Change in Right Inferior Longitudinal Fasciculus Integrity Is Associated With Naming Recovery in Subacute Poststroke Aphasia

Background. Despite progress made in understanding functional reorganization patterns underlying recovery in subacute aphasia, the relation between recovery and changes in white matter structure remains unclear. Objective. To investigate changes in dorsal and ventral language white matter tract integrity in relation to naming recovery in subacute poststroke aphasia. Methods. Ten participants with aphasia after left-hemisphere stroke underwent language testing and diffusion tensor imaging twice within 3 months post onset, with a 1-month interval between sessions. Deterministic tractography was used to bilaterally reconstruct the superior longitudinal fasciculus (SLF), inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), middle longitudinal fasciculus (MdLF), and uncinate fasciculus (UF). Per tract, the mean fractional anisotropy (FA) was extracted as a measure of microstructural integrity. Naming accuracy was assessed with the Boston Naming Test (BNT). Correlational analyses were performed to investigate the relationship between changes in FA values and change in BNT score. Results. A strong positive correlation was found between FA change in the right ILF within the ventral stream and change on the BNT (r = 0.91, P <.001). An increase in FA in the right ILF was associated with considerable improvement of naming accuracy (range BNT change score: 12-14), a reduction with limited improvement or slight deterioration. No significant correlations were found between change in naming accuracy and FA change in any of the other right or left ventral and dorsal language tracts. Conclusions. Naming recovery in subacute aphasia is associated with change in the integrity of the right ILF

The language connectome: insights from advanced structural and functional imaging techniques

One of the most intriguing aspects of human kind is our unique capacity for rapidly acquiring speech and language in the early years of life. However, disorders in speech and language are among the most common developmental problems in childhood. They can restrict the child from social participation and academic achievement and may lead to a permanent dysfunction. Equally, children’s intellectual and linguistic or communicative skills play an important role in their evolving sense of competence and self-esteem. Prevention, early diagnosis and improved support of these language disorders is therefore crucial. Language disorders are currently clinically diagnosed using a standardized psychometric test battery measuring different aspects of language processing. However, over the past years, understanding the pathophysiology of these speech and language disorders has gained great interest by neuroscientists. Although a diagnostic imaging marker is at present still lacking, recent functional and structural neuroimaging techniques seem to reveal subtle, but important, functional and/or microstructural changes in the brain of children and adults with language difficulties. In the last decade, significant progress has been made in more precisely characterising the neurobiology of language in the human brain. The classical language model has been replaced with more comprehensive models influenced by advances in structural and functional neuroimaging methods. These techniques have revealed a far more distributed cortical and subcortical network for the processing and production of language. The emerging framework going forward is one that emphasises processing streams of functional regions anchored by long association fibre pathways and cortico-subcortical projections. However, the current knowledge is far from conclusive and predominantly focused on adulthood. The main goal of this doctoral research is to explore neuroanatomic and neurofunctional substrates underlying language impairment in children as well as in a group of adults after left-hemispheric stroke. Diffusion Tensor Imaging (DTI) is a non-invasive imaging technique capable of visualising and quantifying the white matter architecture of the brain. DTI provides quantitative metrics of the diffusion process, such as the fractional anisotropy (FA) and apparent diffusion coefficient (ADC), which can be used to evaluate the white matter microstructure. DTI tractography allows to reconstruct long association white matter tracts subserving the functional integration among frontal, parietal and temporal association cortices, needed for the execution of complex language processing tasks. Therefore, this technique qualifies as an adequate imaging technique to investigate a potential neuroanatomic substrate underlying language impairment. This doctoral research started with a study assessing the structural language connectome in relation to handedness in typically developing school-aged children. The white matter macro- and microstructure was markedly different between left- and right-handed children in both hemispheres. Right-handed children demonstrated a clear left-hemispheric lateralisation of white matter properties for the majority of the investigated tracts, which may reflect the functional dominance of the left hemisphere for language processing. In contrast, a more bilateral pattern of structural lateralisation was revealed for all studied white matter fibre bundles in left-handed children presuming an increased interhemispheric processing of language in these children. Next, we assessed white matter changes related to language impairment in children with autism, children with developmental dysphasia and children with rolandic epilepsy using DTI. Several structural alterations were found in these children with language impairment. Interestingly, in all these paediatric populations, a structural left-hemisperic dominance of the language network was lacking. In children with autism, children with developmental dysphasia and children with rolandic epilepsy, language lateralisation was more present in bilateral or right-hemispheric language networks. This relative increase of right-hemispheric involvement in language processing might be interpreted as an important compensatory strategy of the central nervous system to stabilise cognitive and in this case specifically language performance. In a second part of this doctoral research, we aimed to detect why a decreased structural left lateralisation of the language conectome is linked to language problems in children with autism, developmental dysphasia or rolandic epilepsy, and why this is not the case in typically developing left-handed children. As DTI can only provide partial answers on the neurobiological origin of the observed language problems, functional MRI (fMRI) was used to assess the functional connectivity of the language network. fMRI is a technique that allows to indirectly visualise brain activity, both during an active task and in rest, using the vascular response nearby electrically active neurons. First, a active verb generation task was used to localize the cortical regions involved in language function which were then used as seed regions for the study of the resting state connectivity of the brain. Interestingly, the intrinsic functional connectivity did not differ between left- and right-handed children. In contrast, in children with autism, children with developmental dysphasia and children with rolandic epilepsy we found a marked loss of intrinsic functional connectivity. Specifically, their language impairment was linked to a loss of connectivity between the right cerebellum and the supratentorial language areas. These novel findings link the observed language impairment to a relative dissociation of the cortical language system from normal cerebellar control, suggesting that the disturbed development and function of the language system might be due to a loss of normal modulatory control and automation function of the cerebellum. Finally, we aimed to identify anatomical predictors of language function after left-hemispheric stroke. Our results suggest that DTI based measurements of the dorsal and ventral language stream may serve as clinically useful predictive biomarkers of chronic aphasia after left-hemispheric stroke. Age, gender, lesion size, level of education as well as the DTI derived variables of both the left- and right-hemispheric dorsal and ventral language stream, explained 87% of the variability in language performance of the included patients with chronic aphasia after left-hemispheric stroke. In conclusion, this doctoral thesis studied the neural correlates of language impairment by applying advanced MR neuroimaging techniques. We have demonstrated several structural and functional changes in the brain of school-aged children and adults with and without language impairment and provided a number of new insights into potential pathways leading to severe language impairment. A better understanding of the neurobiological roots of language difficulties in children, even in utero, may open possibilities for preventive care, early diagnosis and improved support.status: publishe

The language connectome in the left-handed brain: hemispheric (a)symmetries and beyond

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Evaluation of the language profile in children with rolandic epilepsy and developmental dysphasia: Evidence for distinct strengths and weaknesses

Although benign, rolandic epilepsy (RE) or benign childhood epilepsy with centro-temporal spikes is often associated with language impairment. Recently, fronto-rolandic EEG abnormalities have been described in children with developmental dysphasia (DD), suggesting an interaction between language impairment and interictal epileptiform discharges. To investigate if a behavioral-linguistic continuum between RE and DD exists, a clinical prospective study was carried out to evaluate the language profile of 15 children with RE and 22 children with DD. Language skills were assessed using an extensive, standardized test battery. Language was found to be impaired in both study groups, however RE and DD were associated with distinct language impairment profiles. Children with RE had difficulties with sentence comprehension, semantic verbal fluency and auditory short-term memory, which are unrelated to age of epilepsy onset and laterality of epileptic focus. In children with DD, sentence comprehension and verbal fluency were among their relative strengths, whereas sentence and lexical production constituted relative weaknesses.publisher: Elsevier articletitle: Evaluation of the language profile in children with rolandic epilepsy and developmental dysphasia: Evidence for distinct strengths and weaknesses journaltitle: Brain and Language articlelink: http://dx.doi.org/10.1016/j.bandl.2017.03.006 content_type: article copyright: © 2017 Elsevier Inc. All rights reserved.status: publishe

The mis-wired language network in children with developmental language disorder: insights from DTI tractography

This study aims to detect the neural substrate underlying the language impairment in children with developmental language disorder (DLD) using diffusion tensor imaging (DTI) tractography. Deterministic DTI tractography was performed in a group of right-handed children with DLD (N = 17; mean age 10;07 ± 2;01 years) and a typically developing control group matched for age, gender and handedness (N = 22; mean age 11;00 ± 1;11 years) to bilaterally identify the superior longitudinal fascicle, arcuate fascicle, anterior lateral segment and posterior lateral segment (also called dorsal language network) and the middle and inferior longitudinal fascicle, extreme capsule fiber system and uncinate fascicle (also called ventral language network). Language skills were assessed using an extensive, standardized test battery. Differences in language performance, white matter organization and structural lateralization of the language network were statistically analyzed. Children with DLD showed a higher overall volume and higher ADC values for the left-hemispheric language related WM tracts. In addition, in children with DLD, the majority (88%; 7/8) of the studied language related WM tracts did not show a significant left or right lateralization pattern. These structural alterations might underlie the language impairment in children with DLD.status: publishe

Cortical thinning and altered functional brain coherence in survivors of childhood sarcoma

High-dose chemotherapy is increasingly evidenced to be neurotoxic and result in long-term neurocognitive sequelae. However, research investigating grey matter alterations in childhood cancer patients remains limited. As childhood sarcoma patients receive high-dose chemotherapy, we aimed to investigate cortical brain alterations in adult survivors. We analyzed high-resolution structural (T1-weighted) MRI and resting-state functional MRI (rsfMRI), to derive structural and functional cortical information in survivors of childhood sarcoma, treated with high-dose intravenous chemotherapy (n = 33). These scans were compared to age- and gender- matched controls (n = 34). Cortical volume and thickness were investigated using voxel-based morphometry and vertex-wise surface-based morphometry. Brain regions showing significant group differences in volume or thickness were implemented as seeds of interest to estimate their resting state co-activity with other areas (i.e. functional coherence). We explored whether structural measures were associated with potential risk factors, such as age at diagnosis, and cumulative doses of chemotherapeutic agents (methotrexate, ifosfamide). Finally, we investigated the link between functional regional strength, neurocognitive assessments and daily life complaints. In patients relative to controls we observed lower grey matter volumes in cerebellar and frontal areas, as well as frontal cortical thinning. Cerebellar volume and orbitofrontal thickness appeared dose- and age-related, respectively. Cortical thickness of the parahippocampal area appeared lower, only if the group comparison was not adjusted for depression. This region specifically showed lower functional coherence, which was associated with lower processing speed. This study suggests cortical thinning as well as decreased functional coherence in survivors of childhood sarcoma, which could be important for both long-term attentional functioning and emotional distress in daily life. Frontal areas might be specifically vulnerable during adolescence.status: publishe

Long-term leukoencephalopathy and neurocognitive functioning in childhood sarcoma patients treated with high-dose intravenous chemotherapy

PURPOSE: Knowledge is limited regarding the prevalence and persistence of chemotherapy-induced leukoencephalopathy in childhood sarcoma patients. This study explored the presence, clinical relevance, and potential risk factors of leukoencephalopathy in childhood bone and soft tissue sarcoma survivors, treated with intravenous chemotherapy. METHODS: We acquired cross-sectional neurocognitive data in adult survivors (n = 34) (median age at diagnosis [AaD] = 13.32 years, age range = 16-35 years) and healthy age-matched controls (n = 34). Additionally, magnetic resonance imaging included T2-weighted FLAIR (leukoencephalopathy Fazekas rating), multiexponential T2 relaxation (MET2), and multishell diffusion MRI to estimate myelin integrity-related metrics and fluid movement restrictions. Finally, chemotherapy subgroups (methotrexate, alkylating agents, or combination), AaD, and Apoε and MTHFRC677T polymorphisms were explored as potential risk factors for leukoencephalopathy. RESULTS: At the group level, quality of life, working memory, processing speed, and visual memory were significantly lower in patients compared to controls. Furthermore, long-term leukoencephalopathy was observed in 27.2% of the childhood sarcoma survivors, which was related to attentional processing speed. Lesions were related to diffusion-derived, but not to myelin-sensitive metrics. A significant interaction effect between AaD and chemotherapy group demonstrated more lesions in case of high-dose methotrexate (HD-MTX) (F = 3.434, P = .047). However, patients treated with alkylating agents (without HD-MTX) also showed lesions in younger patients. Genetic predictors were nonsignificant. CONCLUSION AND IMPLICATION: This study suggests long-term leukoencephalopathy with possibly underlying changes in vasculature, inflammation, or axonal injury, but not necessarily long-term demyelination. Such lesions could affect processing speed, and as such long-term daily life functioning of these patients.status: publishe

Altered functional connectivity of the language network in ASD: Role of classical language areas and cerebellum

The development of language, social interaction and communicative skills is remarkably different in the child with autism spectrum disorder (ASD). Atypical brain connectivity has frequently been reported in this patient population. However, the neural correlates underlying their disrupted language development and functioning are still poorly understood. Using resting state fMRI, we investigated the functional connectivity properties of the language network in a group of ASD patients with clear comorbid language impairment (ASD-LI; N = 19) and compared them to the language related connectivity properties of 23 age-matched typically developing children. A verb generation task was used to determine language components commonly active in both groups. Eight joint language components were identified and subsequently used as seeds in a resting state analysis. Interestingly, both the interregional and the seed-based whole brain connectivity analysis showed preserved connectivity between the classical intrahemispheric language centers, Wernicke's and Broca's areas. In contrast however, a marked loss of functional connectivity was found between the right cerebellar region and the supratentorial regulatory language areas. Also, the connectivity between the interhemispheric Broca regions and modulatory control dorsolateral prefrontal region was found to be decreased. This disruption of normal modulatory control and automation function by the cerebellum may underlie the abnormal language function in children with ASD-LI.ISSN:2213-158