Silvia Brem

Brain sensitivity to print emerges when children learn letter-speech sound correspondences

The acquisition of reading skills is a major landmark process in a humans cognitive development. On the neural level, a new functional network develops during this time, as children typically learn to associate the well-known sounds of their spoken language with unfamiliar characters in alphabetic languages and finally access the meaning of written words, allowing for later reading. A critical component of the mature reading network located in the left occipito-temporal cortex, termed the “visual word-form system” (VWFS), exhibits print-sensitive activation in readers. When and how the sensitivity of the VWFS to print comes about remains an open question. In this study, we demonstrate the initiation of occipito-temporal cortex sensitivity to print using functional MRI (fMRI) (n = 16) and event-related potentials (ERP) (n = 32) in a controlled, longitudinal training study. Print sensitivity of fast (<250 ms) processes in posterior occipito-temporal brain regions accompanied basic associative learning of letter–speech sound correspondences in young (mean age 6.4 ± 0.08 y) nonreading kindergarten children, as shown by concordant ERP and fMRI results. The occipito-temporal print sensitivity thus is established during the earliest phase of reading acquisition in childhood, suggesting that a crucial part of the later reading network first adopts a role in mapping print and sound.

Emerging Neurophysiological Specialization for Letter Strings

In adult readers, printed words and other letter strings activate specialized visual functions within 200 msec, as evident from neurophysiological recordings of brain activity. These fast, specialized responses to letter strings are thought to develop through plastic changes in the visual system. However, it is unknown whether this specialization emerges only with the onset of word reading, or represents a precursor of literacy. We compared 6-year-old kindergarten children who could not yet read words to adult readers. Both age groups detected immediate repetitions of visually presented words, pseudo-words, symbol strings, and pictures during event-related potential (ERP) mapping. Maps from seven corresponding ERP segments in children and adults were analyzed regarding fast (<250 msec) and slow (>300 msec) specialization for letter strings. Adults reliably differentiated words through increased fast (<150 msec) occipito-temporal N1 activity from symbols. Children showed a later, more mid-occipital N1 with marginal word-symbol differences, which were absent in those children with low letter knowledge. Children with high letter knowledge showed some fast sensitivity to letter strings, which was confined to right occipito-temporal sites, unlike the stronger adult N1 specialization. This suggests that a critical degree of early literacy induces some immature, but fast, specialization for letter strings before word reading becomes possible. Children also differentiated words from symbols in later segments through increased right occipito-temporal negativity for words. This slow specialization for letter strings was not modulated by letter knowledge and was absent in adults, possibly reflecting a visual precursor of literacy due to visual familiarity with letter strings.

Coarse neural tuning for print peaks when children learn to read

Adult readers exhibit increased fast N1 activity to wordlike strings in their event-related brain potential. This increase has been linked to visual expertise for print, implying a protracted monotonic development. We investigated the development of coarse neural tuning for print by studying children longitudinally before and after learning to read, and comparing them to skilled adults. The coarse N1 tuning, which had been absent in nonreading kindergarten children, emerged in less than 2 years after the same children had mastered basic reading skills in 2nd grade. The N1 became larger for words than symbol strings in every child, and this coarse tuning was stronger for faster readers. Fast brain processes thus specialize rapidly for print when children learn to read, and play an important functional role in the fluency of early reading. Comparing 2nd graders with adults revealed a further decrease of the coarse N1 tuning in adults, presumably reflecting further reading practice. This constitutes a prominent nonlinear development of coarse neurophysiological specialization for print. The maximum tuning in novice readers possibly reflects the high sensitivity of their neural network for visual aspects of print, and a more selective tuning in expert adult readers.

Evidence for developmental changes in the visual word processing network beyond adolescence

Late development of specialization in the visual word processing system was examined using event-related potentials (ERP) and functional magnetic resonance imaging (fMRI) of word and symbol string processing in groups of adolescents (15.2-17.3 years) and adults (19.8-30.8 years). We focused our ERP analyses on fast visual activity: the occipital P1 (82-131 ms) modulated by physical stimulus characteristics and the occipito-temporal N1 (132-256 ms) reflecting visual tuning for print. Our fMRI analyses concentrated on basal occipito-temporal activations in the visual word form area VWFA. For words, the correlation of fMRI activation in the VWFA and N1 amplitude confirmed the close relationship of the electrophysiological N1 with metabolic activity in the VWFA. Further support for this relationship came from low resolution electromagnetic tomography localizing the word-specific N1 near the VWFA. Both imaging techniques revealed age-independent differences between words and symbol strings. Late development, however, was preferentially detected with ERPs. Decreases of P1 and N1 amplitudes with age were not limited to words and suggested further maturation of the underlying brain microstructure and function. Following adolescence, decreasing N1 latencies specific to words point to continued specialization of the visual word processing system. Both N1 and fMRI measures correlated with reading performance. In summary, the similarity of global fMRI activation patterns between groups suggests a fully established distribution of the reading network in adolescence, while the decreasing N1 latencies for words indicate protracted fine tuning after adolescence.

The feedback-related negativity (FRN) revisited: New insights into the localization, meaning and network organization

Changes in response contingencies require adjusting ones assumptions about outcomes of behaviors. Such adaptation processes are driven by reward prediction error (RPE) signals which reflect the inadequacy of expectations. Signals resembling RPEs are known to be encoded by mesencephalic dopamine neurons projecting to the striatum and frontal regions. Although regions that process RPEs, such as the dorsal anterior cingulate cortex (dACC), have been identified, only indirect evidence links timing and network organization of RPE processing in humans. In electroencephalography (EEG), which is well known for its high temporal resolution, the feedback-related negativity (FRN) has been suggested to reflect RPE processing. Recent studies, however, suggested that the FRN might reflect surprise, which would correspond to the absolute, rather than the signed RPE signals. Furthermore, the localization of the FRN remains a matter of debate. In this simultaneous EEG-functional magnetic resonance imaging (fMRI) study, we localized the FRN directly using the superior spatial resolution of fMRI without relying on any spatial constraint or other assumption. Using two different single-trial approaches, we consistently found a cluster within the dACC. One analysis revealed additional activations of the salience network. Furthermore, we evaluated the effect of signed RPEs and surprise signals on the FRN amplitude. We considered that both signals are usually correlated and found that only surprise signals modulate the FRN amplitude. Last, we explored the pathway of RPE signals using dynamic causal modeling (DCM). We found that the surprise signals are directly projected to the source region of the FRN. This finding contradicts earlier theories about the network organization of the FRN, but is in line with a recent theory stating that dopamine neurons also encode surprise-like saliency signals. Our findings crucially advance the understanding of the FRN. We found compelling evidence that the FRN originates from the dACC. Furthermore, we clarified the functional role of the FRN, and determined the role of the dACC within the RPE network. These findings should enable us to study the processing of surprise and adjustment signals in the dACC in healthy and also in psychiatric patients.

Tuning of the visual word processing system: distinct developmental ERP and fMRI effects.

Visual tuning for words vs. symbol strings yields complementary increases of fast occipito‐temporal activity (N1 or N170) in the event‐related potential (ERP), and posterior–anterior gradients of increasing word‐specific activity with functional magnetic resonance imaging (fMRI) in the visual word form system (VWFS). However, correlation of these coarse ERP and fMRI tuning responses seems limited to the most anterior part of the VWFS in adult and adolescent readers (Brem et al. [ 2006 ]: Neuroimage 29:822–837). We thus focused on fMRI tuning gradients of young readers with their more pronounced ERP print tuning, and compared developmental aspects of ERP and fMRI response tuning in the VWFS. Children (10.3 y, n = 19), adolescents (16.2 y, n = 13) and adults (25.2 y, n = 18) were tested with the same implicit reading paradigm using counterbalanced ERP and fMRI imaging. The word‐specific occipito‐temporal N1 specialization, its corresponding source activity, as well as the integrated source activity (0–700 ms) were most prominent in children and showed a marked decrease with age. The posterior–anterior fMRI gradient of word‐specific activity instead which was fully established in children did not develop further, but exhibited a dependence on reading skills independent of age. To conclude, prominent developmental dissociation of the ERP and fMRI tuning patterns emerged despite convergent VWFS localization. The ERP response may selectively reflect fast visual aspects of print specialization, which become less important with age, while the fMRI response seems dominated by integrated task‐ and reading‐related activations in the same regions. Hum Brain Mapp, 2009.

Neurophysiology in Preschool Improves Behavioral Prediction of Reading Ability Throughout Primary School

BACKGROUND More struggling readers could profit from additional help at the beginning of reading acquisition if dyslexia prediction were more successful. Currently, prediction is based only on behavioral assessment of early phonological processing deficits associated with dyslexia, but it might be improved by adding brain-based measures. METHODS In a 5-year longitudinal study of children with (n = 21) and without (n = 23) familial risk for dyslexia, we tested whether neurophysiological measures of automatic phoneme and tone deviance processing obtained in kindergarten would improve prediction of reading over behavioral measures alone. RESULTS Together, neurophysiological and behavioral measures obtained in kindergarten significantly predicted reading in school. Particularly the late mismatch negativity measure that indicated hemispheric lateralization of automatic phoneme processing improved prediction of reading ability over behavioral measures. It was also the only significant predictor for long-term reading success in fifth grade. Importantly, this result also held for the subgroup of children at familial risk. CONCLUSIONS The results demonstrate that brain-based measures of processing deficits associated with dyslexia improve prediction of reading and thus may be further evaluated to complement clinical practice of dyslexia prediction, especially in targeted populations, such as children with a familial risk.

Impaired semantic processing during sentence reading in children with dyslexia: Combined fMRI and ERP evidence

Developmental dyslexia is a specific disorder of reading acquisition characterized by a phonological core deficit. Sentence reading is also impaired in dyslexic readers, but whether semantic processing deficits contribute is unclear. Combining spatially and temporally sensitive neuroimaging techniques to focus on semantic processing can provide a more comprehensive characterization of sentence reading in dyslexia. We recorded brain activity from 52 children (16 with dyslexia, 31 controls) with functional magnetic resonance imaging (fMRI) and event-related potentials (ERP) in two separate counterbalanced sessions. The children silently read and occasionally judged simple sentences with semantically congruous or incongruous endings. fMRI and ERP activation during sentence reading and semantic processing was analyzed across all children and also by comparing children with dyslexia to controls. For sentence reading, we analyzed the response to all words in a sentence; for semantic processing, we contrasted responses to incongruous and congruous endings. Sentence reading was characterized by activation in a left-lateralized language network. Semantic processing was characterized by activation in left-hemispheric regions of the inferior frontal and superior temporal cortex and by an electrophysiological N400 effect after 240 ms with consistent left anterior source localization. Children with dyslexia showed decreased activation for sentence reading in inferior parietal and frontal regions, and for semantic processing in inferior parietal regions, and during the N400 effect. Together, this suggests that semantic impairment during sentence reading reduces dyslexic childrens response in left anterior brain regions underlying the more phasic N400 effect and subsequently modulates the more sustained BOLD response in left inferior parietal regions.

Neurophysiological signs of rapidly emerging visual expertise for symbol strings

The current study examined whether the repeated visual presentation of novel, meaningless symbol strings triggers rapid changes in event related potentials (ERP). Adult participants performed three versions of a word and symbol string repetition detection task in the same experimental session. Analyses focussed on the occipito-temporal N1 (∼150 ms) known to reflect early word-specific processing and stimulus categorisation. While the N1 to words did not change, the occipito-temporal negativity to symbol strings increased over runs and converged with the word N1. Later (∼220 ms) more positive occipito-temporal amplitudes to repeated words in the third compared to the first run implied a repetition priming effect. This suggests that symbol string processing changed over time due to visual learning and increased perceptual expertise.

Role of the Medial Prefrontal Cortex in Impaired Decision Making in Juvenile Attention-Deficit/Hyperactivity Disorder

IMPORTANCE Attention-deficit/hyperactivity disorder (ADHD) has been associated with deficient decision making and learning. Models of ADHD have suggested that these deficits could be caused by impaired reward prediction errors (RPEs). Reward prediction errors are signals that indicate violations of expectations and are known to be encoded by the dopaminergic system. However, the precise learning and decision-making deficits and their neurobiological correlates in ADHD are not well known. OBJECTIVE To determine the impaired decision-making and learning mechanisms in juvenile ADHD using advanced computational models, as well as the related neural RPE processes using multimodal neuroimaging. DESIGN, SETTING, AND PARTICIPANTS Twenty adolescents with ADHD and 20 healthy adolescents serving as controls (aged 12-16 years) were examined using a probabilistic reversal learning task while simultaneous functional magnetic resonance imaging and electroencephalogram were recorded. MAIN OUTCOMES AND MEASURES Learning and decision making were investigated by contrasting a hierarchical Bayesian model with an advanced reinforcement learning model and by comparing the model parameters. The neural correlates of RPEs were studied in functional magnetic resonance imaging and electroencephalogram. RESULTS Adolescents with ADHD showed more simplistic learning as reflected by the reinforcement learning model (exceedance probability, Px = .92) and had increased exploratory behavior compared with healthy controls (mean [SD] decision steepness parameter β: ADHD, 4.83 [2.97]; controls, 6.04 [2.53]; P = .02). The functional magnetic resonance imaging analysis revealed impaired RPE processing in the medial prefrontal cortex during cue as well as during outcome presentation (P < .05, family-wise error correction). The outcome-related impairment in the medial prefrontal cortex could be attributed to deficient processing at 200 to 400 milliseconds after feedback presentation as reflected by reduced feedback-related negativity (ADHD, 0.61 [3.90] μV; controls, -1.68 [2.52] μV; P = .04). CONCLUSIONS AND RELEVANCE The combination of computational modeling of behavior and multimodal neuroimaging revealed that impaired decision making and learning mechanisms in adolescents with ADHD are driven by impaired RPE processing in the medial prefrontal cortex. This novel, combined approach furthers the understanding of the pathomechanisms in ADHD and may advance treatment strategies.