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Adolescence is associated with quickly changing environmental demands which require excellent adaptive skills and high cognitive flexibility. Feedback-guided adaptive learning and cognitive flexibility are driven by reward prediction error (RPE) signals, which indicate the accuracy of expectations and can be estimated using computational models. Despite the importance of cognitive flexibility during adolescence, only little is known about how RPE processing in cognitive flexibility deviates between adolescence and adulthood. In this study, we investigated the developmental aspects of cognitive flexibility by means of computational models and functional magnetic resonance imaging (fMRI). We compared the neural and behavioral correlates of cognitive flexibility in healthy adolescents (12–16years) to adults performing a probabilistic reversal learning task. Using a modified risk-sensitive reinforcement learning model, we found that adolescents learned faster from negative RPEs than adults. The fMRI analysis revealed that within the RPE network, the adolescents had a significantly altered RPE-response in the anterior insula. This effect seemed to be mainly driven by increased responses to negative prediction errors. In summary, our findings indicate that decision making in adolescence goes beyond merely increased reward-seeking behavior and provides a developmental perspective to the behavioral and neural mechanisms underlying cognitive flexibility in the context of reinforcement learning. •Adolescents and adults show differences in processing RPEs.•Adolescents learn faster from negative prediction errors.•The anterior insula activation may cause altered sensitivity to RPEs.

ADHD is the most common neurodevelopmental disorder presenting to child and adolescent mental health, paediatric, and primary care services. Timely and effective interventions to address core ADHD symptoms and co-occurring problems are a high priority for healthcare and society more widely. While much research has reported on the benefits and adverse effects of different interventions for ADHD, these individual research reports and the reviews, meta-analyses and guidelines summarizing their findings are sometimes inconsistent and difficult to interpret. We have summarized the current evidence and identified several methodological issues and gaps in the current evidence that we believe are important for clinicians to consider when evaluating the evidence and making treatment decisions. These include understanding potential impact of bias such as inadequate blinding and selection bias on study outcomes; the relative lack of high-quality data comparing different treatments and assessing long-term effectiveness, adverse effects and safety for both pharmacological and non-pharmacological treatments; and the problems associated with observational studies, including those based on large national registries and comparing treatments with each other. We highlight key similarities across current international clinical guidelines and discuss the reasons for divergence where these occur. We discuss the integration of these different perspective into a framework for person/family-centered evidence-based practice approach to care that aims to achieve optimal outcomes that prioritize individual strengths and impairments, as well as the personal treatment targets of children and their families. Finally, we consider how access to care for this common and impairing disorder can be improved in different healthcare systems.

Attention-deficit hyperactivity disorder (ADHD) persists in around two-thirds of individuals in adolescence and early adulthood. To examine the cognitive and neurophysiological processes underlying the persistence or remission of ADHD. Follow-up data were obtained from 110 young people with childhood ADHD and 169 controls on cognitive, electroencephalogram frequency, event-related potential (ERP) and actigraph movement measures after 6 years. ADHD persisters differed from remitters on preparation-vigilance measures (contingent negative variation, delta activity, reaction time variability and omission errors), IQ and actigraph count, but not on executive control measures of inhibition or working memory (nogo-P3 amplitudes, commission errors and digit span backwards). Preparation-vigilance measures were markers of remission, improving concurrently with ADHD symptoms, whereas executive control measures were not sensitive to ADHD persistence/remission. For IQ, the present and previous results combined suggest a role in moderating ADHD outcome. These findings fit with previously identified aetiological separation of the cognitive impairments in ADHD. The strongest candidates for the development of non-pharmacological interventions involving cognitive training and neurofeedback are the preparation-vigilance processes that were markers of ADHD remission.

Error processing and conflict monitoring are essential executive functions for goal directed actions and adaptation to conflicting information. Although medial frontal regions such as the anterior cingulate cortex (ACC) and the pre-supplementary motor area (pre-SMA) are known to be involved in these functions, there is still considerable heterogeneity regarding their spatio-temporal activations. The timing of these functions has been associated with two separable event-related potentials (ERPs) usually localized to the medial frontal wall, one during error processing (ERN — error related negativity) and one during conflict monitoring (N2). In this study we aimed to spatially and temporally dissociate conflict and error processing using simultaneously recorded EEG and fMRI data from a modified Flanker task in healthy adults. We demonstrate a spatial dissociation of conflict monitoring and error processing along the medial frontal wall, with selective conflict level dependent activation of the SMA/pre-SMA. Activation to error processing was located in the ACC, rostral cingulate zone (RCZ) and pre-SMA. The EEG-informed fMRI analysis revealed that stronger ERN amplitudes are associated with increased activation in a large coherent cluster comprising the ACC, RCZ and pre-SMA, while N2 amplitudes increased with activation in the pre-SMA. Conjunction analysis of EEG-informed fMRI revealed common activation of ERN and N2 in the pre-SMA and divergent activation in the RCZ. No conjoint activation between error processing and conflict monitoring was found with standard fMRI analysis along the medial frontal wall. Our fMRI findings clearly demonstrate that conflict monitoring and error processing are spatially dissociable along the medial frontal wall. Moreover, the overlap of ERN- and N2-informed fMRI activation in the pre-SMA provides new evidence that these ERP components share conflict related processing functions and are thus not completely separable. •ACC activation to error processing, pre-SMA to conflict monitoring•More negative ERN amplitude was associated with increased RCZ activation•More negative N2 amplitude was associated with increased pre-SMA activation•Common activation of ERN and N2 in the pre-SMA•Spatial dissociation of conflict and error processing along the medial frontal wall

Children who are poor readers usually experience troublesome school careers and consequently often suffer from secondary emotional and behavioural problems. Early identification and prediction of later reading problems thus are critical in order to start targeted interventions for those children with an elevated risk for emerging reading problems. In this study, behavioural precursors of reading were assessed in nineteen (aged 6.4±0.3years) non-reading kindergarteners before training letter-speech sound associations with a computerized game (Graphogame) for eight weeks. The training aimed to introduce the basic principles of letter-speech sound correspondences and to initialize the sensitization of specific brain areas to print. Event-related potentials (ERP) and functional magnetic resonance imaging (fMRI) data were recorded during an explicit word/symbol processing task after the training. Reading skills were assessed two years later in second grade. The focus of this study was on clarifying whether electrophysiological and fMRI data of kindergarten children significantly improve prediction of future reading skills in 2nd grade over behavioural data alone. Based on evidence from previous studies demonstrating the importance of initial print sensitivity in the left occipito-temporal visual word form system (VWFS) for learning to read, the first pronounced difference in processing words compared to symbols in the ERP, an occipito-temporal negativity (N1: 188–281ms) along with the corresponding functional activation in the left occipito-temporal VWFS were defined as potential predictors. ERP and fMRI data in kindergarteners significantly improved the prediction of reading skills in 2nd grade over behavioural data alone. Together with the behavioural measures they explained up to 88% of the variance. An additional discriminant analysis revealed a remarkably high accuracy in classifying normal (n=11) and poor readers (n=6). Due to the key limitation of the study, i.e. the small group sizes, the results of our prediction analyses should be interpreted with caution and regarded as preliminary despite cross-validation. Nevertheless our results indicate the potential of combining neuroimaging and behavioural measures to improve prediction at an early stage, when literacy skills are acquired and interventions are most beneficial. •Best prediction at preschool achieved by combining behavioural and neuroimaging data.•Preschool ERP and fMRI data contribute to the prediction of reading outcome.•VWFS activation and the visual N1 contribute to the prediction of reading outcome.•Print sensitive VWFS activation detected in future regular reading preschool children.

This review focuses on the evidence for neurotherapeutics for attention deficit/hyperactivity disorder (ADHD). EEG-neurofeedback has been tested for about 45 years, with the latest meta-analyses of randomised controlled trials (RCT) showing small/medium effects compared to non-active controls only. Three small studies piloted neurofeedback of frontal activations in ADHD using functional magnetic resonance imaging or near-infrared spectroscopy, finding no superior effects over control conditions. Brain stimulation has been applied to ADHD using mostly repetitive transcranial magnetic and direct current stimulation (rTMS/tDCS). rTMS has shown mostly negative findings on improving cognition or symptoms. Meta-analyses of tDCS studies targeting mostly the dorsolateral prefrontal cortex show small effects on cognitive improvements with only two out of three studies showing clinical improvements. Trigeminal nerve stimulation has been shown to improve ADHD symptoms with medium effect in one RCT. Modern neurotherapeutics are attractive due to their relative safety and potential neuroplastic effects. However, they need to be thoroughly tested for clinical and cognitive efficacy across settings and beyond core symptoms and for their potential for individualised treatment.

Frontal midline (fm-)theta activity has been related to working memory (WM) processes, as it typically increases with WM load. The robustness of this effect, however, varies across studies and subjects, putting limits to its interpretation. We hypothesized that variation in the fm-theta effect may reflect individual differences in task difficulty with increasing WM load as indicated by behavioural responses. We further tested whether effects in the alpha range are robust markers of WM load. We recorded 64-channel EEG from 24 healthy adults while they memorized either 2 or 4 unfamiliar symbols (low vs. high WM load) in a modified Sternberg task. The last 2 s of the retention phase were analyzed for WM load-related changes in the theta (5–7 Hz) and alpha range (lower: 8–10 Hz, upper: 10.5–12.5 Hz). Higher WM load led to less accurate and slower responses. The increase of fm-theta with WM load was most pronounced at fm electrodes, localized to anterior cingulate regions, and correlated with the participants’ decrease in accuracy due to higher WM load. Alpha peak frequency increased in the high compared to the low WM load condition, corresponding to a decrease in lower alpha range across all channels. The results demonstrate that previously reported variation in fm-theta workload effects can partly be explained by variation in task difficulty indexed by individual task accuracy. Moreover, the results also demonstrate that alpha WM load effects are prominent when separating upper and lower alpha.

The acquisition of reading skills is a major landmark process in a human's 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.

EEG studies of working memory (WM) have demonstrated load dependent frequency band modulations. FMRI studies have localized load modulated activity to the dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (MPFC), and posterior parietal cortex (PPC). Recently, an EEG-fMRI study found that low frequency band (theta and alpha) activity negatively correlated with the BOLD signal during the retention phase of a WM task. However, the coupling of higher (beta and gamma) frequencies with the BOLD signal during WM is unknown. In 16 healthy adult subjects, we first investigated EEG-BOLD signal correlations for theta (5-7 Hz), alpha1 (8-10), alpha2 (10-12 Hz), beta1 (13-20), beta2 (20-30 Hz), and gamma (30-40 Hz) during the retention period of a WM task with set size 2 and 5. Secondly, we investigated whether load sensitive brain regions are characterised by effects that relate frequency bands to BOLD signals effects. We found negative theta-BOLD signal correlations in the MPFC, PPC, and cingulate cortex (ACC and PCC). For alpha1 positive correlations with the BOLD signal were found in ACC, MPFC, and PCC; negative correlations were observed in DLPFC, PPC, and inferior frontal gyrus (IFG). Negative alpha2-BOLD signal correlations were observed in parieto-occipital regions. Beta1-BOLD signal correlations were positive in ACC and negative in precentral and superior temporal gyrus. Beta2 and gamma showed only positive correlations with BOLD, e.g., in DLPFC, MPFC (gamma) and IFG (beta2/gamma). The load analysis revealed that theta and--with one exception--beta and gamma demonstrated exclusively positive load effects, while alpha1 showed only negative effects. We conclude that the directions of EEG-BOLD signal correlations vary across brain regions and EEG frequency bands. In addition, some brain regions show both load sensitive BOLD and frequency band effects. Our data indicate that lower as well as higher frequency brain oscillations are linked to neurovascular processes during WM.

Attention-Deficit Hyperactivity Disorder (ADHD) is a complex and heterogeneous neurodevelopmental condition for which curative treatments are lacking. Whilst pharmacological treatments are generally effective and safe, there is considerable inter-individual variability among patients regarding treatment response, required dose, and tolerability. Many of the non-pharmacological treatments, which are preferred to drug-treatment by some patients, either lack efficacy for core symptoms or are associated with small effect sizes. No evidence-based decision tools are currently available to allocate pharmacological or psychosocial treatments based on the patient’s clinical, environmental, cognitive, genetic, or biological characteristics. We systematically reviewed potential biomarkers that may help in diagnosing ADHD and/or stratifying ADHD into more homogeneous subgroups and/or predict clinical course, treatment response, and long-term outcome across the lifespan. Most work involved exploratory studies with cognitive, actigraphic and EEG diagnostic markers to predict ADHD, along with relatively few studies exploring markers to subtype ADHD and predict response to treatment. There is a critical need for multisite prospective carefully designed experimentally controlled or observational studies to identify biomarkers that index inter-individual variability and/or predict treatment response.