanos , Ácido Glutâmico , Individualidade , Córtex Visual/diagnóstico por imagem , Estimulação Luminosa/métodos , Imageamento por Ressonância Magnética/métodos , Ácido gama-Aminobutírico , Acidente Vascular Cerebral/diagnóstico por imagemRESUMO
Children with developmental language disorder (DLD) struggle to learn their native language for no apparent reason. While research on the neurobiological underpinnings of the disorder has focused on the role of cortico-striatal systems, little is known about the role of the cerebellum in DLD. Cortico-cerebellar circuits might be involved in the disorder as they contribute to complex sensorimotor skill learning, including the acquisition of spoken language. Here, we used diffusion-weighted imaging data from 77 typically developing and 54 children with DLD and performed probabilistic tractography to identify the cerebellum's white matter tracts: the inferior, middle, and superior cerebellar peduncles. Children with DLD showed lower fractional anisotropy (FA) in the inferior cerebellar peduncles (ICP), fiber tracts that carry motor and sensory input via the inferior olive to the cerebellum. Lower FA in DLD was driven by lower axial diffusivity. Probing this further with more sophisticated modeling of diffusion data, we found higher orientation dispersion but no difference in neurite density in the ICP of DLD. Reduced FA is therefore unlikely to be reflecting microstructural differences in myelination in this tract, rather the organization of axons in these pathways is disrupted. ICP microstructure was not associated with language or motor coordination performance in our sample. We also found no differences in the middle and superior peduncles, the main pathways connecting the cerebellum with the cortex. To conclude, it is not cortico-cerebellar but atypical olivocerebellar white matter connections that characterize DLD and suggest the involvement of the olivocerebellar system in speech acquisition and development.
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We consider how analysis of brain lateralization using functional transcranial Doppler ultrasound (fTCD) data can be brought in line with modern statistical methods typically used in functional magnetic resonance imaging (fMRI). Conventionally, a laterality index is computed in fTCD from the difference between the averages of each hemisphere's signal within a period of interest (POI) over a series of trials. We demonstrate use of generalized linear models (GLMs) and generalized additive models (GAM) to analyze data from individual participants in three published studies (N = 154, 73 and 31), and compare this with results from the conventional POI averaging approach, and with laterality assessed using fMRI (N = 31). The GLM approach was based on classic fMRI analysis that includes a hemodynamic response function as a predictor; the GAM approach estimated the response function from the data, including a term for time relative to epoch start (simple GAM), plus a categorical index corresponding to individual epochs (complex GAM). Individual estimates of the fTCD laterality index are similar across all methods, but error of measurement is lowest using complex GAM. Reliable identification of cases of bilateral language appears to be more accurate with complex GAM. We also show that the GAM-based approach can be used to efficiently analyze more complex designs that incorporate interactions between tasks.
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Encéfalo , Lateralidade Funcional , Humanos , Lateralidade Funcional/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Ultrassonografia Doppler Transcraniana/métodos , Idioma , Imageamento por Ressonância MagnéticaRESUMO
Developmental language disorder (DLD) is a common neurodevelopmental disorder characterised by receptive or expressive language difficulties or both. While theoretical frameworks and empirical studies support the idea that there may be neural correlates of DLD in frontostriatal loops, findings are inconsistent across studies. Here, we use a novel semiquantitative imaging protocol - multi-parameter mapping (MPM) - to investigate microstructural neural differences in children with DLD. The MPM protocol allows us to reproducibly map specific indices of tissue microstructure. In 56 typically developing children and 33 children with DLD, we derived maps of (1) longitudinal relaxation rate R1 (1/T1), (2) transverse relaxation rate R2* (1/T2*), and (3) Magnetization Transfer saturation (MTsat). R1 and MTsat predominantly index myelin, while R2* is sensitive to iron content. Children with DLD showed reductions in MTsat values in the caudate nucleus bilaterally, as well as in the left ventral sensorimotor cortex and Heschl's gyrus. They also had globally lower R1 values. No group differences were noted in R2* maps. Differences in MTsat and R1 were coincident in the caudate nucleus bilaterally. These findings support our hypothesis of corticostriatal abnormalities in DLD and indicate abnormal levels of myelin in the dorsal striatum in children with DLD.
Seven percent of children struggle to learn their native language for no obvious reason. This condition is called Developmental Language Disorder (DLD). Children with DLD often have difficulty learning to read and write. They are at higher risk for academic underachievement and may struggle to find good jobs. Their language difficulties also contribute to difficulties making friends and emotional challenges. Scientists suspect children with DLD may have differences in areas deep in the brain that help people learn habits and rules. A new magnetic resonance imaging technique called multiparameter mapping (MPM) can help scientists determine if this is true. The technique measures the properties of brain tissue. It is particularly useful for measuring the amounts of a fatty protective sheath on brain cells called myelin. Myelin helps brain cells send information faster. Using MPM, Krishnan et al. show that children with DLD have less myelin in parts of the brain responsible for speaking, listening, and learning rules and habits. In the experiments, 56 children with typical language development and 33 children with DLD were scanned using MPM. Krishnan et al. then compared the two groups and found reduced myelin in these critical areas associated with learning a language in most of the children with DLD. But not all children with DLD had these differences. More studies are needed to determine if these brain differences cause language problems and how or if experiencing language difficulties could cause these changes in the brain. Further research may help scientists find new treatments that target these brain differences.
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Imageamento por Ressonância Magnética , Bainha de Mielina , Núcleo Caudado , Criança , Substância Cinzenta , Humanos , Ferro , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Most people have strong left-brain lateralisation for language, with a minority showing right- or bilateral language representation. On some receptive language tasks, however, lateralisation appears to be reduced or absent. This contrasting pattern raises the question of whether and how language laterality may fractionate within individuals. Building on our prior work, we postulated (a) that there can be dissociations in lateralisation of different components of language, and (b) these would be more common in left-handers. A subsidiary hypothesis was that laterality indices will cluster according to two underlying factors corresponding to whether they involve generation of words or sentences, versus receptive language. METHODS: We tested these predictions in two stages: At Step 1 an online laterality battery (Dichotic listening, Rhyme Decision and Word Comprehension) was given to 621 individuals (56% left-handers); At Step 2, functional transcranial Doppler ultrasound (fTCD) was used with 230 of these individuals (51% left-handers). 108 left-handers and 101 right-handers gave useable data on a battery of three language generation and three receptive language tasks. RESULTS: Neither the online nor fTCD measures supported the notion of a single language laterality factor. In general, for both online and fTCD measures, tests of language generation were left-lateralised. In contrast, the receptive tasks were at best weakly left-lateralised or, in the case of Word Comprehension, slightly right-lateralised. The online measures were only weakly correlated, if at all, with fTCD measures. Most of the fTCD measures had split-half reliabilities of at least .7, and showed a distinctive pattern of intercorrelation, supporting a modified two-factor model in which Phonological Decision (generation) and Sentence Decision (reception) loaded on both factors. The same factor structure fitted data from left- and right-handers, but mean scores on the two factors were lower (less left-lateralised) in left-handers. CONCLUSIONS: There are at least two factors influencing language lateralization in individuals, but they do not correspond neatly to language generation and comprehension. Future fMRI studies could help clarify how far they reflect activity in specific brain regions.
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Lateralidade Funcional , Idioma , Encéfalo , Circulação Cerebrovascular , Humanos , Ultrassonografia Doppler TranscranianaRESUMO
Individuals with congenital blindness due to bilateral anophthalmia offer a unique opportunity to examine cross-modal plasticity in the complete absence of any stimulation of the 'visual' pathway even during development in utero. Our previous work has suggested that this complete sensory deafferentation results in different patterns of reorganisation compared with those seen in other early blind populations. Here, we further test the functional specialisation of occipital cortex in six well-studied cases with anophthalmia. Whole brain functional MRI was obtained while these human participants and a group of sighted controls performed two experiments involving phonological and semantic processing of words (verbal experiment) and spatial and identity processing of piano chords (nonverbal experiment). Both experiments were predicted to show a dorsal-ventral difference in activity based on the specific task performed. All tasks evoked activation in occipital cortex in the individuals with anophthalmia but not in the sighted controls. For the verbal experiment, both dorsal and ventral occipital areas were strongly activated by the phonological and semantic tasks in anophthalmia. For the nonverbal experiment, both the spatial and the identity task robustly activated the dorsal occipital area V3a but showed inconsistent activity elsewhere in the occipital lobe. V1 was most strongly activated by the verbal tasks, showing greater activity on the left for the verbal task relative to the nonverbal one. For individual anophthalmic participants, however, activity in V1 was inconsistent across tasks and hemispheres with many participants showing activity levels in the control range, which was not significantly above baseline. Despite the homogeneous nature of the cause of blindness in the anophthalmic group, there remain differences in patterns of activation among the individuals with this condition. Investigation at the case level might further our understanding of how post-natal experiences shape functional reorganisation in deafferented cortex.
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Anoftalmia , Córtex Visual , Anoftalmia/complicações , Anoftalmia/diagnóstico por imagem , Percepção Auditiva/fisiologia , Cegueira/diagnóstico por imagem , Humanos , Idioma , Imageamento por Ressonância Magnética/métodos , Lobo Occipital/diagnóstico por imagem , Córtex Visual/fisiologiaRESUMO
INTRODUCTION: Most of the previous articulatory studies of stuttering have focussed on the fluent speech of people who stutter. However, to better understand what causes the actual moments of stuttering, it is necessary to probe articulatory behaviors during stuttered speech. We examined the supralaryngeal articulatory characteristics of stuttered speech using real-time structural magnetic resonance imaging (RT-MRI). We investigated how articulatory gestures differ across stuttered and fluent speech of the same speaker. METHODS: Vocal tract movements of an adult man who stutters during a pseudoword reading task were recorded using RT-MRI. Four regions of interest (ROIs) were defined on RT-MRI image sequences around the lips, tongue tip, tongue body, and velum. The variation of pixel intensity in each ROI over time provided an estimate of the movement of these four articulators. RESULTS: All disfluencies occurred on syllable-initial consonants. Three articulatory patterns were identified. Pattern 1 showed smooth gestural formation and release like fluent speech. Patterns 2 and 3 showed delayed release of gestures due to articulator fixation or oscillation respectively. Block and prolongation corresponded to either pattern 1 or 2. Repetition corresponded to pattern 3 or a mix of patterns. Gestures for disfluent consonants typically exhibited a greater constriction than fluent gestures, which was rarely corrected during disfluencies. Gestures for the upcoming vowel were initiated and executed during these consonant disfluencies, achieving a tongue body position similar to the fluent counterpart. CONCLUSION: Different perceptual types of disfluencies did not necessarily result from distinct articulatory patterns, highlighting the importance of collecting articulatory data of stuttering. Disfluencies on syllable-initial consonants were related to the delayed release and the overshoot of consonant gestures, rather than the delayed initiation of vowel gestures. This suggests that stuttering does not arise from problems with planning the vowel gestures, but rather with releasing the overly constricted consonant gestures.
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Gagueira , Adulto , Gestos , Humanos , Imageamento por Ressonância Magnética , Masculino , Fala , Medida da Produção da FalaRESUMO
Theoretical accounts of developmental stuttering implicate dysfunctional cortico-striatal-thalamo-cortical motor loops through the putamen. However, the analysis of conventional MRI brain scans in individuals who stutter has failed to yield strong support for this theory in terms of reliable differences in the structure or function of the basal ganglia. Here, we performed quantitative mapping of brain tissue, which can be used to measure iron content alongside markers sensitive to myelin and thereby offers particular sensitivity to the measurement of iron-rich structures such as the basal ganglia. Analysis of these quantitative maps in 41 men and women who stutter and 32 individuals who are typically fluent revealed significant group differences in maps of R2*, indicative of higher iron content in individuals who stutter in the left putamen and in left hemisphere cortical regions important for speech motor control. Higher iron levels in brain tissue in individuals who stutter could reflect elevated dopamine levels or lysosomal dysfunction, both of which are implicated in stuttering. This study represents the first use of these quantitative measures in developmental stuttering and provides new evidence of microstructural differences in the basal ganglia and connected frontal cortical regions.
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Mapeamento Encefálico/métodos , Lobo Frontal/metabolismo , Ferro/metabolismo , Rede Nervosa/metabolismo , Putamen/metabolismo , Gagueira/metabolismo , Adulto , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/metabolismo , Estudos de Coortes , Feminino , Lobo Frontal/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Putamen/diagnóstico por imagem , Gagueira/diagnóstico por imagem , Adulto JovemRESUMO
When auditory feedback perturbation is introduced in a predictable way over a number of utterances, speakers learn to compensate by adjusting their own productions, a process known as sensorimotor adaptation. Despite multiple lines of evidence indicating the role of primary motor cortex (M1) in motor learning and memory, whether M1 causally contributes to sensorimotor adaptation in the speech domain remains unclear. Here, we aimed to assay whether temporary disruption of the articulatory representation in left M1 by repetitive transcranial magnetic stimulation (rTMS) impairs speech adaptation. To induce sensorimotor adaptation, the frequencies of first formants (F1) were shifted up and played back to participants when they produced "head", "bed", and "dead" repeatedly (the learning phase). A low-frequency rTMS train (.6 Hz, subthreshold, 12 min) over either the tongue or the hand representation of M1 (between-subjects design) was applied before participants experienced altered auditory feedback in the learning phase. We found that the group who received rTMS over the hand representation showed the expected compensatory response for the upwards shift in F1 by significantly reducing F1 and increasing the second formant (F2) frequencies in their productions. In contrast, these expected compensatory changes in both F1 and F2 did not occur in the group that received rTMS over the tongue representation. Critically, rTMS (subthreshold) over the tongue representation did not affect vowel production, which was unchanged from baseline. These results provide direct evidence that the articulatory representation in left M1 causally contributes to sensorimotor learning in speech. Furthermore, these results also suggest that M1 is critical to the network supporting a more global adaptation that aims to move the altered speech production closer to a learnt pattern of speech production used to produce another vowel.
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Córtex Motor , Fala , Adaptação Fisiológica , Retroalimentação Sensorial , Humanos , Estimulação Magnética TranscranianaRESUMO
Purpose People who stutter (PWS) have more unstable speech motor systems than people who are typically fluent (PWTF). Here, we used real-time magnetic resonance imaging (MRI) of the vocal tract to assess variability and duration of movements of different articulators in PWS and PWTF during fluent speech production. Method The vocal tracts of 28 adults with moderate to severe stuttering and 20 PWTF were scanned using MRI while repeating simple and complex pseudowords. Midsagittal images of the vocal tract from lips to larynx were reconstructed at 33.3 frames per second. For each participant, we measured the variability and duration of movements across multiple repetitions of the pseudowords in three selected articulators: the lips, tongue body, and velum. Results PWS showed significantly greater speech movement variability than PWTF during fluent repetitions of pseudowords. The group difference was most evident for measurements of lip aperture using these stimuli, as reported previously, but here, we report that movements of the tongue body and velum were also affected during the same utterances. Variability was not affected by phonological complexity. Speech movement variability was unrelated to stuttering severity within the PWS group. PWS also showed longer speech movement durations relative to PWTF for fluent repetitions of multisyllabic pseudowords, and this group difference was even more evident as complexity increased. Conclusions Using real-time MRI of the vocal tract, we found that PWS produced more variable movements than PWTF even during fluent productions of simple pseudowords. PWS also took longer to produce multisyllabic words relative to PWTF, particularly when words were more complex. This indicates general, trait-level differences in the control of the articulators between PWS and PWTF. Supplemental Material https://doi.org/10.23641/asha.14782092.
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Fala , Gagueira , Adulto , Humanos , Imageamento por Ressonância Magnética , Movimento , Medida da Produção da Fala , Gagueira/diagnóstico por imagemRESUMO
Speech processing relies on interactions between auditory and motor systems and is asymmetrically organized in the human brain. The left auditory system is specialized for processing of phonemes, whereas the right is specialized for processing of pitch changes in speech affecting prosody. In speakers of tonal languages, however, processing of pitch (i.e., tone) changes that alter word meaning is left-lateralized indicating that linguistic function and language experience shape speech processing asymmetries. Here, we investigated the asymmetry of motor contributions to auditory speech processing in male and female speakers of tonal and non-tonal languages. We temporarily disrupted the right or left speech motor cortex using transcranial magnetic stimulation (TMS) and measured the impact of these disruptions on auditory discrimination (mismatch negativity; MMN) responses to phoneme and tone changes in sequences of syllables using electroencephalography (EEG). We found that the effect of motor disruptions on processing of tone changes differed between language groups: disruption of the right speech motor cortex suppressed responses to tone changes in non-tonal language speakers, whereas disruption of the left speech motor cortex suppressed responses to tone changes in tonal language speakers. In non-tonal language speakers, the effects of disruption of left speech motor cortex on responses to tone changes were inconclusive. For phoneme changes, disruption of left but not right speech motor cortex suppressed responses in both language groups. We conclude that the contributions of the right and left speech motor cortex to auditory speech processing are determined by the functional roles of acoustic cues in the listener's native language.SIGNIFICANCE STATEMENT The principles underlying hemispheric asymmetries of auditory speech processing remain debated. The asymmetry of processing of speech sounds is affected by low-level acoustic cues, but also by their linguistic function. By combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG), we investigated the asymmetry of motor contributions to auditory speech processing in tonal and non-tonal language speakers. We provide causal evidence that the functional role of the acoustic cues in the listener's native language affects the asymmetry of motor influences on auditory speech discrimination ability [indexed by mismatch negativity (MMN) responses]. Lateralized top-down motor influences can affect asymmetry of speech processing in the auditory system.
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Estimulação Acústica/métodos , Percepção Auditiva/fisiologia , Idioma , Córtex Motor/fisiologia , Percepção da Fala/fisiologia , Estimulação Magnética Transcraniana/métodos , Adolescente , Adulto , Eletroencefalografia/métodos , Feminino , Humanos , Masculino , Adulto JovemRESUMO
There is a long-established link between anatomy and function in the somatomotor system in the mammalian cerebral cortex. The morphology of the central sulcus is predictive of the location of functional activation peaks relating to movement of different effectors in individuals. By contrast, morphological variation in the subcentral region and its relationship to function is, as yet, unknown. Investigating the subcentral region is particularly important in the context of speech, since control of the larynx during human speech production is related to activity in this region. Here, we examined the relationship between morphology in the central and subcentral region and the location of functional activity during movement of the hand, lips, tongue, and larynx at the individual participant level. We provide a systematic description of the sulcal patterns of the subcentral and adjacent opercular cortex, including the inter-individual variability in sulcal morphology. We show that, in the majority of participants, the anterior subcentral sulcus is not continuous, but consists of two distinct segments. A robust relationship between morphology of the central and subcentral sulcal segments and movement of different effectors is demonstrated. Inter-individual variability of underlying anatomy might thus explain previous inconsistent findings, in particular regarding the ventral larynx area in subcentral cortex. A surface registration based on sulcal labels indicated that such anatomical information can improve the alignment of functional data for group studies.
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Córtex Motor/diagnóstico por imagem , Movimento/fisiologia , Fala/fisiologia , Adolescente , Adulto , Mapeamento Encefálico , Feminino , Mãos/fisiologia , Humanos , Laringe/fisiologia , Lábio/fisiologia , Imageamento por Ressonância Magnética , Masculino , Córtex Motor/fisiologia , Língua/fisiologia , Adulto JovemRESUMO
Developmental language disorder (DLD) is characterised by difficulties in learning one's native language for no apparent reason. These language difficulties occur in 7% of children and are known to limit future academic and social achievement. Our understanding of the brain abnormalities associated with DLD is limited. Here, we used a simple four-minute verb generation task (children saw a picture of an object and were instructed to say an action that goes with that object) to test children between the ages of 10-15 years (DLD N = 50, typically developing N = 67). We also tested 26 children with poor language ability who did not meet our criteria for DLD. Contrary to our registered predictions, we found that children with DLD did not have (i) reduced activity in language relevant regions such as the left inferior frontal cortex; (ii) dysfunctional striatal activity during overt production; or (iii) a reduction in left-lateralised activity in frontal cortex. Indeed, performance of this simple language task evoked activity in children with DLD in the same regions and to a similar level as in typically developing children. Consistent with previous reports, we found sub-threshold group differences in the left inferior frontal gyrus and caudate nuclei, but only when analysis was limited to a subsample of the DLD group (N = 14) who had the poorest performance on the task. Additionally, we used a two-factor model to capture variation in all children studied (N = 143) on a range of neuropsychological tests and found that these language and verbal memory factors correlated with activity in different brain regions. Our findings indicate a lack of support for some neurological models of atypical language learning, such as the procedural deficit hypothesis or the atypical lateralization hypothesis, at least when using simple language tasks that children can perform. These results also emphasise the importance of controlling for and monitoring task performance.
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Encéfalo/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Adolescente , Criança , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Idioma , Imageamento por Ressonância Magnética/métodos , MasculinoRESUMO
The Staphylococcus aureus type VII secretion system (T7SS) exports several proteins that are pivotal for bacterial virulence. The mechanisms underlying T7SS-mediated staphylococcal survival during infection nevertheless remain unclear. Here we report that S. aureus lacking T7SS components are more susceptible to host-derived antimicrobial fatty acids. Unsaturated fatty acids such as linoleic acid (LA) elicited an increased inhibition of S. aureus mutants lacking T7SS effectors EsxC, EsxA and EsxB, or the membrane-bound ATPase EssC, compared to the wild-type (WT). T7SS mutants generated in different S. aureus strain backgrounds also displayed an increased sensitivity to LA. Analysis of bacterial membrane lipid profiles revealed that the esxC mutant was less able to incorporate LA into its membrane phospholipids. Although the ability to bind labelled LA did not differ between the WT and mutant strains, LA induced more cell membrane damage in the T7SS mutants compared to the WT. Furthermore, proteomic analyses of WT and mutant cell fractions revealed that, in addition to compromising membranes, T7SS defects induce oxidative stress and hamper their response to LA challenge. Thus, our findings indicate that T7SS contribute to maintaining S. aureus membrane integrity and homeostasis when bacteria encounter antimicrobial fatty acids.
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Proteínas de Bactérias/metabolismo , Membrana Celular/metabolismo , Ácidos Graxos/metabolismo , Staphylococcus aureus/metabolismo , Sistemas de Secreção Tipo VII/metabolismo , Regulação Bacteriana da Expressão GênicaRESUMO
Staphylococcus aureus is one of the leading causes of hospital and community-acquired infections worldwide. The increasing occurrence of antibiotic resistant strains and the high rates of recurrent staphylococcal infections have placed several treatment challenges on healthcare systems. In recent years, it has become evident that S. aureus is a facultative intracellular pathogen, able to invade and survive in a range of cell types. The ability to survive intracellularly provides this pathogen with yet another way to evade antibiotics and immune responses during infection. Intracellular S. aureus have been strongly linked to several recurrent infections, including severe bone infections and septicemias. S. aureus is armed with an array of virulence factors as well as an intricate network of regulators that enable it to survive, replicate and escape from a number of immune and nonimmune host cells. It is able to successfully manipulate host cell pathways and use it as a niche to multiply, disseminate, as well as persist during an infection. This bacterium is also known to adapt to the intracellular environment by forming small colony variants, which are metabolically inactive. In this review we will discuss the clinical evidence, the molecular pathways involved in S. aureus intracellular persistence, and new treatment strategies for targeting intracellular S. aureus.
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Citoplasma/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Apoptose , Autofagia , Citoplasma/patologia , Variação Genética , Humanos , Viabilidade Microbiana , Reinfecção/tratamento farmacológico , Reinfecção/microbiologia , Reinfecção/patologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/patologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidade , Fatores de Virulência/genética , Fatores de Virulência/metabolismoRESUMO
The representations of the articulators involved in human speech production are organized somatotopically in primary motor cortex. The neural representation of the larynx, however, remains debated. Both a dorsal and a ventral larynx representation have been previously described. It is unknown, however, whether both representations are located in primary motor cortex. Here, we mapped the motor representations of the human larynx using functional magnetic resonance imaging and characterized the cortical microstructure underlying the activated regions. We isolated brain activity related to laryngeal activity during vocalization while controlling for breathing. We also mapped the articulators (the lips and tongue) and the hand area. We found two separate activations during vocalization-a dorsal and a ventral larynx representation. Structural and quantitative neuroimaging revealed that myelin content and cortical thickness underlying the dorsal, but not the ventral larynx representation, are similar to those of other primary motor representations. This finding confirms that the dorsal larynx representation is located in primary motor cortex and that the ventral one is not. We further speculate that the location of the ventral larynx representation is in premotor cortex, as seen in other primates. It remains unclear, however, whether and how these two representations differentially contribute to laryngeal motor control.
Assuntos
Laringe/fisiologia , Córtex Motor/fisiologia , Fala/fisiologia , Adolescente , Adulto , Mapeamento Encefálico , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Adulto JovemRESUMO
Transcranial direct current stimulation (tDCS) modulates cortical excitability in a polarity-specific way and, when used in combination with a behavioural task, it can alter performance. TDCS has the potential, therefore, for use as an adjunct to therapies designed to treat disorders affecting speech, including, but not limited to acquired aphasias and developmental stuttering. For this reason, it is important to conduct studies evaluating its effectiveness and the parameters optimal for stimulation. Here, we aimed to evaluate the effects of bi-hemispheric tDCS over speech motor cortex on performance of a complex speech motor learning task, namely the repetition of tongue twisters. A previous study in older participants showed that tDCS could modulate performance on a similar task. To further understand the effects of tDCS, we also measured the excitability of the speech motor cortex before and after stimulation. Three groups of 20 healthy young controls received: (i) anodal tDCS to the left IFG/LipM1 and cathodal tDCS to the right hemisphere homologue; or (ii) cathodal tDCS over the left and anodal over the right; or (iii) sham stimulation. Participants heard and repeated novel tongue twisters and matched simple sentences before, during and 10 min after the stimulation. One mA tDCS was delivered concurrent with task performance for 13 min. Motor excitability was measured using transcranial magnetic stimulation to elicit motor-evoked potentials in the lip before and immediately after tDCS. The study was double-blind, randomized, and sham-controlled; the design and analysis were pre-registered. Performance on the task improved from baseline to after stimulation but was not significantly modulated by tDCS. Similarly, a small decrease in motor excitability was seen in all three stimulation groups but did not differ among them and was unrelated to task performance. Bayesian analyses provide substantial evidence in support of the null hypotheses in both cases, namely that tongue twister performance and motor excitability were not affected by tDCS. We discuss our findings in the context of the previous positive results for a similar task. We conclude that tDCS may be most effective when brain function is sub-optimal due to age-related declines or pathology. Further study is required to determine why tDCS failed to modulate excitability in the speech motor cortex in the expected ways.