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  • Thiede, Anja; Virtala, Paula; Ala-Kurikka, Iina; Partanen, Eino; Huotilainen, Minna; Mikkola, Kaija; Leppänen, Paavo HT; Kujala, Teija (2019)
    Objective: Identifying early signs of developmental dyslexia, associated with deficient speech-sound processing, is paramount to establish early interventions. We aimed to find early speech-sound processing deficiencies in dyslexia, expecting diminished and atypically lateralized event-related potentials (ERP) and mismatch responses (MMR) in newborns at dyslexia risk. Methods: ERPs were recorded to a pseudoword and its variants (vowel-duration, vowel-identity, and syllable-frequency changes) from 88 newborns at high or no familial risk. The response significance was tested, and group, laterality, and frontality effects were assessed with repeated-measures ANOVA. Results: An early positive and right-lateralized ERP component was elicited by standard pseudowords in both groups, the response amplitude not differing between groups. Early negative MMRs were absent in the at-risk group, and MMRs to duration changes diminished compared to controls. MMRs to vowel changes had significant laterality x group interactions resulting from right-lateralized MMRs in controls. Conclusions: The MMRs of high-risk infants were absent or diminished, and morphologically atypical, suggesting atypical neural speech-sound discrimination. Significance: This atypical neural basis for speech discrimination may contribute to impaired language development, potentially leading to future reading problems. (C) 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.
  • Gonda, Yuko; Namba, Takashi; Hanashima, Carina (2020)
    The formation of the neocortex relies on intracellular and extracellular signaling molecules that are involved in the sequential steps of corticogenesis, ranging from the proliferation and differentiation of neural progenitor cells to the migration and dendrite formation of neocortical neurons. Abnormalities in these steps lead to disruption of the cortical structure and circuit, and underly various neurodevelopmental diseases, including dyslexia and autism spectrum disorder (ASD). In this review, we focus on the axon guidance signaling Slit-Robo, and address the multifaceted roles of Slit-Robo signaling in neocortical development. Recent studies have clarified the roles of Slit-Robo signaling not only in axon guidance but also in progenitor cell proliferation and migration, and the maturation of neocortical neurons. We further discuss the etiology of neurodevelopmental diseases, which are caused by defects in Slit-Robo signaling during neocortical formation.
  • Tammimies, Kristiina; Bieder, Andrea; Lauter, Gilbert; Sugiaman-Trapman, Debora; Torchet, Rachel; Hokkanen, Marie-Estelle; Burghoorn, Jan; Castrén, Eero; Kere, Juha; Tapia-Paez, Isabel; Swoboda, Peter (2016)
    DYX1C1, DCDC2, and KIAA0319 are three of the most replicated dyslexia candidate genes (DCGs). Recently, these DCGs were implicated in functions at the cilium. Here, we investigate the regulation of these DCGs by Regulatory Factor X transcription factors (RFX TFs), a gene family known for transcriptionally regulating ciliary genes. We identify conserved X-box motifs in the promoter regions of DYX1C1, DCDC2, and KIAA0319 and demonstrate their functionality, as well as the ability to recruit RFX TFs using reporter gene and electrophoretic mobility shift assays. Furthermore, we uncover a complex regulation pattern between RFX1, RFX2, and RFX3 and their significant effect on modifying the endogenous expression of DYX1C1 and DCDC2 in a human retinal pigmented epithelial cell line immortalized with hTERT (hTERT-RPE1). In addition, induction of ciliogenesis increases the expression of RFX TFs and DCGs. At the protein level, we show that endogenous DYX1C1 localizes to the base of the cilium, whereas DCDC2 localizes along the entire axoneme of the cilium, thereby validating earlier localization studies using overexpression models. Our results corroborate the emerging role of DCGs in ciliary function and characterize functional noncoding elements, X-box promoter motifs, in DCG promoter regions, which thus can be targeted for mutation screening in dyslexia and ciliopathies associated with these genes.
  • Ylinen, Sari; Junttila, Katja; Laasonen, Marja; Iverson, Paul; Ahonen, Lauri; Kujala, Teija (2019)
    Dyslexia is characterized by poor reading skills, yet often also difficulties in second-language learning. The differences between native- and second-language speech processing and the establishment of new brain representations for spoken second language in dyslexia are not, however, well understood. We used recordings of the mismatch negativity component of event-related potential to determine possible differences between the activation of long-term memory representations for spoken native- and second-language word forms in Finnish-speaking 9-11-year-old children with or without dyslexia, studying English as their second language in school. In addition, we sought to investigate whether the bottleneck of dyslexic readers' second-language learning lies at the level of word representations or smaller units and whether the amplitude of mismatch negativity is correlated with native-language literacy and related skills. We found that the activation of brain representations for familiar second-language words, but not for second-language speech sounds or native-language words, was weaker in children with dyslexia than in typical readers. Source localization revealed that dyslexia was associated with weak activation of the right temporal cortex, which has been previously linked with word-form learning. Importantly, the amplitude of the mismatch negativity for familiar second-language words correlated with native-language literacy and rapid naming scores, suggesting a close link between second-language processing and these skills.
  • Simon, Júlia; Balla, Viktoria Roxana (2020)
    The study investigated auditory temporal processing on a tens of milliseconds scale that is the interval when two consecutive stimuli are processed either together or as distinct events. Distinctiveness is defined by one's ability to make correct order judgments of the presented sounds and is measured via the spatial temporal order judgement task (TOJ). The study aimed to identify electrophysiological indices of the TOJ performance. Tone pairs were presented with inter-stimulus intervals (ISI) varying between 25 and 75 ms while EEG was recorded. A pronounced amplitude change in the P2 interval was found between the event-related potential (ERP) of tone pairs having ISI = 55 and 65 ms, but it was a characteristic only of the group having poor behavioral thresholds. With the two groups combined, the amplitude change between these ERPs in the P2 interval showed a medium-size correlation with the behavioral threshold.
  • Gialluisi, Alessandro; Andlauer, Till F. M.; Mirza-Schreiber, Nazanin; Moll, Kristina; Becker, Jessica; Hoffmann, Per; Ludwig, Kerstin U.; Czamara, Darina; St Pourcain, Beate; Brandler, William; Honbolygo, Ferenc; Toth, Denes; Csepe, Valeria; Huguet, Guillaume; Morris, Andrew P.; Hulslander, Jacqueline; Willcutt, Erik G.; DeFries, John C.; Olson, Richard K.; Smith, Shelley D.; Pennington, Bruce F.; Vaessen, Anniek; Maurer, Urs; Lyytinen, Heikki; Peyrard-Janvid, Myriam; Leppanen, Paavo H. T.; Brandeis, Daniel; Bonte, Milene; Stein, John F.; Talcott, Joel B.; Fauchereau, Fabien; Wilcke, Arndt; Francks, Clyde; Bourgeron, Thomas; Monaco, Anthony P.; Ramus, Franck; Landerl, Karin; Kere, Juha; Scerri, Thomas S.; Paracchini, Silvia; Fisher, Simon E.; Schumacher, Johannes; Noethen, Markus M.; Mueller-Myhsok, Bertram; Schulte-Koerne, Gerd (2019)
    Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p <1 x 10(-8)) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 x 10(-9)), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 x 10(-8)). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 x 10(-8)) and with all the cognitive traits tested (p = 3.07 x 10(-8)), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p similar to [10(-5)-10(-7)]) and negatively associated with ADHD PRS (p similar to [10(-8)-10(-17)]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
  • Massinen, Satu; Wang, Jingwen; Laivuori, Krista; Bieder, Andrea; Paez, Isabel Tapia; Jiao, Hong; Kere, Juha (2016)
    Background: The DYX5 locus for developmental dyslexia was mapped to chromosome 3 by linkage study of a large Finnish family, and later, roundabout guidance receptor 1 (ROBO1) was implicated as a candidate gene at DYX5 with suppressed expression from the segregating rare haplotype. A functional magnetoencephalographic study of several family members revealed abnormal auditory processing of interaural interaction, supporting a defect in midline crossing of auditory pathways. In the current study, we have characterized genetic variation in the broad ROBO1 gene region in the DYX5-linked family, aiming to identify variants that would increase our understanding of the altered expression of ROBO1. Methods: We have used a whole genome sequencing strategy on a pooled sample of 19 individuals in combination with two individually sequenced genomes. The discovered genetic variants were annotated and filtered. Subsequently, the most interesting variants were functionally tested using relevant methods, including electrophoretic mobility shift assay (EMSA), luciferase assay, and gene knockdown by lentiviral small hairpin RNA (shRNA) in lymphoblasts. Results: We found one novel intronic single nucleotide variant (SNV) and three novel intergenic SNVs in the broad region of ROBO1 that were specific to the dyslexia susceptibility haplotype. Functional testing by EMSA did not support the binding of transcription factors to three of the SNVs, but one of the SNVs was bound by the LIM homeobox 2 (LHX2) protein, with increased binding affinity for the non-reference allele. Knockdown of LHX2 in lymphoblast cell lines extracted from subjects from the DYX5-linked family showed decreasing expression of ROBO1, supporting the idea that LHX2 regulates ROBO1 also in human. Conclusions: The discovered variants may explain the segregation of dyslexia in this family, but the effect appears subtle in the experimental settings. Their impact on the developing human brain remains suggestive based on the association and subtle experimental support.
  • Kimppa, Lilli; Shtyrov, Yury; Partanen, Eino; Kujala, Teija (2018)
    Developmental dyslexia is characterised as an inability to read fluently. Apart from literacy problems, dyslexics have other language difficulties including inefficient speech encoding and deficient novel word learning. Yet, the neural mechanisms underlying these impairments are largely unknown. We tracked online formation of neural memory traces for a novel spoken word-form in dyslexic and normal-reading children by recording the brain’s electrophysiological response dynamics in a passive perceptual exposure session. Crucially, no meaning was assigned to the new word-form nor was there any task related to the stimulus, enabling us to explore the memory-trace formation of a purely phonological form in the absence of any short-term or working memory demands. Similar to previously established neural index of rapid word learning in adults, the control children demonstrated an early brain response enhancement within minutes of exposure to the novel word-form that originated in frontal cortices. Dyslexic children, however, lacked this neural enhancement over the entire course of exposure. Furthermore, the magnitude of the rapid neural enhancement for the novel word-form was positively associated with reading and writing fluency. This suggests that the rapid neural learning mechanism for online acquisition of novel speech material is associated with reading skills. Furthermore, the deficient online learning of novel words in dyslexia, consistent with poor rapid adaptation to familiar stimuli, may underlie the difficulty of learning to read.
  • Thiede, A.; Parkkonen, L.; Virtala, P.; Laasonen, M.; Makela, J. P.; Kujala, T. (2020)
    Poor neural speech discrimination has been connected to dyslexia, and may represent phonological processing deficits that are hypothesized to be the main cause for reading impairments. Thus far, neural speech discrimination impairments have rarely been investigated in adult dyslexics, and even less by examining sources of neuromagnetic responses. We compared neuromagnetic speech discrimination in dyslexic and typical readers with mismatch fields (MMF) and determined the associations between MMFs and reading-related skills. We expected weak and atypically lateralized MMFs in dyslexic readers, and positive associations between readingrelated skills and MMF strength. MMFs were recorded to a repeating pseudoword /ta-ta/ with occasional changes in vowel identity, duration, or syllable frequency from 43 adults, 21 with confirmed dyslexia. Phonetic (vowel and duration) changes elicited left-lateralized MMFs in the auditory cortices. Contrary to our hypothesis, MMF source strengths or lateralization did not differ between groups. However, better verbal working memory was associated with stronger left-hemispheric MMFs to duration changes across groups, and better reading was associated with stronger right-hemispheric late MMFs across speech-sound changes in dyslexic readers. This suggests a link between neural speech processing and reading-related skills, in line with previous work. Furthermore, our findings suggest a right-hemispheric compensatory mechanism for language processing in dyslexia. The results obtained promote the use of MMFs in investigating reading-related brain processes.
  • Virtala, P.; Talola, S.; Partanen, E.; Kujala, T. (2020)
    Whereas natural acoustic variation in speech does not compromise phoneme discrimination in healthy adults, it was hypothesized to be a challenge for developmental dyslexics. We investigated dyslexics’ neural and perceptual discrimination of native language phonemes during acoustic variation. Dyslexics and non-dyslexics heard /æ/ and /i/ phonemes in a context with fo variation and then in a context without it. Mismatch negativity (MMN) and P3a responses to phoneme changes were recorded with electroencephalogram to compare groups during ignore and attentive listening. perceptual phoneme discrimination in the variable context was evaluated with hit-ratios and reaction times. MMN/N2bs were diminished in dyslexics in the variable context. Hit-ratios were smaller in dyslexics than controls. MMNs did not differ between groups in the context without variation. These results suggest that even distinctive vowels are challenging to discriminate for dyslexics when the context resembles natural variability of speech. This most likely reflects poor categorical perception of phonemes in dyslexics. Difficulties to detect linguistically relevant invariant information during acoustic variation in speech may contribute to dyslexics’ deficits in forming native language phoneme representations during infancy. Future studies should acknowledge that simple experimental paradigms with repetitive stimuli can be insensitive to dyslexics’ speech processing deficits.
  • Laasonen, Marja; Lahti-Nuuttila, Pekka; Leppämäki, Sami; Tani, Pekka; Wikgren, Jan; Harno, Hanna; Oksanen-Hennah, Henna; Pothos, Emmanuel; Cleeremans, Axel; Dye, Matthew W. G.; Cousineau, Denis; Hokkanen, Laura (2020)
    Two themes have puzzled the research on developmental and learning disorders for decades. First, some of the risk and protective factors behind developmental challenges are suggested to be shared and some are suggested to be specific for a given condition. Second, language-based learning difficulties like dyslexia are suggested to result from or correlate with non-linguistic aspects of information processing as well. In the current study, we investigated how adults with developmental dyslexia or ADHD as well as healthy controls cluster across various dimensions designed to tap the prominent non-linguistic theories of dyslexia. Participants were 18-55-year-old adults with dyslexia (n= 36), ADHD (n= 22), and controls (n= 35). Non-linguistic theories investigated with experimental designs included temporal processing impairment, abnormal cerebellar functioning, procedural learning difficulties, as well as visual processing and attention deficits. Latent profile analysis (LPA) was used to investigate the emerging groups and patterns of results across these experimental designs. LPA suggested three groups: (1) a large group with average performance in the experimental designs, (2) participants predominantly from the clinical groups but with enhanced conditioning learning, and (3) participants predominantly from the dyslexia group with temporal processing as well as visual processing and attention deficits. Despite the presence of these distinct patterns, participants did not cluster very well based on their original status, nor did the LPA groups differ in their dyslexia or ADHD-related neuropsychological profiles. Remarkably, the LPA groups did differ in their intelligence. These results highlight the continuous and overlapping nature of the observed difficulties and support the multiple deficit model of developmental disorders, which suggests shared risk factors for developmental challenges. It also appears that some of the risk factors suggested by the prominent non-linguistic theories of dyslexia relate to the general level of functioning in tests of intelligence.
  • Sihvonen, Aleksi J.; Virtala, Paula; Thiede, Anja; Laasonen, Marja; Kujala, Teija (2021)
    Current views on the neural network subserving reading and its deficits in dyslexia rely largely on evidence derived from functional neuroimaging studies. However, understanding the structural organization of reading and its aberrations in dyslexia requires a hodological approach, studies of which have not provided consistent findings. Here, we adopted a whole brain hodological approach and investigated relationships between structural white matter connectivity and reading skills and phonological processing in a cross-sectional study of 44 adults using individual local connectome matrix from diffusion MRI data. Moreover, we performed quantitative anisotropy aided differential tractography to uncover structural white matter anomalies in dyslexia (23 dyslexics and 21 matched controls) and their correlation to reading-related skills. The connectometry analyses indicated that reading skills and phonological processing were both associated with corpus callosum (tapetum), forceps major and minor, as well as cerebellum bilaterally. Furthermore, the left dorsal and right thalamic pathways were associated with phonological processing. Differential tractography analyses revealed structural white matter anomalies in dyslexics in the left ventral route and bilaterally in the dorsal route compared to the controls. Connectivity deficits were also observed in the corpus callosum, forceps major, vertical occipital fasciculus and corticostriatal and thalamic pathways. Altered structural connectivity in the observed differential tractography results correlated with poor reading skills and phonological processing. Using a hodological approach, the current study provides novel evidence for the extent of the reading-related connectome and its aberrations in dyslexia. The results conform current functional neuroanatomical models of reading and developmental dyslexia but provide novel network-level and tract-level evidence on structural connectivity anomalies in dyslexia, including the vertical occipital fasciculus.
  • Scerri, Thomas S.; Darki, Fahimeh; Newbury, Dianne F.; Whitehouse, Andrew J. O.; Peyrard-Janvid, Myriam; Matsson, Hans; Ang, Qi W.; Pennell, Craig E.; Ring, Susan; Stein, John; Morris, Andrew P.; Monaco, Anthony P.; Kere, Juha; Talcott, Joel B.; Klingberg, Torkel; Paracchini, Silvia (2012)
  • Chandrasekar, Gayathri; Vesterlund, Liselotte; Hultenby, Kjell; Tapia-Paez, Isabel; Kere, Juha (2013)
  • Lobier, Muriel A.; Peyrin, Carole; Pichat, Cedric; Le Bas, Jean-Francois; Valdois, Sylviane (2014)
  • Kujala, Teija; Sihvonen, Aleksi; Thiede, Anja; Palo-oja, Peter; Virtala, Paula Maarit; Numminen, Jussi; Laasonen, Marja (2021)
    Developmental dyslexia (DD) is the most prevalent neurodevelopmental disorder with a substantial negative influence on the individual's academic achievement and career. Research on its neuroanatomical origins has continued for half a century, yielding, however, inconsistent results, lowered total brain volume being the most consistent finding. We set out to evaluate the grey matter (GM) volume and cortical abnormalities in adult dyslexic individuals, employing a combination of whole-brain voxel- and surface-based morphometry following current recommendations on analysis approaches, coupled with rigorous neuropsychological testing. Whilst controlling for age, sex, total intracranial volume, and performance IQ, we found both decreased GM volume and cortical thickness in the left insula in participants with DD. Moreover, they had decreased GM volume in left superior temporal gyrus, putamen, globus pallidus, and parahippocampal gyrus. Higher GM volumes and cortical thickness in these areas correlated with better reading and phonological skills, deficits of which are pivotal to DD. Crucially, total brain volume did not influence our results, since it did not differ between the groups. Our findings demonstrating abnormalities in brain areas in individuals with DD, which previously were associated with phonological processing, are compatible with the leading hypotheses on the neurocognitive origins of DD.