Predicting learning and achievement using GABA and glutamate concentrations in human development.

Previous research has highlighted the role of glutamate and gamma-aminobutyric acid (GABA) in learning and plasticity. What is currently unknown is how this knowledge translates to real-life complex cognitive abilities that emerge slowly and how the link between these neurotransmitters and human learning and plasticity is shaped by development. While some have suggested a generic role of glutamate and GABA in learning and plasticity, others have hypothesized that their involvement shapes sensitive periods during development. Here we used a cross-sectional longitudinal design with 255 individuals (spanning primary school to university) to show that glutamate and GABA in the intraparietal sulcus explain unique variance both in current and future mathematical achievement (approximately 1.5 years). Furthermore, our findings reveal a dynamic and dissociable role of GABA and glutamate in predicting learning, which is reversed during development, and therefore provide novel implications for models of learning and plasticity during childhood and adulthood.

The effect of parietal glutamate/GABA balance on test anxiety levels in early childhood in a cross-sectional and longitudinal study.

The increased prevalence of test anxiety in our competitive society makes it a health issue of public concern. However, its neurobiological basis, especially during the years of formal education, is currently scant. Previous research has highlighted the association between neural excitation/inhibition balance and psychopathology and disease. We examined whether the glutamate/GABA profile tracks test anxiety levels in development, using a cross-sectional and longitudinal design in a cohort spanning from early childhood to early adulthood (N = 289), reassessed approximately 21 months later (N = 194). We used magnetic resonance spectroscopy to noninvasively quantify glutamate and gamma-Aminobutyric acid (GABA) levels in the intraparietal sulcus (IPS) and the middle frontal gyrus. We show that the glutamate/GABA balance within the IPS relates to current individual variation in test anxiety levels and predict future test anxiety approximately 21 months later. Critically, this relationship was observed during early childhood but not during the later developmental stages. Our results extend the use of the excitation/inhibition balance framework to characterize the psychopathology mechanisms of test anxiety, an underexplored yet widespread and debilitating condition that can impact early child development. Our findings provide a better understanding of the neurotransmitter basis underlying the emergence of anxiety disorders during development.

Predictors of real-time fMRI neurofeedback performance and improvement - A machine learning mega-analysis.

Real-time fMRI neurofeedback is an increasingly popular neuroimaging technique that allows an individual to gain control over his/her own brain signals, which can lead to improvements in behavior in healthy participants as well as to improvements of clinical symptoms in patient populations. However, a considerably large ratio of participants undergoing neurofeedback training do not learn to control their own brain signals and, consequently, do not benefit from neurofeedback interventions, which limits clinical efficacy of neurofeedback interventions. As neurofeedback success varies between studies and participants, it is important to identify factors that might influence neurofeedback success. Here, for the first time, we employed a big data machine learning approach to investigate the influence of 20 different design-specific (e.g. activity vs. connectivity feedback), region of interest-specific (e.g. cortical vs. subcortical) and subject-specific factors (e.g. age) on neurofeedback performance and improvement in 608 participants from 28 independent experiments. With a classification accuracy of 60% (considerably different from chance level), we identified two factors that significantly influenced neurofeedback performance: Both the inclusion of a pre-training no-feedback run before neurofeedback training and neurofeedback training of patients as compared to healthy participants were associated with better neurofeedback performance. The positive effect of pre-training no-feedback runs on neurofeedback performance might be due to the familiarization of participants with the neurofeedback setup and the mental imagery task before neurofeedback training runs. Better performance of patients as compared to healthy participants might be driven by higher motivation of patients, higher ranges for the regulation of dysfunctional brain signals, or a more extensive piloting of clinical experimental paradigms. Due to the large heterogeneity of our dataset, these findings likely generalize across neurofeedback studies, thus providing guidance for designing more efficient neurofeedback studies specifically for improving clinical neurofeedback-based interventions. To facilitate the development of data-driven recommendations for specific design details and subpopulations the field would benefit from stronger engagement in open science research practices and data sharing.

Can we predict real-time fMRI neurofeedback learning success from pretraining brain activity?

Neurofeedback training has been shown to influence behavior in healthy participants as well as to alleviate clinical symptoms in neurological, psychosomatic, and psychiatric patient populations. However, many real-time fMRI neurofeedback studies report large inter-individual differences in learning success. The factors that cause this vast variability between participants remain unknown and their identification could enhance treatment success. Thus, here we employed a meta-analytic approach including data from 24 different neurofeedback studies with a total of 401 participants, including 140 patients, to determine whether levels of activity in target brain regions during pretraining functional localizer or no-feedback runs (i.e., self-regulation in the absence of neurofeedback) could predict neurofeedback learning success. We observed a slightly positive correlation between pretraining activity levels during a functional localizer run and neurofeedback learning success, but we were not able to identify common brain-based success predictors across our diverse cohort of studies. Therefore, advances need to be made in finding robust models and measures of general neurofeedback learning, and in increasing the current study database to allow for investigating further factors that might influence neurofeedback learning.

Training the anxious brain: using fMRI-based neurofeedback to change brain activity in adolescence.

Anxiety disorders are a leading cause of morbidity and entail a lot of costs. Adolescence is characterized by social fears and poor emotion regulation abilities which together increase the likelihood of the emergence of anxiety disorders. This emotion dysregulation is potentially caused by the emotion regulating brain areas, such as the prefrontal cortex and temporal cortex, that are still undergoing developmental changes throughout late adolescence. Recently, new approaches have used functional magnetic resonance imaging-based neurofeedback to help participants gain control over emotion regulation brain networks by receiving real-time feedback on their brain activity and to use effective emotion regulation abilities. In this review, we provide an overview of the developmental changes in the brain and the corresponding behavioural changes, and explore how these can be influenced during adolescence using neurofeedback. We conclude that recent studies show promising results that children and adolescents can self-regulate emotion regulation brain networks thereby supporting the development of effective emotion regulation abilities. WHAT THIS PAPER ADDS: Functional magnetic resonance imaging-based neurofeedback can be used for brain self-regulation in development. The emotion regulation networks play a key role in treating social anxiety with neurofeedback.

Current progress in real-time functional magnetic resonance-based neurofeedback: Methodological challenges and achievements.

Neurofeedback (NF) is a research and clinical technique, characterized by live demonstration of brain activation to the subject. The technique has become increasingly popular as a tool for the training of brain self-regulation, fueled by the superiority in spatial resolution and fidelity brought along with real-time analysis of fMRI (functional magnetic resonance imaging) data, compared to the more traditional EEG (electroencephalography) approach. NF learning is a complex phenomenon and a controversial discussion on its feasibility and mechanisms has arisen in the literature. Critical aspects of the design of fMRI-NF studies include the localization of neural targets, cognitive and operant aspects of the training procedure, personalization of training, and the definition of training success, both through neural effects and (for studies with therapeutic aims) through clinical effects. In this paper, we argue that a developmental perspective should inform neural target selection particularly for pediatric populations, and different success metrics may allow in-depth analysis of NF learning. The relevance of the functional neuroanatomy of NF learning for brain target selection is discussed. Furthermore, we address controversial topics such as the role of strategy instructions, sometimes given to subjects in order to facilitate learning, and the timing of feedback. Discussion of these topics opens sight on problems that require further conceptual and empirical work, in order to improve the impact that fMRI-NF could have on basic and applied research in future.

Investigating the effectiveness of brief cognitive reappraisal training to reduce fear in adolescents.

As adolescent anxiety is common and costly, identifying effective strategies to reduce symptoms is a priority. This study tested whether adolescents could learn to use cognitive reappraisal strategies to attenuate fear during extinction learning. Fifty-seven participants (12-15 years) viewed images of two neutral faces, one which was paired with a fearful expression and shrieking scream (conditioned threat stimulus) and the other that was never paired with the aversive outcome (conditioned safety stimulus) during fear acquisition. Before extinction, participants either received cognitive appraisal training, which explored alternative, benign meanings associated with the scream or a control activity. Self-reported fear ratings in the cognitive reappraisal group were significantly lower to both the conditioned threat and safety stimuli after extinction than the control group. These findings did not characterise fear-potentiated startle data. Potential reasons for the lack of consistency between measures are considered.

Using real-time fMRI to influence effective connectivity in the developing emotion regulation network.

For most people, adolescence is synonymous with emotional turmoil and it has been shown that early difficulties with emotion regulation can lead to persistent problems for some people. This suggests that intervention during development might reduce long-term negative consequences for those individuals. Recent research has highlighted the suitability of real-time fMRI-based neurofeedback (NF) in training emotion regulation (ER) networks in adults. However, its usefulness in directly influencing plasticity in the maturing ER networks remains unclear. Here, we used NF to teach a group of 17 7-16 year-olds to up-regulate the bilateral insula, a key ER region. We found that all participants learned to increase activation during the up-regulation trials in comparison to the down-regulation trials. Importantly, a subsequent Granger causality analysis of Granger information flow within the wider ER network found that during up-regulation trials, bottom-up driven Granger information flow increased from the amygdala to the bilateral insula and from the left insula to the mid-cingulate cortex, supplementary motor area and the inferior parietal lobe. This was reversed during the down-regulation trials, where we observed an increase in top-down driven Granger information flow to the bilateral insula from mid-cingulate cortex, pre-central gyrus and inferior parietal lobule. This suggests that: 1) NF training had a differential effect on up-regulation vs down-regulation network connections, and that 2) our training was not only superficially concentrated on surface effects but also relevant with regards to the underlying neurocognitive bases. Together these findings highlight the feasibility of using NF in children and adolescents and its possible use for shaping key social cognitive networks during development.

Psychotic Experiences, Working Memory, and the Developing Brain: A Multimodal Neuroimaging Study.

Psychotic experiences (PEs) occur in the general population, especially in children and adolescents, and are associated with poor psychosocial outcomes, impaired cognition, and increased risk of transition to psychosis. It is unknown how the presence and persistence of PEs during early adulthood affects cognition and brain function. The current study assessed working memory as well as brain function and structure in 149 individuals, with and without PEs, drawn from a population cohort. Observer-rated PEs were classified as persistent or transient on the basis of longitudinal assessments. Working memory was assessed using the n-back task during fMRI. Dynamic causal modeling (DCM) was used to characterize frontoparietal network configuration and voxel-based morphometry was utilized to examine gray matter. Those with persistent, but not transient, PEs performed worse on the n-back task, compared with controls, yet showed no significant differences in regional brain activation or brain structure. DCM analyses revealed greater emphasis on frontal connectivity within a frontoparietal network in those with PEs compared with controls. We propose that these findings portray an altered configuration of working memory function in the brain, potentially indicative of an adaptive response to atypical development associated with the manifestation of PEs.

Linking GABA and glutamate levels to cognitive skill acquisition during development.

Developmental adjustments in the balance of excitation and inhibition are thought to constrain the plasticity of sensory areas of the cortex. It is unknown however, how changes in excitatory or inhibitory neurochemical expression (glutamate, γ-aminobutyric acid (GABA)) contribute to skill acquisition during development. Here we used single-voxel proton magnetic resonance spectroscopy (1H-MRS) to reveal how differences in cortical glutamate vs. GABA ratios relate to face proficiency and working memory abilities in children and adults. We show that higher glutamate levels in the inferior frontal gyrus correlated positively with face processing proficiency in the children, but not the adults, an effect which was independent of age-dependent differences in underlying cortical gray matter. Moreover, we found that glutamate/GABA levels and gray matter volume are dissociated at the different maturational stages. These findings suggest that increased excitation during development is linked to neuroplasticity and the acquisition of new cognitive skills. They also offer a new, neurochemical approach to investigating the relationship between cognitive performance and brain development across the lifespan.

High trait anxiety during adolescence interferes with discriminatory context learning.

Persistent adult anxiety disorders often begin in adolescence. As emphasis on early treatment grows, we need a better understanding of how adolescent anxiety develops. In the current study, we used a fear conditioning paradigm to identify disruptions in cue and context threat-learning in 19 high anxious (HA) and 24 low anxious (LA) adolescents (12-17years). We presented three neutral female faces (conditioned stimulus, CS) in three contingent relations with an unconditioned stimulus (UCS, a shrieking female scream) in three virtual room contexts. The degree of contingency between the CSs and the UCSs varied across the rooms: in the predictable scream condition, the scream followed the face on 100% of trials; in the unpredictable scream condition, the scream and face appeared randomly and independently of each other; in the no-scream condition the CS was presented in the absence of any UCS. We found that the LA adolescents showed higher levels of fear-potentiated startle to the faces relative to the rooms. This difference was independent of the contingency condition. The HA adolescents showed non-differential startle between the CSs, but, in contrast to previous adult data, across both cue types displayed lowest startle to the unpredictable condition and highest startle to the no-scream condition. Our study is the first to examine context conditioning in adolescents, and our results suggest that high trait anxiety early in development may be associated with an inability to disambiguate the signalling roles of cues and contexts, and a mislabelling of safety or ambiguous signals.

Effects of age, task performance, and structural brain development on face processing.

In this combined structural and functional MRI developmental study, we tested 48 participants aged 7-37 years on 3 simple face-processing tasks (identity, expression, and gaze task), which were designed to yield very similar performance levels across the entire age range. The same participants then carried out 3 more difficult out-of-scanner tasks, which provided in-depth measures of changes in performance. For our analysis we adopted a novel, systematic approach that allowed us to differentiate age- from performance-related changes in the BOLD response in the 3 tasks, and compared these effects to concomitant changes in brain structure. The processing of all face aspects activated the core face-network across the age range, as well as additional and partially separable regions. Small task-specific activations in posterior regions were found to increase with age and were distinct from more widespread activations that varied as a function of individual task performance (but not of age). Our results demonstrate that activity during face-processing changes with age, and these effects are still observed when controlling for changes associated with differences in task performance. Moreover, we found that changes in white and gray matter volume were associated with changes in activation with age and performance in the out-of-scanner tasks.

Excitatory and inhibitory neurochemical markers of anxiety in young females.

Between the ages of 10-25 years the maturing brain is sensitive to a multitude of changes, including neurochemical variations in metabolites. Of the different metabolites, gamma-aminobutyric acid (GABA) has long been linked neurobiologically to anxiety symptomology, which begins to manifest in adolescence. To prevent persistent anxiety difficulties into adulthood, we need to understand the maturational trajectories of neurochemicals and how these relate to anxiety levels during this sensitive period. We used magnetic resonance spectroscopy in a sample of younger (aged 10-11) and older (aged 18-25) females to estimate GABA and glutamate levels in brain regions linked to emotion regulation processing, as well as a conceptually distinct control region. Within the Bayesian framework, we found that GABA increased and glutamate decreased with age, negative associations between anxiety and glutamate and GABA ratios in the dorsolateral prefrontal cortex, and a positive relationship of GABA with anxiety levels. The results support the neural over-inhibition hypothesis of anxiety based on GABAergic activity.

Diet quality and anxiety: a critical overview with focus on the gut microbiome.

Anxiety disorders disproportionally affect females and are frequently comorbid with eating disorders. With the emerging field of nutritional psychiatry, focus has been put on the impact of diet quality in anxiety pathophysiology and gut microbiome underlying mechanisms. While the relationship between diet and anxiety is bidirectional, improving dietary habits could better facilitate the actions of pharmacological and psychological therapies, or prevent their use. A better understanding of how gut bacteria mediate and moderate such relationship could further contribute to develop personalized programs and inform probiotics and prebiotics manufacturing. To date, studies that look simultaneously at diet, the gut microbiome, and anxiety are missing as only pairwise relationships among them have been investigated. Therefore, this study aims at summarizing and integrating the existing knowledge on the dietary effects on anxiety with focus on gut microbiome. Findings on the effects of diet on anxiety are critically summarized and reinterpreted in relation to findings on (i) the effects of diet on the gut microbiome composition, and (ii) the associations between the abundance of certain gut bacteria and anxiety. This novel interpretation suggests a theoretical model where the relationship between diet and anxiety is mediated and/or modulated by the gut microbiome through multiple mechanisms. In parallel, this study critically evaluates methodologies employed in the nutritional field to investigate the effects of diet on anxiety highlighting a lack of systematic operationalization and assessment strategies. Therefore, it ultimately proposes a novel evidence-based approach that can enhance studies validity, reliability, systematicity, and translation to clinical and community settings.

Differential face-network adaptation in children, adolescents and adults.

Faces are complex social stimuli, which can be processed both at the categorical and the individual level. Behavioral studies have shown that children take more than a decade of exposure and training to become proficient at processing faces at the individual level. The neurodevelopmental trajectories for different aspects of face-processing are still poorly understood. In this study, we used an fMR-adaptation design to investigate differential processing of three face aspects (identity, expression and gaze) in children, adolescents and adults. We found that, while all three tasks showed some overlap in activation patterns, there was a significant age effect in the occipital and temporal lobes and the inferior frontal gyrus. More importantly, the degree of adaptation differed across the three age groups in the inferior occipital gyrus, a core face processing area that has been shown in previous studies to be both integral and necessary for individual-level face processing. In the younger children, adaptation in this region seemed to suggest the use of a predominantly featural processing strategy, whereas adaptation effects in the adults exhibited a more strategic pattern that depended on the task. Interestingly, our sample of adolescents did not exhibit any differential adaptation effects; possibly reflecting increased heterogeneity in processing strategies in this age group. Our results support the notion that, in line with improving behavioral face-processing abilities, core face-responsive regions develop throughout the first two decades of life.

The role of peer rejection in adolescent depression.

Adolescence is a period of major risk for depression, which is associated with negative personal, social, and educational outcomes. Yet, in comparison to adult models of depression, very little is known about the specific psychosocial stressors that contribute to adolescent depression, and whether these can be targeted by interventions. In this review, we consider the role of peer rejection. First, we present a comprehensive review of studies using innovative experimental paradigms to understand the role of peer rejection in adolescent depression. We show how reciprocal relationships between peer rejection and depressive symptoms across adolescence powerfully shape and maintain maladaptive trajectories. Second, we consider how cognitive biases and their neurobiological substrates may explain why some adolescents are more vulnerable to the effects of, and perhaps exposure to, peer rejection compared to others. Finally, we draw attention to emerging cognitive and functional magnetic resonance imaging-based neurofeedback training, which by modifying aspects of information processing may promote more adaptive responses to peer rejection. A better understanding of the mechanisms underlying adolescent depression may not only alleviate symptoms during a period of substantial developmental challenges, but may also reduce the burden of the disorder across the lifespan.

Plasticity during childhood and adolescence: innovative approaches to investigating neurocognitive development.

Adolescence is a period of profound change, which holds substantial developmental milestones, but also unique challenges to the individual. In this opinion paper, we highlight the potential of combining two recently developed behavioural and neural training techniques (cognitive bias modification and functional magnetic neuroimaging-based neurofeedback) into a research approach that could help make the most of increased levels of plasticity during childhood and adolescence. We discuss how this powerful combination could be used to explore changing brain-behaviour relationships throughout development in the context of emotion processing, a cognitive domain that exhibits continuous development throughout the second decade of life. By targeting both behaviour and brain response, we would also be in an excellent position to define sensible time windows for enhancing plasticity, thereby allowing for targeted intervention approaches that can help improve emotion processing in both typically and atypically developing populations.

Differentiating core and co-opted mechanisms in calculation: the neuroimaging of calculation in aphasia.

The role of language in exact calculation is the subject of debate. Some behavioral and functional neuroimaging investigations of healthy participants suggest that calculation requires language resources. However, there are also reports of individuals with severe aphasic language impairment who retain calculation ability. One possibility in resolving these discordant findings is that the neural basis of calculation has undergone significant reorganization in aphasic calculators. Using fMRI, we examined brain activations associated with exact addition and subtraction in two patients with severe agrammatic aphasia and retained calculation ability. Behavior and brain activations during two-digit addition and subtraction were compared to those of a group of 11 healthy, age-matched controls. Behavioral results confirmed that both patients retained calculation ability. Imaging findings revealed individual differences in processing, but also a similar activation pattern across patients and controls in bilateral parietal cortices. Patients differed from controls in small areas of increased activation in peri-lesional regions, a shift from left fronto-temporal activation to the contralateral region, and increased activations in bilateral superior parietal regions. Our results suggest that bilateral parietal cortex represents the core of the calculation network and, while healthy controls may recruit language resources to support calculation, these mechanisms are not mandatory in adult cognition.

Developmental changes in effective connectivity in the emerging core face network.

Little is currently known about the postnatal emergence of functional cortical networks supporting complex perceptual and cognitive skills, such as face processing. The present study examined the emergence of the core cortical network underlying face processing in younger and older school-age children as well as young adults. Participants performed 3 functional magnetic resonance imaging target detection tasks where they either had to detect a specific facial identity, expression, or direction of eye gaze in a stream of consecutively presented faces. We compared the connectivity of the face network using dynamic causal modelling and observed that it emerges gradually during childhood. Further, we found that while the relative strength of functional network connections were differentially modulated by task demands in adults, there was no such modulation of this network in either older or younger children. These results were independent of the behavioral performance in the 3 age groups. We suggest that the emergence of the face network is due to continuous specialization and fine-tuning within the regions of this network. The current results have important implications for future studies investigating trajectories of brain development and cortical specialization both in typically and atypically developing populations.

A Systematic Review of Psychobiotic Interventions in Children and Adolescents to Enhance Cognitive Functioning and Emotional Behavior.

This systematic review brings together human psychobiotic interventions in children and adolescents (aged 6-25 years) to evaluate the efficacy of pre- and probiotic supplements on stress, anxiety, and cognitive outcomes. Psychobiotic interventions in animal studies highlighted sensitivity to effects during development and maturation in multiple domains from emotion to cognitive processing. Several translational psychobiotic interventions in humans have been carried out to assess effects on emotion and cognition during childhood and into adulthood. The findings illustrate that there are limited consistent psychobiotic effects in developing human populations, and this is proposed to be due to heterogeneity in the trials conducted. Consequentially, it is recommended that three specific factors are considered in future psychobiotic trials: (1) Specificity of population studied (e.g., patients, developmental age), (2) specificity of intervention, and (3) homogeneity in outcome measures.