Atypical Development of Broca’s Area in a Large Family with Inherited Stuttering

Developmental stuttering is a condition of speech dysfluency, characterised by pauses, blocks, prolongations, and sound or syllable repetitions. It affects around 1% of the population, with potential detrimental effects on mental health and long-term employment. Accumulating evidence points to a genetic aetiology, yet gene-brain associations remain poorly understood due to a lack of MRI studies in affected families. Here we report the first neuroimaging study of developmental stuttering in a family with autosomal dominant inheritance of persistent stuttering. We studied a four-generation family, sixteen family members were included in genotyping analysis. T1-weighted and diffusion weighted MRI scans were conducted on seven family members (6 male; aged 9–63 years) with two age and sex matched controls without stuttering (N = 14). Using Freesurfer, we analysed cortical morphology (cortical thickness, surface area and local gyrification index) and basal ganglia volumes. White matter integrity in key speech and language tracts (i.e. frontal aslant tract and arcuate fasciculus) was also analysed using MRtrix and probabilistic tractography. We identified a significant age by group interaction effect for cortical thickness in the left hemisphere pars opercularis (Broca’s area). In affected family members this region failed to follow the typical trajectory of age-related thinning observed in controls. Surface area analysis revealed the middle frontal gyrus region was reduced bilaterally in the family (all cortical morphometry significance levels set at a vertex-wise threshold of p < 0.01, corrected for multiple comparisons). Both the left and right globus pallidus were larger in the family than in the control group (left p = 0.017; right p=0.037), and a larger right globus pallidus was associated with more severe stuttering (rho =0.86, p=0.01). No white matter differences were identified. Genotyping identified novel loci on chromosomes 1 and 4 that map with the stuttering phenotype. Our findings denote disruption within the cortico-basal ganglia-thalamo-cortical network. The lack of typical development of these structures reflects the anatomical basis of the abnormal inhibitory control network between Broca’s area and the striatum underpinning stuttering in these individuals. This is the first evidence of a neural phenotype in a family with an autosomal dominantly inherited stuttering

Brain structural predispositions for music and language processing

[eng] It has been shown that music and language training can elicit plastic changes on brain structure and function bringing along behavioural benefits. For instance, musicians have been reported to have better auditory discrimination including pitch and speech-in-noise perception, motor-synchronization, verbal memory and general IQ than individuals without formal musical background. Also, bilinguals have shown higher executive function and attention-related abilities than monolinguals. Furthermore, altered functional and structural connectivity can be tracked to brain areas related to the activities most frequently performed by both musicians (instrumentalists and singers) and linguistic experts (such as bilinguals or professional phoneticians). While research in the last decade has devoted important effort to the study of brain plasticity, only a few investigations have addressed the connection between the initial functional or structural properties of brain networks related to auditory-motor function and subsequent language or musical training. Indeed, brain structural markers such as grey matter volume/density or white-matter diffusivity measurements from diffusion tensor imaging (DTI) data, as well as functional measurements from task- related activity or resting-state data from magnetic resonance imaging (MRI) or electroenceplhalography (EEG) have been demonstrated to correlate with consecutive performance and learning in the auditory-motor domain. The main goal of the present dissertation was twofold: we aimed to further the existing knowledge regarding brain plasticity elicited during putative sensitive periods and after long-term music practice, and to explore the white-matter pathways that predict linguistic or musical skills at baseline . Our secondary goals were to confirm previous findings regarding the brain structures involved in music and language processing, as well as to provide evidence of the benefits of usingstructural measurements and correlational analyses between imaging and behavioural data to study inter-individual differences. Study I focused on the comparison between professional pianists and non- musicians observing a complex pattern of increases and decreases in grey matter volume. In comparison to non-musician individuals, pianists showed greater grey matter volume in areas related to motor skill and the automatization of learned movements, as well as reinforcement learning and emotional processing. On the other hand, regions associated to sensorimotor control, score reading and auditory and musical perception presented a reduction in grey matter volume. Study II explored the relationship between white-matter structural properties of the arcuate fasciculus (AF) and the performance of native German speakers in a foreign- language (Hindi) sentence and word imitation task. We found that a greater left lateralization of the AF volume predicted performance on the imitation task. This result was confirmed by using not only a manual deterministic approach but also an automatic atlas-based fibre-reconstruction method, which in addition pointed out to a specific region in the anterior half of the left AF as the most related to imitation ability. Study III aimed to investigate whether the white-matter structural connectivity of the pathways previously described as targets for plasticity mechanisms in professional musicians predicted musical abilities in non-musicians. We observed that the white- matter microstructural organization of the right hemisphere pathways involved in motor-control (corticospinal tract) and auditory-motor transformations (AF) correlated with the performance of non-musician individuals during the initial stages of rhythmic and melodic learning. The present work confirmed the involvement of several brain structures previously described to display plastic effects associated to music and language training in the first stages of audio-motor learning. Furthermore, they challenge previous views regarding music-induced plasticity by showing that expertise is not always or uniquely correlated with increases in brain tissue. This raises the question of the role of efficiency mechanisms derived from professional-like practice. Most importantly, the results from these three studies converge in showing that a prediction-feedback-feedforward loop for auditory-motor processing may be crucially involved in both musical and language learning and skills. We thus suggest that brain auditory-motor systems previously described as participating in native language processing (cortical areas of the dorsal route for language processing and the AF that connects them) may also be recruited during exposure to new linguistic or musical material, being refined after sustained music practice.[spa] Estudios previos muestran que la formación musical y lingüística provoca cambios plásticos en las estructuras y funciones cerebrales, acompañándose también de beneficios conductuales. Por ejemplo, se ha descrito que los músicos poseen mejores habilidades de discriminación auditiva (incluyendo la percepción tonal y la discriminación del habla en un ambiente ruidoso), una mayor capacidad de sincronización motora, así como mejor memoria verbal y coeficiente intelectual general en comparación con personas sin formación musical. Paralelamente, los bilingües muestran mejores funciones ejecutivas y habilidades relacionadas con la atención en comparación con individuos monolingües. Además, las alteraciones en la conectividad cerebral funcional y estructural pueden ser rastreadas estudiando las áreas cerebrales relacionadas con las actividades más utilizadas por músicos (instrumentistas y cantantes) y expertos lingüísticos (como bilingües o fonetistas profesionales). Pese a que en la última década se han dedicado esfuerzos importantes en el campo de la investigación sobre la plasticidad cerebral, sólo unos pocos estudios han tratado de investigar la conexión entre las propiedades iniciales del cerebro, en cuanto a las funciones y estructuras que se relacionan con las funciones auditivo-motoras, y el posterior aprendizaje musical o del lenguaje. Sin embargo, los marcadores estructurales cerebrales, tales como volumen/densidad de materia gris o medidas de difusividad en la sustancia blanca a partir de datos de imagen del tensor de difusión, así como medidas funcionales de la actividad relacionada con una tarea o datos de resting-state (estado de reposo) obtenidos por resonancia magnética o electroencefalografía, han demostrado que pueden correlacionar con el rendimiento y el aprendizaje en el dominio auditivo- motor. En la presente tesis pretendíamos ampliar nuestro conocimiento en cuanto a la plasticidad cerebral obtenida durante los supuestos “períodos sensibles” y después de la práctica musical mantenida en el tiempo, por un lado, y explorar las vías de sustancia blanca que pueden predecir habilidades lingüísticas o musicales al inicio del aprendizaje, por otro lado. Como objetivos secundarios, queríamos confirmar resultados previos con respecto a las estructuras cerebrales involucradas en el procesamiento de la música y el lenguaje, así como apoyar el uso de mediciones estructurales y enfoques correlacionales (entre datos de neuroimagen y conductuales) para estudiar las diferencias inter- individuales. El Estudio I se centró en la comparación entre pianistas profesionales y no músicos, observando un complejo patrón de aumentos y disminuciones en el volumen de materia gris. En comparación con los individuos no músicos, los pianistas mostraron mayor volumen de sustancia gris en áreas relacionadas con la habilidad motora y la automatización de movimientos aprendidos, así como el aprendizaje a través del refuerzo y el procesamiento emocional, mientras que las regiones asociadas al control sensoriomotor, lectura de partituras y percepción auditiva y musical presentaron una reducción del volumen de materia gris. El Estudio II exploró la relación entre las propiedades estructurales de la materia blanca del fascículo arqueado (AF por sus siglas en inglés) y el rendimiento de hablantes nativos de alemán en una tarea de imitación de frases y palabras en una lengua extranjera (hindi). Encontramos que una mayor lateralización del volumen de AF hacia la izquierda predecía el desempeño en la tarea de imitación. Este resultado se confirmó utilizando no sólo un enfoque determinístico-manual sino también una reconstrucción automática (basada en atlas anatómicos) de las fibras de sustancia blanca que, además, señalaba una región específica en la mitad anterior del AF izquierdo como la más relacionada con las capacidades de imitación. El Estudio III tenía como objetivo investigar si la conectividad estructural de vías de sustancia blanca anteriormente descritas como dianas para los mecanismos de plasticidad en músicos profesionales, podría predecir las habilidades musicales en los no músicos. Se observó que la organización micro-estructural de la materia blanca en el hemisferio derecho en vías involucradas en el control motor (tracto corticoespinal) y en transformaciones auditivo-motoras (AF) correlacionaba con el desempeño de individuos no músicos en las etapas iniciales del aprendizaje rítmico y melódico. El presente trabajo ha confirmado la implicación en las primeras etapas del aprendizaje audio-motor de varias estructuras cerebrales que previamente habían mostrado efectos plásticos asociados al aprendizaje musical y del lenguaje. Además, estos resultados desafían las opiniones anteriores sobre la plasticidad inducida por la experiencia musical al demostrar que la experiencia no se correlaciona siempre ni únicamente con un aumento del tejido cerebral, y planteando así preguntas sobre los mecanismos de eficiencia derivados de la práctica musical a nivel profesional. Más importante aún es que los resultados de estos tres estudios convergen mostrando que un bucle de predicción–retroalimentación (feedback)–alimentación directa (feedforward) para el procesamiento auditivo-motor puede estar implicado de manera crucial tanto en el aprendizaje musical como en el aprendizaje de idiomas. Por tanto, sugerimos que los sistemas auditivo-motrices del cerebro, que previamente se habían descrito como participantes en el procesamiento del lenguaje nativo (áreas corticales involucradas en la vía dorsal para el procesamiento del lenguaje, y el AF, que las conecta) también pueden ser reclutados durante la exposición a material lingüístico o musical nuevo, siendo refinado tras años de práctica musical activ

Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine

Imaging genetics : Methodological approaches to overcoming high dimensional barriers

Imaging genetics is still a quite novel area of research which attempts to discover how genetic factors affect brain structures and functions. In this thesis, using a various methodological approaches I showed how it can contribute to our understanding of the complex genetic architecture of the human brain

White Matter Integrity as a Biomarker for Stroke Recovery: Implications for TMS Treatment

White matter consists of myelinated axons which integrate information across remote brain regions. Following stroke white matter integrity is often compromised leading to functional impairment and disability. Despite its prevalence among stroke patients the role of white matter in development of post-stroke rehabilitation has been largely ignored. Rehabilitation interventions like repetitive transcranial magnetic stimulation (rTMS) are promising but reports on its efficacy have been conflicting. By understanding the role of white matter integrity in post-stroke motor recovery, brain reorganization and TMS efficacy we may be able to improve the development of future interventions. In this dissertation we set out answer these questions by investigating the relationship between white matter integrity and 1) bimanual motor performance following stroke, 2) cortical laterality following stroke and 3) TMS signal propagation (in a group of cocaine users without stroke). We identified white matter integrity of the corpus callosum as a key structure influencing bimanual performance using kinematic measures of hand symmetry (Chapter 2). Second, we found that reduced white matter integrity of corpus callosum was correlated with loss of functional laterality of the primary motor cortex during movement of the affected hand (Chapter 3). Lastly, we found that reduced white matter tract integrity from the site of stimulation to a downstream subcortical target, was correlated to the ability to modulate that target (Chapter 4). Taken together these studies support white matter integrity as a valuable biomarker for future rTMS trials in stroke. To emphasize the implications of these findings, we provide an example of how to incorporate white matter integrity at multiple levels of rTMS study design

Global associations between regional gray matter volume and diverse complex cognitive functions: evidence from a large sample study

Correlations between regional gray matter volume (rGMV) and psychometric test scores have been measured to investigate the neural bases for individual differences in complex cognitive abilities (CCAs). However, such studies have yielded different rGMV correlates of the same CCA. Based on the available evidence, we hypothesized that diverse CCAs are all positively but only weakly associated with rGMV in widespread brain areas. To test this hypothesis, we used the data from a large sample of healthy young adults [776 males and 560 females; mean age: 20.8 years, standard deviation (SD) = 0.8] and investigated associations between rGMV and scores on multiple CCA tasks (including non-verbal reasoning, verbal working memory, Stroop interference, and complex processing speed tasks involving spatial cognition and reasoning). Better performance scores on all tasks except non-verbal reasoning were associated with greater rGMV across widespread brain areas. The effect sizes of individual associations were generally low, consistent with our previous studies. The lack of strong correlations between rGMV and specific CCAs, combined with stringent corrections for multiple comparisons, may lead to different and diverse findings in the field

Neural Correlates of Parkinsonian Syndromes

The thesis investigated objective neuroimaging biomarkers in parkinsonian syndromes, which could be applied to increase diagnostic accuracy. To find convergence of the literature concerning disease-specific patterns in Parkinson’s disease and progressive supranuclear palsy, we conducted meta-analyses. In Parkinson’s disease glucose hypometabolism was re- vealed in bilateral inferior parietal cortex and left caudate nucleus and focal gray matter atrophy in the middle occipital gyrus. In progressive supranu- clear palsy we identified gray matter atrophy in the midbrain and white mat- ter atrophy in the cerebral/cerebellar pedunculi and midbrain. In sum, in Parkinson’s disease hypometabolism outperforms atrophy and in progres- sive supranuclear palsy we validated pathognomonic markers as disease- specific. Our studies create a novel framework to investigate disease- specific regional alterations for use in clinical routine. Further, we inves- tigated neural correlates by voxel-based morphometry and discriminated disease and clinical syndrome by multivariate pattern recognition in sin- gle patients with corticobasal syndrome and corticobasal syndrome with a unique syndrome - alien/ anarchic limb phenomenon. We found gray matter volume differences between patients and controls in asymmetric frontotem- poral/ occipital regions, motor areas, and insulae. The frontoparietal gyrus including the supplementary motor area contralateral to the side of the af- fected limb was specific for alien/ anarchic limb phenomenon. The predic- tion of the disease among controls was 79.0% accurate. The prediction of the specific syndrome within a disease reached an accuracy of 81.3%. In conclusion, we reliably classified patients and controls by objective pattern recognition. Moreover, we were able to predict a specific clinical syndrome within a disease, paving the way to individualized disease prediction.:SELBSTSTÄNDIGKEITSERKLÄRUNG I ACKNOWLEDGMENTS II SUMMARY III ZUSAMMENFASSUNG VIII BIBLIOGRAPHISCHE DARSTELLUNG XIV CONTENTS XVI 1 GENERAL INTRODUCTION 1 1.1 ParkinsonianSyndromes .................... 2 1.2 Parkinson’sDisease ....................... 2 1.2.1 DiagnosticCriteria .................... 3 1.3 ProgressiveSupranuclearPalsy ................ 4 1.3.1 DiagnosticCriteria .................... 5 1.4 CorticobasalDegeneration ................... 5 1.4.1 DiagnosticCriteria .................... 7 1.5 ImagingBiomarkers ....................... 7 1.6 CurrentThesis .......................... 9 1.6.1 MotivationandFramework ............... 9 1.6.2 ResearchQuestions................... 9 2 GENERAL MATERIALS AND METHODS 12 2.1 MagneticResonanceImaging.................. 12 2.2 AnalyticalMethods........................ 13 2.2.1 Meta-Analysis ...................... 13 2.2.2 Voxel-BasedMorphometry ............... 14 2.2.3 Support-Vector Machine Classification . . . . . . . . . 15 2.3 Multi-CentricData ........................ 16 2.4 ClinicalAssessment ....................... 17 3 Study 1 4 Study 2 5 Study 3 6 Study 4 7 Study 5 8 DISCUSSION 73 8.1 MainFindings........................... 73 8.2 Statistical Approaches to Find Imaging Biomarker . . . . . . 76 8.3 Brain Alterations and their Utility as Imaging Biomarker . . . . 77 8.4 Limitations ............................ 78 8.5 Contributions of the Current Thesis and Future Directions . . 79 9 REFERENCES APPENDIX XVIII LIST OF AUTHORSHIP XXVII CURRICULUM VITÆ XXXVII

Neuroimaging biomarkers associated with clinical dysfunction in Parkinson disease

Parkinson disease (PD) is the second most common neurodegenerative disorder in the world, directly affecting 2-3% of the population over the age of 65. People diagnosed with the disorder can experience motor, autonomic, cognitive, sensory and neuropsychiatric symptoms that can significantly impact quality of life. Uncertainty still exists about the pathophysiological mechanisms that underlie a range of clinical features of the disorder, linked to structural as well as functional brain changes. This thesis thus aimed to uncover neuroimaging biomarkers associated with clinical dysfunction in PD. A 'hubs-and-spokes' neural circuit-based approach can contribute to this aim, by analysing the component elements and also the interconnections of important brain networks. This thesis focusses on structures within basal ganglia-thalamocortical neuronal circuits that are linked to a range functions impacted in the disorder, and that are vulnerable to the consequences of PD pathology. This thesis investigated neuronal 'hubs' by studying the morphology of the caudate nucleus, putamen, thalamus and neocortex. The caudate nucleus, putamen and thalamus are all vital subcortical 'hubs' that play important roles in a number of functional domains that are compromised in PD. The neocortex, on the other hand, has a range of 'hubs' spread across it, regions of the brain that are crucial for neuronal signalling and communication. The interconnections, or 'spokes', between these hubs and other brain regions were investigated using seed-based resting-state functional connectivity analyses. Finally, a morphological analysis was used to investigate possible structural changes to the corpus callosum, the major inter-hemispheric white matter tract of the brain, crucial to effective higher-order brain processes. This thesis demonstrates that the caudate nucleus, putamen, thalamus, corpus callosum and neocortex are all atrophied in PD participants with dementia. PD participants also demonstrated a significant correlation between volumes of the caudate nuclei and general cognitive functioning and speed, while putamina volumes were correlated with general motor function. Cognitively unimpaired PD participants demonstrated minimal morphological alterations compared to control participants, however they demonstrated significant increases in functional connectivity of the caudate nucleus, putamen and thalamus with areas across the frontal lobe, and decreases in functional connectivity with parietal and cerebellar regions. PD participants with mild cognitive impairment and dementia show decreased functional connectivity of the thalamus with paracingulate and posterior cingulate cortices, respectively. This thesis contributes a deeper understanding of the relationship between structures of basal ganglia-thalamocortical neuronal circuits, corpus callosal and neocortical morphology, and the clinical dysfunction associated with PD. This thesis suggests that functional connectivity changes are more common in early stages of the disorder, while morphological alterations are more pronounced in advanced disease stages

Neuropathology and cognitive dysfunction after early hypoglycaemia

Hypoglycaemia is the most common metabolic problem in neonatal medicine, occurring during the first days of life and usually resolving within the same time frame. However, some neonates and infants experience severe and recurrent episodes of hypoglycaemia, the most common aetiologies being congenital hyperinsulinism (CHI) and ketotic hypoglycaemia (KH). Children with CHI are at risk of lasting brain injury, while children with KH are considered to be protected from adverse sequelae owing to the presence of ketone bodies during hypoglycaemia. This thesis investigated the neuropsychological and neuroimaging profiles of these two patient groups in neurologically normal school-aged children. Thirty-one patients with CHI and twenty-one patients with KH participated in the study alongside a cohort of healthy controls. A comprehensive battery of neuropsychological tests revealed specific impairments in attention and motor skills in both patient groups, with additional impairments observed in children with CHI. Automated and manual measurements of subcortical volumes, as well as whole brain analyses (voxel based morphometry and tract based spatial statistics) were conducted. Compared to controls, patients with CHI have reduced volume of subcortical structures, as well as extensive white matter volume loss (accompanied by decreased intracranial volume) and reduced white matter integrity across the entire brain. Patients with KH did not significantly differ from controls on any brain measures, but the only significant difference between patient groups was in thalamic and intracranial volumes. Integrity of subcortical structures and white matter was found to be predictive of scores in memory, motor skills and attention. This study is the first to show the extent of brain abnormality as a result of CHI in neurologically normal children. Furthermore, the finding that both patient groups share a similar cognitive profile refutes the notion that children with KH are protected from adverse sequelae. The implications of these findings are discussed

Convergent and diver gent brain structural and functional abnormalities associated with developmental dyslexia

Brain abnormalities in the reading network have been repeatedly reported in individuals with developmental dyslexia (DD); however, it is still not totally understood where the structural and functional abnormalities are consistent/inconsistent across languages. In the current multimodal meta-analysis, we found convergent structural and functional alterations in the left superior temporal gyrus across languages, suggesting a neural signature of DD. We found greater reduction in grey matter volume and brain activation in the left inferior frontal gyrus in morpho-syllabic languages (e.g. Chinese) than in alphabetic languages, and greater reduction in brain activation in the left middle temporal gyrus and fusiform gyrus in alphabetic languages than in morpho-syllabic languages. These language differences are explained as consequences of being DD while learning a specific language. In addition, we also found brain regions that showed increased grey matter volume and brain activation, presumably suggesting compensations and brain regions that showed inconsistent alterations in brain structure and function. Our study provides important insights about the etiology of DD from a cross-linguistic perspective with considerations of consistency/inconsistency between structural and functional alterations