Functional and structural correlates of dyslexia and reading-relevant skills in the brain : Evidence from newborns and adults

Developmental dyslexia is at the low end of a spectrum in reading and writing abilities, and may arise despite normal intelligence and education. It often is accompanied by difficulties in domains important for reading, such as phonological processing and verbal working memory. Neural impairments in speech processing are evident in the majority of dyslexic individuals and could be linked to phonological and temporal sampling problems. This thesis integrates four studies for which neuropsychological assessments, magnetoencephalography (MEG), electroencephalography (EEG), and magnetic resonance imaging (MRI) were conducted. The first study examined the influence of familial dyslexia risk on neural speech-sound discrimination in newborn infants (Study I). The second and third study investigated neural processing of speech-sound changes (Study II) and natural speech (Study III) in adult dyslexic and typical readers. The fourth study analyzed anatomical brain abnormalities in dyslexia (Study IV). In addition, the associations of neural measures to reading and related phonological-processing and working-memory skills were investigated (Studies II–IV). The main findings of this thesis were neural speech-processing impairments in newborns at risk of and adults with dyslexia, neuroanatomical abnormalities in adults with dyslexia, and links between the neural measures and skills relevant for reading. Specifically, newborns at risk of dyslexia compared to a group of low risk showed atypical neural speech discrimination responses that may be precursors of phonological deficits in dyslexia (Study I). However, neuromagnetic discrimination responses elicited by the same speech-sound changes suggested no abnormalities in adults with dyslexia, yet, the responses were associated with reading and working memory functions (Study II). Inter-subject correlation (ISC) to natural speech was weaker between dyslexic than typically-reading adults in delta- and high gamma-frequency bands, and stronger in the theta, beta, and low gamma bands, possibly reflecting temporal sampling deficits of natural speech features (Study III). The ISC strength was related to all three reading-relevant skills of interest. Structural abnormalities were observed in dyslexic adults as decreases in grey- and white-matter volumes in temporal, frontal, and subcortical structures important for reading (Study IV). Furthermore, grey- and white-matter volumes were associated with reading and working memory functions. Taken together, this thesis illuminates neural speech processing deficits in dyslexia and its risk at birth and pinpoints associations between reading skills and neurofunctional and -anatomical measures.Lukivaikeus on luku- ja kirjoitustaitojen jatkumon matala ääripää, jota ilmenee normaalista älykkyydestä ja koulutuksesta huolimatta. Usein lukivaikeuden ohella esiintyy vaikeuksia muilla lukemiselle tärkeillä osa-alueilla, kuten fonologisessa prosessoinnissa ja kielellisessä työmuistissa. Suurimmalla osalla lukivaikeudesta kärsiviä voidaan todeta puheen hermostollisen käsittelyn häiriöitä, joita on selitetty fonologisen (engl. phonological deficit theory) tai ajallisen käsittelyn (engl. temporal sampling deficit theory) puutteilla. Tämä väitöskirja koostuu neljästä osajulkaisusta, joita varten tehtiin neuropsykologisia arviointeja, magnetoenkefalografia- (MEG) ja elektroenkefalografiamittauksia (EEG) sekä aivojen rakenteellinen magneettikuvaus (MRI). Ensimmäisessä tutkimuksessa selvitettiin perinnöllisen lukivaikeusriskin vaikutusta puheäänten hermostolliseen erottelutarkkuuteen vastasyntyneillä (Tutkimus I). Toisessa ja kolmannessa tutkimuksessa tarkasteltiin puheäänimuutosten (Tutkimus II) ja luonnollisen puheen (Tutkimus III) hermostollista käsittelyä lukivaikeudesta kärsivillä ja tyypillisesti lukevilla aikuisilla. Neljännessä tutkimuksessa analysoitiin aivojen rakenteellisia poikkeavuuksia lukivaikeudessa (Tutkimus IV). Lisäksi tutkittiin käytettyjen hermostollisten mittarien yhteyksiä lukemiseen ja siihen liittyviin fonologisen prosessoinnin ja työmuistin taitoihin (Tutkimukset II–IV). Väitöskirjan päälöydöksenä olivat puheen hermostollisen käsittelyn vaikeudet riskiryhmän vastasyntyneillä sekä lukivaikeudesta kärsivillä aikuisilla, aivorakenteen poikkeavuudet lukivaikeudesta kärsivillä aikuisilla ja yhteydet näiden hermostollisten mittarien ja lukemiselle tärkeiden taitojen välillä. Vastasyntyneillä, joilla oli lukivaikeusriski, ilmeni matalan riskin ryhmään verrattuna epätyypillisiä puheäänten erotteluvasteita, jotka saattavat edeltää fonologista häiriötä lukivaikeudessa (Tutkimus I). Samojen puheäänimuutosten aiheuttamat neuromagneettiset erotteluvasteet eivät viitanneet poikkeamiin aikuisilla, joilla oli lukivaikeus, mutta vasteet olivat kuitenkin yhteydessä lukutaitoon ja työmuistitoimintoihin (Tutkimus II). Aivojen hermosoluryhmien synkronoituminen luonnolliseen puheeseen oli heikompaa lukivaikeuksisten kuin tyypillisesti lukevien aikuisten välillä delta- ja korkeilla gammataajuuskaistoilla ja voimakkaampaa teeta-, beeta- ja matalilla gammakaistoilla, mikä saattaa heijastaa luonnollisen puheen piirteiden käsittelyn häiriöitä (engl. temporal sampling deficits; Tutkimus III). Aivojen hermosoluryhmien synkronoitumisen vahvuus liittyi kaikkiin kolmeen tutkittuun lukemiselle tärkeään taitoon. Aikuisilla, joilla oli lukivaikeus, havaittiin harmaan ja valkean aineen pienentyneitä tilavuuksia lukemisen kannalta tärkeillä alueilla ohimolohkolla, otsalohkolla sekä aivokuoren alaisissa rakenteissa (Tutkimus IV). Lisäksi harmaan ja valkean aineen tilavuudet olivat yhteydessä lukutaitoon ja työmuistitoimintoihin. Kokonaisuutena tämä väitöskirja valottaa puheen hermostollisen käsittelyn häiriöitä lukivaikeudessa ja sen riskissä vastasyntyneillä sekä tuo esiin yhteyksiä lukutaitojen ja toiminnallisten ja rakenteellisten hermostollisten mittarien välillä

Magnetoencephalographic (MEG) Inter-subject Correlation using Continuous Music Stimuli

Music has existed throughout cultures for thousands of years and has been able to create powerful and intercultural connections between humans. Yet, early neurocognitive studies on music have utilized mainly artificial stimuli. Going towards more complex, real-world stimuli, this study examines magnetoencephalographic (MEG) brain responses to listening to continuous music in 24 musically trained and 19 untrained listeners. Three whole musical pieces of different genres were presented as stimuli. To investigate how similarly listeners’ brains process the music, inter-subject correlations (ISC) of the dynamics of specific MEG frequency bands were computed. This approach is a novel method for analyzing complex stimuli with MEG. Compared to functional magnetic resonance imaging (fMRI) studies, it adds to the information about synchronous processing of continuous music stimuli in the brain. Our MEG results show that auditory processing areas, including middle and superior temporal gyri, transverse temporal cortex and insula with enhanced right hemispheric responses, synchronize across subjects. The extend of synchronization differs depending on the selected frequency band and music stimulus. For the song that elicited highest ISCs across subjects, in the 4–8 Hz and 8–12 Hz frequency bands, musicians exhibit higher synchrony in auditory processing areas compared to non-musicians. In summary, listening to real music induces brain-to-brain coupling especially in auditory cortices. Coupling in musicians during listening to a piece with a variety and complexity of musical features is higher compared to non-trained participants

Structural white matter connectometry of reading and dyslexia

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.Peer reviewe

Inhibitory effects of rat bone marrow-derived dendritic cells on naïve and alloantigen-specific CD4+ T cells: a comparison between dendritic cells generated with GM-CSF plus IL-4 and dendritic cells generated with GM-CSF plus IL-10

BACKGROUND: Unlike mouse immature bone marrow (BM)-derived dendritic cells (DC), rat immature BMDC have not been thoroughly characterised in vitro for the mechanisms underlying their suppressive effect. To better characterise these mechanisms we therefore analysed the phenotypes and immune inhibitory properties of rat BMDC generated with GM-CSF plus IL-4 (= IL-4 DC) and with GM-CSF plus IL-10 (= IL-10 DC). RESULTS: Both IL-4 DC and IL-10 DC exhibited lower surface expression of MHC class II and costimulatory molecules than mature splenic DC. They had a strong inhibitory effect on responsive T cells in vitro and despite their weak function as antigen-presenting cells they induced anergic T cells. However, only anergic T cells induced by IL-4 DC had a suppressive effect on responsive T cells. Induction of suppressive/tolerogenic T cells by IL-4 DC required direct contact between antigen-specific T cells and IL-4 DC. In addition, IL-4 DC and IL-10 DC prolonged allograft survival in an antigen-specific manner. CONCLUSION: A unique phenotype of immature BMDC was isolated from the cultures. The mechanisms underlying the suppressive effect may be caused by their inability to deliver adequate costimulatory signals for T-cell activation. In addition, IL-4 DC but not IL-10 DC induce anergic T cells with suppressive function. This indicates that IL-4 DC and IL-10 DC may differ in the quality of their costimulation although no differences in the surface expression of costimulatory molecules were found

Body sway predicts romantic interest in speed dating

Social bonding is fundamental to human society, and romantic interest involves an important type of bonding. Speed dating research paradigms offer both high external validity and experimental control for studying romantic interest in real-world settings. While previous studies focused on the effect of social and personality factors on romantic interest, the role of non-verbal interaction has been little studied in initial romantic interest, despite being commonly viewed as a crucial factor. The present study investigated whether romantic interest can be predicted by non-verbal dyadic interactive body sway, and enhanced by movement-promoting (‘groovy’) background music. Participants’ body sway trajectories were recorded during speed dating. Directional (predictive) body sway coupling, but not body sway similarity, predicted interest in a long-term relationship above and beyond rated physical attractiveness. In addition, presence of groovy background music promoted interest in meeting a dating partner again. Overall, we demonstrate that romantic interest is reflected by non-verbal body sway in dyads in a real-world dating setting. This novel approach could potentially be applied to investigate non-verbal aspects of social bonding in other dynamic interpersonal interactions such as between infants and parents and in non-verbal populations including those with communication disorders.Peer reviewe

Infant event-related potentials to speech are associated with prelinguistic development

Neural auditory processing and prelinguistic communication build the foundation for later language development, but how these two are associated is not well known. The current study investigated how neural speech processing is associated with the level and development of prelinguistic skills in 102 infants. We recorded event-related potentials (ERPs) in 6-months-olds to assess the neural detection of a pseudoword (obligatory responses), as well as the neural discrimination of changes in the pseudoword (mismatch responses, MMRs). Prelinguistic skills were assessed at 6 and 12 months of age with a parental questionnaire (Infant-Toddler Checklist). The association between the ERPs and prelinguistic skills was examined using latent change score models, a method specifically constructed for longitudinal analyses and explicitly modeling intra-individual change. The results show that a large obligatory P1 at 6 months of age predicted strong improvement in prelinguistic skills between 6 and 12 months of age. The MMR to a frequency change was associated with the concurrent level of prelinguistic skills, but not with the improvement of the skills. Overall, our results highlight the strong association between ERPs and prelinguistic skills, possibly offering opportunities for early detection of atypical linguistic and communicative development.Peer reviewe

An extensive pattern of atypical neural speech-sound discrimination in newborns at risk of dyslexia

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.Peer reviewe

Infancy and early childhood maturation of neural auditory change detection and its associations to familial dyslexia risk

ObjectiveWe investigated early maturation of the infant mismatch response MMR, including mismatch negativity (MMN), positive MMR (P-MMR), and late discriminative negativity (LDN), indexing auditory discrimination abilities, and the influence of familial developmental dyslexia risk.MethodsWe recorded MMRs to vowel, duration, and frequency deviants in pseudo-words at 0, 6, and 28 months and compared MMRs in subgroups with vs. without dyslexia risk, in a sample over-represented by risk infants.ResultsNeonatal MMN to the duration deviant became larger and earlier by 28 months; MMN was elicited by more deviants only at 28 months. The P-MMR was predominant in infancy; its amplitude increased by 6 and decreased by 28 months; latency decreased with increasing age. An LDN emerged by 6 months and became larger and later by 28 months. Dyslexia risk affected MMRs and their maturation.ConclusionsMMRs demonstrate an expected maturational pattern with 2–3 peaks by 28 months. The effects of dyslexia risk are prominent but not always as expected.SignificanceThis large-scale longitudinal study shows MMR maturation with three age groups and three deviants. Results illuminate MMR’s relation to the adult responses, and hence their cognitive underpinnings, and help in identifying typical/atypical auditory development in early childhood.</p

Feasibility of azacitidine added to standard chemotherapy in older patients with acute myeloid leukemia - a randomised SAL pilot study

INTRODUCTION: Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML. TRIAL DESIGN: Prospective, randomised, open, phase II trial with parallel group design and fixed sample size. PATIENTS AND METHODS: Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of <20,000/µl at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint. RESULTS: Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days. CONCLUSIONS: The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm

Feasibility of Azacitidine Added to Standard Chemotherapy in Older Patients with Acute Myeloid Leukemia — A Randomised SAL Pilot Study

Introduction: Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML. Trial Design: Prospective, randomised, open, phase II trial with parallel group design and fixed sample size. Patients and Methods: Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of ,20,000/ml at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint. Results: Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days. Conclusions: The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm. Trial Registration: This trial is registered at clinical trials.gov (identifier: NCT00915252)