Detailed profile of cognitive dysfunction in children with aspartylglucosaminuria.

Aspartylglucosaminuria (AGU) is a rare, recessively inherited lysosomal disease with relatively high prevalence in Finnish population. This progressive disease has a vast impact on patient's cognition and physical health, leading to intellectual disability and shorter life expectancy. Cognitive functions of 21 7- to 14-year-old children with AGU were studied cross-sectionally using Wechsler's Intelligence Scale for Children IV and the results were compared with a standardized Finnish sample. In addition to overall cognitive performance, abilities in discrete cognitive domains, including verbal comprehension, perceptual reasoning, working memory, and processing speed, were examined. The results showed that despite the very low overall level of cognitive performance, there were notable differences between individuals. All those children whose performance was closer to their own age level were 7 to 10 years old. Processing speed appeared more compromised, as compared with verbal comprehension. Furthermore, examining the subtest raw scores, there were no significant positive correlations between age and subtest scores, suggesting that the developmental level of AGU children could be rather stable throughout ages 7 to 14. This study gives insight to the severe nature of AGU disease. Since younger children performed better compared to their age norms than older children, the results raise a question whether the highest peak in cognitive functions is reached at an earlier age than previously thought.

Children show hemispheric differences in the basic auditory response properties.

Auditory cortex in each hemisphere shows preference to sounds from the opposite hemifield in the auditory space. Besides this contralateral dominance, the auditory cortex shows functional and structural lateralization, presumably influencing the features of subsequent auditory processing. Children have been shown to differ from adults in the hemispheric balance of activation in higher-order auditory based tasks. We studied, first, whether the contralateral dominance can be detected in 7- to 8-year-old children and, second, whether the response properties of auditory cortex in children differ between hemispheres. Magnetoencephalography (MEG) responses to simple tones revealed adult-like contralateral preference that was, however, extended in time in children. Moreover, we found stronger emphasis towards mature response properties in the right than left hemisphere, pointing to faster maturation of the right-hemisphere auditory cortex. The activation strength of the child-typical prolonged response was significantly decreased with age, within the narrow age-range of the studied child population. Our results demonstrate that although the spatial sensitivity to the opposite hemifield has emerged by 7 years of age, the population-level neurophysiological response shows salient immature features, manifested particularly in the left hemisphere. The observed functional differences between hemispheres may influence higher-level processing stages, for example, in language function.

Attentional modulation of interhemispheric (a)symmetry in children with developmental language disorder.

The nature of auditory processing problems in children with developmental language disorder (DLD) is still poorly understood. Much research has been devoted to determining the extent to which DLD is associated with general auditory versus language-specific dysfunction. However, less emphasis has been given to the role of different task conditions in these dysfunctions. We explored whether children with DLD demonstrate atypical interhemispheric asymmetry during the auditory processing of speech and non-speech sounds and whether this interhemispheric balance is modulated by attention. Magnetoencephalography was used to record auditory evoked fields in 18 children (9 to 10 years old), 9 with DLD and 9 with language typical development, during active or passive listening to speech and non-speech sounds. A linear mixed model analysis revealed a bilateral effect of attention in both groups. Participants with DLD demonstrated atypical interhemispheric asymmetry, specifically in the later (185-600 ms) time window but only during the passive listening condition. During the active task, the DLD group did not differ from the typically developed children in terms of hemispheric balance of activation. Our results support the idea of an altered interhemispheric balance in passive auditory response properties in DLD. We further suggest that an active task condition, or top-down attention, can help to regain leftward lateralization, particularly in a later stage of activation. Our study highlights the highly dynamic and interhemispheric nature of auditory processing, which may contribute to the variability in reports of auditory language processing deficits in DLD.

Speech perception in the child brain: cortical timing and its relevance to literacy acquisition.

Speech processing skills go through intensive development during mid-childhood, providing basis also for literacy acquisition. The sequence of auditory cortical processing of speech has been characterized in adults, but very little is known about the neural representation of speech sound perception in the developing brain. We used whole-head magnetoencephalography (MEG) to record neural responses to speech and nonspeech sounds in first-graders (7-8-year-old) and compared the activation sequence to that in adults. In children, the general location of neural activity in the superior temporal cortex was similar to that in adults, but in the time domain the sequence of activation was strikingly different. Cortical differentiation between sound types emerged in a prolonged response pattern at about 250 ms after sound onset, in both hemispheres, clearly later than the corresponding effect at about 100 ms in adults that was detected specifically in the left hemisphere. Better reading skills were linked with shorter-lasting neural activation, speaking for interdependence of the maturing neural processes of auditory perception and developing linguistic skills. This study uniquely utilized the potential of MEG in comparing both spatial and temporal characteristics of neural activation between adults and children. Besides depicting the group-typical features in cortical auditory processing, the results revealed marked interindividual variability in children.

Neural correlates of late positivities associated with infrequent visual events and response errors.

The P3 response has been one of the most extensively studied event-related potential (ERP) components. Still, the exact functional role and cortical basis of P3 has remained unsettled. To explore the cortical processes underlying the generation of late positivities, we recorded the activation evoked by frequent Go and infrequent NoGo stimuli and correct versus erroneous responses using combined magnetoencephalography (MEG) and ERP measurements during a visual Go/NoGo task. The stimulus-locked signals in the ERP channels revealed an enhanced negative N2 and a prominent late positive component (LPC) after the complex NoGo stimuli associated with successfully withheld responses. The response-locked ERP signals revealed error-related negativity (ERN) and positivity (Pe) after erroneous responses. The positive LPC and Pe components were coupled with functionally and temporally comparable MEG signals. This MEG activation detected during the positive components was localized bilaterally in the posterior temporal cortex. In the response-locked averages, the temporal activity was enhanced around 200 ms after a commission of an error. In the stimulus-locked averages, the activation was also enhanced after infrequent NoGo stimuli around 500 ms after stimulus onset and delayed about 80 ms for the initially miscategorized NoGo stimuli accompanied by erroneous response. The results suggest that the cortical correlates of Pe are not specifically related to commission of an error, but both the LPC and Pe components, and bilateral temporal cortices, are more generally involved in stimulus-driven attentional processing evoked by unexpected stimuli. The negative ERP components evoked by NoGo stimuli (N2) and erroneous responses (ERN) were found to be associated with partly non-overlapping neural sources.

Neural processing of spoken words in specific language impairment and dyslexia.

Young adults with a history of specific language impairment (SLI) differ from reading-impaired (dyslexic) individuals in terms of limited vocabulary and poor verbal short-term memory. Phonological short-term memory has been shown to play a significant role in learning new words. We investigated the neural signatures of auditory word recognition and word repetition in young adults with SLI, dyslexia and normal language development using magnetoencephalography. The stimuli were 7-8 letter spoken real words and pseudo-words. They evoked a transient peak at 100 ms (N100m) followed by longer-lasting activation peaking around 400 ms (N400m) in the left and right superior temporal cortex. Both word repetition (first vs. immediately following second presentation) and lexicality (words vs. pseudowords) modulated the N400m response. An effect of lexicality was detected about 400 ms onwards as activation culminated for words but continued for pseudo-words. This effect was more pronounced in the left than right hemisphere in the control subjects. The left hemisphere lexicality effect was also present in the dyslexic adults, but it was non-significant in the subjects with SLI, possibly reflecting their limited vocabulary. The N400m activation between 200 and 700 ms was attenuated by the immediate repetition of words and pseudo-words in both hemispheres. In SLI adults the repetition effect evaluated at 200-400 ms was abnormally weak. This finding suggests impaired short-term maintenance of linguistic activation that underlies word recognition. Furthermore, the size of the repetition effect decreased from control subjects through dyslexics to SLIs, i.e. when advancing from milder to more severe language impairment. The unusually rapid decay of speech-evoked activation could have a detrimental role on vocabulary growth in children with SLI.

Left hemisphere enhancement of auditory activation in language impaired children.

Specific language impairment (SLI) is a developmental disorder linked to deficient auditory processing. In this magnetoencephalography (MEG) study we investigated a specific prolonged auditory response (N250m) that has been reported predominantly in children and is associated with level of language skills. We recorded auditory responses evoked by sine-wave tones presented alternately to the right and left ear of 9-10-year-old children with SLI (n = 10) and children with typical language development (n = 10). Source analysis was used to isolate the N250m response in the left and right hemisphere. In children with language impairment left-hemisphere N250m responses were enhanced compared to those of controls, while no group difference was found in the right hemisphere. Consequently, language impaired children lacked the typical right-ward asymmetry that was found in control children. Furthermore, left but not right hemisphere N250m responses correlated positively with performance on a phonological processing task in the SLI group exclusively, possibly signifying a compensatory mechanism for delayed maturation of language processing. These results suggest that enhanced left-hemisphere auditory activation reflects a core neurophysiological manifestation of developmental language disorders, and emphasize the relevance of this developmentally specific activation pattern for competent language development.

Cortical sequence of word perception in beginning readers.

Efficient analysis of written words in normal reading is likely to reflect use of neural circuits formed by experience during childhood rather than an innate process. We investigated the cortical sequence of word perception in first-graders (7-8 years old), with special emphasis on occipitotemporal cortex in which, in adults, letter-string-sensitive responses are detected at 150 ms after stimulus. To identify neural activation that is sensitive to either the amount of basic visual features or specifically to letter strings, we recorded whole-head magnetoencephalography responses to words embedded in three different levels of noise and to symbol strings. As was shown previously in adults, activation reflecting stimulus nonspecific visual feature analysis was localized to occipital cortex in children. It was followed by letter-string-sensitive activation in the left occipitotemporal cortex and, subsequently, in the temporal cortex. These processing stages were correlated in timing and activation strength. Compared with adults, however, the timing of activation was clearly delayed in children, and the delay was progressively increased from occipital to occipitotemporal and further to temporal areas. This finding is likely to reflect increasing immaturity of the underlying neural generators when advancing from low-level visual analysis to higher-order areas involved in written word perception. When a salient occipitotemporal letter-string-sensitive activation was detected (10 of 18 children), its strength was correlated with phonological skills, in line with the known relevance of phonological awareness in reading acquisition.

Language control mechanisms differ for native languages: Neuromagnetic evidence from trilingual language switching.

How does the brain process and control languages that are learned at a different age, when proficiency in all these languages is high? Early acquired strong languages are likely to have higher baseline activation levels than later learned less-dominant languages. However, it is still largely unknown how the activation levels of these different languages are controlled, and how interference from an irrelevant language is prevented. In this magnetoencephalography (MEG) study on language switching during auditory perception, early Finnish-Swedish bilinguals (N = 18) who mastered English with high proficiency after childhood were presented with spoken words in each of the three languages, while performing a simple semantic categorisation task. Switches from the later learned English to either of the native languages resulted in increased neural activation in the superior temporal gyrus (STG) 400-600ms after word onset (N400m response), whereas such increase was not detected for switches from native languages to English or between the native languages. In an earlier time window of 350-450ms, English non-switch trials showed higher activation levels in the inferior frontal gyrus (IFG), pointing to ongoing inhibition of the native languages during the use of English. Taken together, these asymmetric switch costs suggest that native languages are suppressed during the use of a non-native language, despite the receptive nature of the language task. This effect seems to be driven mostly by age of acquisition or language exposure, rather than proficiency. Our results indicate that mechanisms of control between two native languages differ from those of a later learned language, as upbringing in an early bilingual environment has likely promoted automatiation of language control specifically for the native languages.

Cortical activation during spoken-word segmentation in nonreading-impaired and dyslexic adults.

We used magnetoencephalography to elucidate the cortical activation associated with the segmentation of spoken words in nonreading-impaired and dyslexic adults. The subjects listened to binaurally presented sentences where the sentence-ending words were either semantically appropriate or inappropriate to the preceding sentence context. Half of the inappropriate final words shared two or three initial phonemes with the highly expected semantically appropriate words. Two temporally and functionally distinct response patterns were detected in the superior temporal lobe. The first response peaked at approximately 100 msec in the supratemporal plane and showed no sensitivity to the semantic appropriateness of the final word. This presemantic N100m response was abnormally strong in the left hemisphere of dyslexic individuals. After the N100m response, the semantically inappropriate sentence-ending words evoked stronger activation than the expected endings in the superior temporal cortex in the vicinity of the auditory cortex. This N400m response was delayed for words starting with the same two or three first few phonemes as the expected words but only until the first evidence of acoustic-phonetic dissimilarity emerged. This subtle delay supports the notion of initial lexical access being based on phonemes or acoustic features. In dyslexic participants, this qualitative aspect of word processing appeared to be normal. However, for all words alike, the ascending slope of the semantic activation in the left hemisphere was delayed by approximately 50 msec as compared with control subjects. The delay in the auditory N400m response in dyslexic subjects is likely to result from presemantic-phonological deficits possibly reflected in the abnormal N100m response.

Context affects L1 but not L2 during bilingual word recognition: an MEG study.

How do bilinguals manage the activation levels of the two languages and prevent interference from the irrelevant language? Using magnetoencephalography, we studied the effect of context on the activation levels of languages by manipulating the composition of word lists (the probability of the languages) presented auditorily to late Finnish-English bilinguals. We first determined the upper limit time-window for semantic access, and then focused on the preceding responses during which the actual word recognition processes were assumedly ongoing. Between 300 and 500 ms in the temporal cortices (in the N400 m response) we found an asymmetric language switching effect: the responses to L1 Finnish words were affected by the presentation context unlike the responses to L2 English words. This finding suggests that the stronger language is suppressed in an L2 context, supporting models that allow auditory word recognition to be affected by contextual factors and the language system to be subject to inhibitory influence.

Abnormal functioning of the left temporal lobe in language-impaired children.

Specific language impairment is associated with enduring problems in language-related functions. We followed the spatiotemporal course of cortical activation in SLI using magnetoencephalography. In the experiment, children with normal and impaired language development heard spoken real words and pseudowords presented only once or two times in a row. In typically developing children, the activation in the bilateral superior temporal cortices was attenuated to the second presentation of the same word. In SLI children, this repetition effect was nearly nonexistent in the left hemisphere. Furthermore, the activation was equally strong to words and pseudowords in SLI children whereas in the typically developing children the left hemisphere activation persisted longer for pseudowords than words. Our results indicate that the short-term maintenance of linguistic activation that underlies spoken word recognition is defective in SLI particularly in the left language-dominant hemisphere. The unusually rapid decay of speech-evoked activation can contribute to impaired vocabulary growth.

Cortical activation patterns during subitizing and counting.

The exact amount of small number of items (1-4) can be detected fast and accurately (subitizing) while the enumeration of large number of items (over 4) is slower and error-prone (counting). Several counting-related cortical areas have been identified mainly in frontal and parietal regions, but cortical events associated with subitizing have remained unclear. Similarly, little is known about the temporal sequence of cortical activation during enumeration. In this study, we examined the temporal and spatial pattern of subitizing and counting using magnetoencephalography (MEG). During the MEG-recordings, black dots (2-8) in a visual display were shown to ten adults, who then responded with a button press as soon as they knew the number of items. The behavioural results showed a regularly reported dichotomy in enumeration of small (2-4) and large (5-8) numbers. In brain responses, pronounced activation peak during subitizing was detected around 250 ms in the bilateral posterior temporo-parietal area, which presumably reflects the function of ventral visual stream. During counting, pronounced activation was first detected in bilateral parietal areas, followed by a growing activation in the frontal cortices. The activation of frontal areas indicates the involvement of task guidance and attention, while the parietal areas activated earlier may have a key role in maintaining numerical representations and spatial attention. Brain functions during counting seem to consist of several constituent processes that reflect number processing, attention and task guidance. Our results demonstrated temporally and spatially specific brain activation for fast subitizing and effortful counting.

Impaired engagement of the ventral attentional pathway in ADHD.

In the cognitive theories of Attention Deficit Hyperactivity Disorder (ADHD) impaired behavioral adjustment has been linked to a deficit in learning to detect regularities or irregularities in the environment. In the neural level, the P3 component of event-related potential (ERP) is modulated by stimulus probability and has been suggested to index activation of the ventral attention network, which constitutes the reorienting system of the human brain. To explore the cortical basis of late positive ERP components and the engagement of the ventral attentional pathway in ADHD, we used ERP recordings complemented by spatiotemporally sensitive magnetoencephalography (MEG) measurements. We followed the activation evoked by frequent Go and infrequent NoGo stimuli in 10 ADHD adults and 13 control subjects. In the ERP recordings, a prominent positive deflection was detected after the infrequent visual stimuli (late positive component, LPC) in both subject groups. In ADHD adults the difference between the responses evoked by infrequent NoGo and frequent Go stimuli was markedly reduced compared to the control group during the LPC. The MEG recordings revealed that the activation detected during the LPC was localized bilaterally in the posterior temporal cortex. Activation of the left and right temporal regions was enhanced after infrequent NoGo stimuli in both subject groups. In ADHD adults, however, the effect of stimulus frequency was less pronounced. We suggest that the activation in the superior temporal cortices during the LPC reflects the action of ventral attention network. The engagement of this stimulus-driven reorienting system is defective in ADHD.

Localization of syntactic and semantic brain responses using magnetoencephalography.

Electrophysiological methods have been used to study the temporal sequence of syntactic and semantic processing during sentence comprehension. Two responses associated with syntactic violations are the left anterior negativity (LAN) and the P600. A response to semantic violation is the N400. Although the sources of the N400 response have been identified in the left (and right) temporal lobe, the neural signatures of the LAN and P600 have not been revealed. The present study used magnetoencephalography to localize sources of syntactic and semantic activation in Finnish sentence reading. Participants were presented with sentences that ended in normally inf lected nouns, nouns in an unacceptable case, verbs instead of nouns, or nouns that were correctly inflected but made no sense in the context. Around 400 msec, semantically anomalous last words evoked strong activation in the left superior temporal lobe with significant activation also for word class errors (N400). Weaker activation was seen for the semantic errors in the right hemisphere. Later, 600-800 msec after word onset, the strongest activation was seen to word class and morphosyntactic errors (P600). Activation was significantly weaker to semantically anomalous and correct words. The P600 syntactic activation was localized to bilateral sources in the temporal lobe, posterior to the N400 sources. The results suggest that the same general region of the superior temporal cortex gives rise to both LAN and N400 with bilateral reactivity to semantic manipulation and a left hemisphere effect to syntactic manipulation. The bilateral P600 response was sensitive to syntactic but not semantic factors.

Cortical differentiation of speech and nonspeech sounds at 100 ms: implications for dyslexia.

Neurophysiological measures indicate cortical sensitivity to speech sounds by 150 ms after stimulus onset. In this time window dyslexic subjects start to show abnormal cortical processing. We investigated whether phonetic analysis is reflected in the robust auditory cortical activation at approximately 100 ms (N100m), and whether dyslexic subjects show abnormal N100m responses to speech or nonspeech sounds. We used magnetoencephalography to record auditory responses of 10 normally reading and 10 dyslexic adults. The speech stimuli were synthetic Finnish speech sounds (/a/, /u/, /pa/, /ka/). The nonspeech stimuli were complex nonspeech sounds and simple sine wave tones, composed of the F1+F2+F3 and F2 formant frequencies of the speech sounds, respectively. All sounds evoked a prominent N100m response in the bilateral auditory cortices. The N100m activation was stronger to speech than nonspeech sounds in the left but not in the right auditory cortex, in both subject groups. The leftward shift of hemispheric balance for speech sounds is likely to reflect analysis at the phonetic level. In dyslexic subjects the overall interhemispheric amplitude balance and timing were altered for all sound types alike. Dyslexic individuals thus seem to have an unusual cortical organization of general auditory processing in the time window of speech-sensitive analysis.

Cortical effects of shifting letter position in letter strings of varying length.

Neuroimaging and lesion studies suggest that occipito-temporal brain areas play a necessary role in recognizing a wide variety of objects, be they faces, letters, numbers, or household items. However, many questions remain regarding the details of exactly what kinds of information are processed by the occipito-temporal cortex. Here, we address this question with respect to reading. Ten healthy adult subjects performed a single word reading task. We used whole-head magnetoencephalography to measure the spatio-temporal dynamics of brain responses, and investigated their sensitivity to: (1) lexicality (defined here as the difference between words and consonant strings), (2) word length, and (3) variation in letter position. Analysis revealed that midline occipital activity around 100 msec, consistent with low-level visual feature analysis, was insensitive to lexicality and variation in letter position, but was slightly affected by string length. Bilateral occipito-temporal activations around 150 msec were insensitive to lexicality and reacted to word length only in the timing (and not strength) of activation. However, vertical shifts in letter position revealed a hemispheric imbalance: The right hemisphere activation increased with the shifts, whereas the opposite pattern was evident in the left hemisphere. The results are discussed in the light of Caramazza and Hillis's (1990) model of early reading.

Abnormal auditory cortical activation in dyslexia 100 msec after speech onset.

Reading difficulties are associated with problems in processing and manipulating speech sounds. Dyslexic individuals seem to have, for instance, difficulties in perceiving the length and identity of consonants. Using magnetoencephalography (MEG), we characterized the spatio-temporal pattern of auditory cortical activation in dyslexia evoked by three types of natural bisyllabic pseudowords (/ata/, /atta/, and /a a/), complex nonspeech sound pairs (corresponding to /atta/ and /a a/) and simple 1-kHz tones. The most robust difference between dyslexic and non-reading-impaired adults was seen in the left supratemporal auditory cortex 100 msec after the onset of the vowel /a/. This N100m response was abnormally strong in dyslexic individuals. For the complex nonspeech sounds and tone, the N100m response amplitudes were similar in dyslexic and nonimpaired individuals. The responses evoked by syllable /ta/ of the pseudoword /atta/ also showed modest latency differences between the two subject groups. The responses evoked by the corresponding nonspeech sounds did not differ between the two subject groups. Further, when the initial formant transition, that is, the consonant, was removed from the syllable /ta/, the N100m latency was normal in dyslexic individuals. Thus, it appears that dyslexia is reflected as abnormal activation of the auditory cortex already 100 msec after speech onset, manifested as abnormal response strengths for natural speech and as delays for speech sounds containing rapid frequency transition. These differences between the dyslexic and nonimpaired individuals also imply that the N100m response codes stimulus-specific features likely to be critical for speech perception. Which features of speech (or nonspeech stimuli) are critical in eliciting the abnormally strong N100m response in dyslexic individuals should be resolved in future studies.