Association of Intrinsic Brain Architecture With Changes in Attentional and Mood Symptoms During Development.

Importance: Understanding the neurodevelopmental trajectory of psychiatric symptoms is important for improving early identification, intervention, and prevention of mental disorders. Objective: To test whether the strength of the coupling of activation between specific brain regions, as measured by resting-state functional magnetic resonance imaging (fMRI), predicted individual children's developmental trajectories in terms of attentional problems characteristic of attention-deficit/hyperactivity disorder and internalizing problems characteristics of major depressive disorder (MDD). Design, Setting, and Participants: A community cohort of 94 children was recruited from Vanderbilt University between 2010 and 2013. They were followed up longitudinally for 4 years and the data were analyzed from 2016 to 2019. Based on preregistered hypotheses and an analytic plan, we examined whether specific brain connectivity patterns would be associated with longitudinal changes in scores on the Child Behavior Checklist (CBCL), a parental-report assessment used to screen for emotional, behavioral, and social problems and to predict psychiatric illnesses. Main Outcomes and Measures: We used the strength of resting-state fMRI connectivity at age 7 years to predict subsequent changes in CBCL measures 4 years later and investigated the mechanisms of change by associating brain connectivity changes with changes in the CBCL. Results: We analyzed data from a longitudinal brain development study involving children assessed at age 7 years (n = 94; 41 girls [43.6%]) and 11 years (n = 54; 32 girls [59.3%]). As predicted, less positive coupling at age 7 years between the medial prefrontal cortex and dorsolateral prefrontal cortex (DLPFC) was associated with a decrease in attentional symptoms by age 11 years (t49 = 2.38; P = .01; ß = 0.32). By contrast, a less positive coupling between a region implicated in mood, the subgenual anterior cingulate cortex (sgACC), and DLPFC at age 7 years was associated with an increase in internalizing (eg, anxiety/depression) behaviors by age 11 years (t49 = -2.4; P = .01; ß = -0.30). Logistic regression analyses revealed that sgACC-DLPFC connectivity was a more accurate predictor than baseline CBCL measures for progression to a subclinical score on internalization (t50 = -2.61; P = .01; ß = -0.29). We then replicated and extended the sgACC-DLPFC result in an independent sample of children with (n = 25) or without (n = 18) familial risk for MDD. Conclusions and Relevance: These resting-state fMRI metrics are promising biomarkers for the early identification of children at risk of developing MDD or attention-deficit/hyperactivity disorder.

The Importance of Knowing When You Don't Remember: Neural Signaling of Retrieval Failure Predicts Memory Improvement Over Time.

Just as the ability to remember prior events is critical for guiding our decision-making, so too is the ability to recognize the limitations of our memory. Indeed, we hypothesize that neural signaling of retrieval failure promotes more accurate memory judgments over time. To test this hypothesis, we collected longitudinal functional magnetic resonance imaging data from 8 to 9 years olds, 10 to 12 years olds, and adults, with two time points spaced approximately 1.4 years apart (198 scan sessions in total). Participants performed an episodic memory retrieval task in which they could either select a response or report uncertainty about the target memory detail. Children who engaged anterior insula more strongly during inaccurate or uncertain responses exhibited greater longitudinal increases in anterior prefrontal cortex activation for decisions to report uncertainty; both of these neural variables predicted improvements in episodic memory. Together, the results suggest that the brain processes supporting effective cognitive control and decision-making continue to develop in middle childhood and play an important role for memory development.

Neuroscientific insights into the development of analogical reasoning.

Analogical reasoning, or the ability to find correspondences between entities based on shared relationships, supports knowledge acquisition. As such, the development of this ability during childhood is thought to promote learning. Here, we sought to better understand the mechanisms by which analogical reasoning about semantic relations improves over childhood and adolescence (e.g. chalk is to chalkboard as pen is to…?). We hypothesized that age-related differences would manifest as differences in the brain regions associated with one or more of the following cognitive functions: (1) controlled semantic retrieval, or the ability to retrieve task-relevant semantic associations; (2) response control, or the ability to override the tendency to respond to a salient distractor; and/or (3) relational integration, or the ability to consider jointly two mental relations. In order to test these hypotheses, we analyzed patterns of fMRI activation during performance of a pictorial propositional analogy task across 95 typically developing children between the ages of 6 and 18 years old. Despite large age-related differences in task performance, particularly over ages 6-10 but through to around age 14, participants across the whole age range recruited a common network of frontal, parietal and temporal regions. However, activation in a brain region that has been implicated in controlled semantic retrieval - left anterior prefrontal cortex (BA 47/45) - was positively correlated with age, and also with performance after controlling for age. This finding indicates that improved performance over middle childhood and early adolescence on this analogical reasoning task is driven largely by improvements in the ability to selectively retrieve task-relevant semantic relationships.

Frontoparietal Structural Connectivity in Childhood Predicts Development of Functional Connectivity and Reasoning Ability: A Large-Scale Longitudinal Investigation.

Prior research points to a positive concurrent relationship between reasoning ability and both frontoparietal structural connectivity (SC) as measured by diffusion tensor imaging (Tamnes et al., 2010) and frontoparietal functional connectivity (FC) as measured by fMRI (Cocchi et al., 2014). Further, recent research demonstrates a link between reasoning ability and FC of two brain regions in particular: rostrolateral prefrontal cortex (RLPFC) and the inferior parietal lobe (IPL) (Wendelken et al., 2016). Here, we sought to investigate the concurrent and dynamic, lead-lag relationships among frontoparietal SC, FC, and reasoning ability in humans. To this end, we combined three longitudinal developmental datasets with behavioral and neuroimaging data from 523 male and female participants between 6 and 22 years of age. Cross-sectionally, reasoning ability was most strongly related to FC between RLPFC and IPL in adolescents and adults, but to frontoparietal SC in children. Longitudinal analysis revealed that RLPFC-IPL SC, but not FC, was a positive predictor of future changes in reasoning ability. Moreover, we found that RLPFC-IPL SC at one time point positively predicted future changes in RLPFC-IPL FC, whereas, in contrast, FC did not predict future changes in SC. Our results demonstrate the importance of strong white matter connectivity between RLPFC and IPL during middle childhood for the subsequent development of both robust FC and good reasoning ability.SIGNIFICANCE STATEMENT The human capacity for reasoning develops substantially during childhood and has a profound impact on achievement in school and in cognitively challenging careers. Reasoning ability depends on communication between lateral prefrontal and parietal cortices. Therefore, to understand how this capacity develops, we examined the dynamic relationships over time among white matter tracts connecting frontoparietal cortices (i.e., structural connectivity, SC), coordinated frontoparietal activation (functional connectivity, FC), and reasoning ability in a large longitudinal sample of subjects 6-22 years of age. We found that greater frontoparietal SC in childhood predicts future increases in both FC and reasoning ability, demonstrating the importance of white matter development during childhood for subsequent brain and cognitive functioning.

Changes in ventromedial prefrontal and insular cortex support the development of metamemory from childhood into adolescence.

Metamemory monitoring, or the ability to introspect on the accuracy of one's memories, improves considerably during childhood, but the underlying neural changes and implications for intellectual development are largely unknown. The present study examined whether cortical changes in key brain areas hypothesized to support metacognition contribute to the development of metamemory monitoring from late childhood into early adolescence. Metamemory monitoring was assessed among 7- to 12-y-old children (n = 145) and adults (n = 31). Children returned for up to two additional assessments at 8 to 14 y of age (n = 120) and at 9 to 15 y of age (n = 107) (n = 347 longitudinal scans). Results showed that metamemory monitoring continues to improve from childhood into adolescence. More pronounced cortical thinning in the anterior insula and a greater increase in the thickness of the ventromedial prefrontal cortex over the three assessment points predicted these improvements. Thus, performance benefits are linked to the unique patterns of regional cortical change during development. Metamemory monitoring at the first time point predicted intelligence at the third time point and vice versa, suggesting parallel development of these abilities and their reciprocal influence. Together, these results provide insights into the neuroanatomical correlates supporting the development of the capacity to self-reflect, and highlight the role of this capacity for general intellectual development.

Age- and performance-related differences in hippocampal contributions to episodic retrieval.

The goal of the present study was to investigate whether hippocampal contribution to episodic memory retrieval varies as a function of age (8-9 versus 10-11 versus adults), performance levels (high versus low) and hippocampal sub-region (head, body, tail). We examined fMRI data collected during episodic retrieval from a large sample (N=126). Participants judged whether a stimulus had been encoded previously, and, if so, which of three scenes it had been paired with (i.e., source judgment). For 8- to 9-years-olds as well as low-performing 10- to 11-year-olds, hippocampal activations did not reliably differentiate between trials on which item-scene associations were correctly recalled (correct source), incorrectly recalled (incorrect source), or trials on which the item was forgotten (miss trials). For high-performing 10-11-year olds and low-performing adults, selective hippocampal activation was observed for correct source relative to incorrect source and miss trials; this effect was observed across the entire hippocampus. For high-performing adults, hippocampal activation also distinguished between correct and incorrect source trialsl, but only in the hippocampal head, suggesting that good performance in adults is associated with more focal hippocampal recruitment. Thus, both age and performance are important factors for understanding the development of memory and hippocampal function.

Fronto-Parietal Network Reconfiguration Supports the Development of Reasoning Ability.

The goal of this fMRI study was to examine how well developmental improvements in reasoning ability can be explained by changes in functional connectivity between specific nodes in prefrontal and parietal cortices. To this end, we examined connectivity within the lateral fronto-parietal network (LFPN) and its relation to reasoning ability in 132 children and adolescents aged 6-18 years, 56 of whom were scanned twice over the course of 1.5 years. Developmental changes in strength of connections within the LFPN were most prominent in late childhood and early adolescence. Reasoning ability was related to functional connectivity between left rostrolateral prefrontal cortex (RLPFC) and inferior parietal lobule (IPL), but only among 12-18-year olds. For 9-11-year olds, reasoning ability was most strongly related to connectivity between left and right RLPFC; this relationship was mediated by working memory. For 6-8-year olds, significant relationships between connectivity and performance were not observed; in this group, processing speed was the primary mediator of improvement in reasoning ability. We conclude that different connections best support reasoning at different points in development and that RLPFC-IPL connectivity becomes an important predictor of reasoning during adolescence.

A Time and Place for Everything: Developmental Differences in the Building Blocks of Episodic Memory.

This research investigated whether episodic memory development can be explained by improvements in relational binding processes, involved in forming novel associations between events and the context in which they occurred. Memory for item-space, item-time, and item-item relations was assessed in an ethnically diverse sample of 151 children aged 7-11 years and 28 young adults. Item-space memory reached adult performance by 9½ years, whereas item-time and item-item memory improved into adulthood. In path analysis, item-space, but not item-time best explained item-item memory. Across age groups, relational binding related to source memory and performance on standardized memory assessments. In conclusion, relational binding development depends on relation type, but relational binding overall supports episodic memory development.

Characterizing Behavioral and Brain Changes Associated with Practicing Reasoning Skills.

We have reported previously that intensive preparation for a standardized test that taxes reasoning leads to changes in structural and functional connectivity within the frontoparietal network. Here, we investigated whether reasoning instruction transfers to improvement on unpracticed tests of reasoning, and whether these improvements are associated with changes in neural recruitment during reasoning task performance. We found behavioral evidence for transfer to a transitive inference task, but no evidence for transfer to a rule generation task. Across both tasks, we observed reduced lateral prefrontal activation in the trained group relative to the control group, consistent with other studies of practice-related changes in brain activation. In the transitive inference task, we observed enhanced suppression of task-negative, or default-mode, regions, consistent with work suggesting that better cognitive skills are associated with more efficient switching between networks. In the rule generation task, we found a pattern consistent with a training-related shift in the balance between phonological and visuospatial processing. Broadly, we discuss general methodological considerations related to the analysis and interpretation of training-related changes in brain activation. In summary, we present preliminary evidence for changes in brain activation associated with practice of high-level cognitive skills.

Tourette Syndrome: Complementary Insights from Measures of Cognitive Control, Eyeblink Rate, and Pupil Diameter.

Some individuals with Tourette syndrome (TS) have severe motoric and vocal tics that interfere with all aspects of their lives, while others have mild tics that pose few problems. We hypothesize that observed tic severity reflects a combination of factors, including the degree to which dopaminergic (DA) and/or noradrenergic (NE) neurotransmitter systems have been affected by the disorder, and the degree to which the child can exert cognitive control to suppress unwanted tics. To explore these hypotheses, we collected behavioral and eyetracking data from 26 patients with TS and 26 controls between ages 7 and 14, both at rest and while they performed a test of cognitive control. To our knowledge, this is the first study to use eyetracking measures in patients with TS. We measured spontaneous eyeblink rate as well as pupil diameter, which have been linked, respectively, to DA and NE levels in the central nervous system. Here, we report a number of key findings that held when we restricted analyses to unmedicated patients. First, patients' accuracy on our test of cognitive control accounted for fully 50% of the variance in parentally reported tic severity. Second, patients exhibited elevated spontaneous eyeblink rates compared to controls, both during task performance and at rest, consistent with heightened DA transmission. Third, although neither task-evoked pupil dilation nor resting pupil diameter differed between TS patients and controls, pupil diameter was positively related to parentally reported anxiety levels in patients, suggesting heightened NE transmission in patients with comorbid anxiety. Thus, with the behavioral and eyetracking data gathered from a single task, we can gather objective data that are related both to tic severity and anxiety levels in pediatric patients with TS, and that likely reflect patients' underlying neurochemical disturbances.

Delay of gratification in childhood linked to cortical interactions with the nucleus accumbens.

Delay of gratification (DG) is the ability to forego immediate temptations in the service of obtaining larger, delayed rewards. An extensive body of behavioral research has revealed that DG ability in childhood is associated with a host of important outcomes throughout development, and that attentional focus away from temptations underlies this ability. In this study, we conducted a functional magnetic resonance imaging study to identify the neural underpinnings of individual differences in DG among children. We observed a relationship between behavior during the classic DG task, a well-studied and ecologically valid measure, and functional connectivity during a modified version of this task in the scanner. Specifically, greater attentional focus away from temptations was associated with stronger functional coupling between the nucleus accumbens, a brain region that supports approach behavior, and several regions within prefrontal and parietal cortex that support self-control. These results shed light on the network interactions that contribute to DG and that account for individual differences in this capacity.

White Matter Tracts Connected to the Medial Temporal Lobe Support the Development of Mnemonic Control.

One of the most important factors driving the development of memory during childhood is mnemonic control, or the capacity to initiate and maintain the processes that guide encoding and retrieval operations. The ability to selectively attend to and encode relevant stimuli is a particularly useful form of mnemonic control, and is one that undergoes marked improvement over childhood. We hypothesized that structural integrity of white matter tracts, in particular those connecting medial temporal lobe memory regions to other cortical areas, and/or those connecting frontal and parietal control regions, should contribute to successful mnemonic control. To test this hypothesis, we examined the relationship between structural integrity of selected white matter tracts and an experimental measure of mnemonic control, involving enhancement of memory by attention at encoding, in 116 children aged 7-11 and 25 young adults. We observed a positive relationship between integrity of uncinate fasciculus and mnemonic enhancement across age groups. In adults, but not in children, we also observed an association between mnemonic enhancement and integrity of ventral cingulum bundle and ventral fornix/fimbria. Integrity of fronto-parietal tracts, including dorsal cingulum and superior longitudinal fasciculus, was unrelated to mnemonic enhancement.

Meta-analysis: how does posterior parietal cortex contribute to reasoning?

Reasoning depends on the contribution of posterior parietal cortex (PPC). But PPC is involved in many basic operations-including spatial attention, mathematical cognition, working memory, long-term memory, and language-and the nature of its contribution to reasoning is unclear. Psychological theories of the processes underlying reasoning make divergent claims about the neural systems that are likely to be involved, and better understanding the specific contribution of PPC can help to inform these theories. We set out to address several competing hypotheses, concerning the role of PPC in reasoning: (1) reasoning involves application of formal logic and is dependent on language, with PPC activation for reasoning mainly reflective of linguistic processing; (2) reasoning involves probabilistic computation and is thus dependent on numerical processing mechanisms in PPC; and (3) reasoning is built upon the representation and processing of spatial relations, and PPC activation associated with reasoning reflects spatial processing. We conducted two separate meta-analyses. First, we pooled data from our own studies of reasoning in adults, and examined activation in PPC regions of interest (ROI). Second, we conducted an automated meta-analysis using Neurosynth, in which we examined overlap between activation maps associated with reasoning and maps associated with other key functions of PPC. In both analyses, we observed reasoning-related activation concentrated in the left Inferior Parietal Lobe (IPL). Reasoning maps demonstrated the greatest overlap with mathematical cognition. Maintenance, visuospatial, and phonological processing also demonstrated some overlap with reasoning, but a large portion of the reasoning map did not overlap with the map for any other function. This evidence suggests that the PPC's contribution to reasoning may be most closely related to its role in mathematical cognition, but that a core component of this contribution may be specific to reasoning.

White matter maturation supports the development of reasoning ability through its influence on processing speed.

The structure of the human brain changes in several ways throughout childhood and adolescence. Perhaps the most salient of these changes is the strengthening of white matter tracts that enable distal brain regions to communicate with one another more quickly and efficiently. Here, we sought to understand whether and how white matter changes contribute to improved reasoning ability over development. In particular, we sought to understand whether previously reported relationships between white matter microstructure and reasoning are mediated by processing speed. To this end, we analyzed diffusion tensor imaging data as well as data from standard psychometric tests of cognitive abilities from 103 individuals between the ages of 6 and 18. We used structural equation modeling to investigate the network of relationships between brain and behavior variables. Our analyses provide support for the hypothesis that white matter maturation (as indexed either by microstructural organization or volume) supports improved processing speed, which, in turn, supports improved reasoning ability.

Flexible rule use: common neural substrates in children and adults.

Flexible rule-guided behavior develops gradually, and requires the ability to remember the rules, switch between them as needed, and implement them in the face of competing information. Our goals for this study were twofold: first, to assess whether these components of rule-guided behavior are separable at the neural level, and second, to identify age-related differences in one or more component that could support the emergence of increasingly accurate and flexible rule use over development. We collected event-related fMRI data while 36 children aged 8-13 and adults aged 20-27 performed a task that manipulated rule representation, rule switching, and stimulus incongruency. Several regions - left dorsolateral prefrontal cortex (DLPFC), left posterior parietal cortex, and pre-supplementary motor area - were engaged by both the rule representation and the rule-switching manipulations. These regions were engaged similarly across age groups, though contrasting timecourses of activation in left DLPFC suggest that children updated task rules more slowly than did adults. These findings support the idea that common networks can contribute to a variety of executive functions, and that some developmental changes take the form of changes in temporal dynamics rather than qualitative changes in the network of brain regions engaged.

Rostrolateral prefrontal cortex: domain-general or domain-sensitive?

The ability to jointly consider several structured mental representations, or relations, is fundamental to human cognition. Prior studies have consistently linked this capacity for relational integration to rostrolateral prefrontal cortex (RLPFC). Here, we sought to test two competing hypotheses: (1) RLPFC processes relations in a domain-general manner, interacting with different brain regions as a function of the type of lower-level relations that must be integrated; or (2) A dorsal-ventral gradient exists within RLPFC, such that relational integration in the visuospatial domain involves relatively more dorsal RLPFC than integration in the semantic domain. To this end, we examined patterns of fMRI activation and functional connectivity during performance of visuospatial and semantic variants of a relational matching task. Across the two task variants, the regions that were most strongly engaged during relational comparison were left RLPFC and left intraparietal sulcus (IPS). Within left RLPFC, there was considerable overlap in activation for the semantic and visuospatial tasks. However, visuospatial task activation peaks were located dorsally to the semantic task peaks. In addition, RLPFC exhibited differential functional connectivity on the two tasks, interacting with different brain regions as a function of the type of relations being compared. While neurons throughout RLPFC may share the function of integrating diverse inputs, individual RLPFC neurons may have privileged access to particular representations depending on their anatomical inputs, organized along a dorsal-ventral gradient. Thus, RLPFC is well-positioned as a locus of abstraction from concrete, domain-specific details to the general principles and rules that enable higher-level cognition.

Increased functional selectivity over development in rostrolateral prefrontal cortex.

Relational reasoning, or the ability to identify and consider relationships between multiple mental representations, is a fundamental component of high-level cognition (Robin and Holyoak, 1995). The capacity to reason with relations enables abstract thought and may be at the core of what makes human cognition unique (Penn et al., 2008). This capacity improves throughout childhood and adolescence (Ferrer et al., 2009). Here, we sought to better understand the neural mechanisms that support its emergence. We have hypothesized previously, based on fMRI research in adults, that (1) inferior parietal lobe (IPL) plays a central role in representing relationships between mental representations (first-order relations) and (2) rostrolateral prefrontal cortex (RLPFC) integrates inputs from IPL to build second-order relational structures (i.e., relations between relations). In the present study, we examined fMRI and cortical thickness data from 85 children and adolescents (ages 6-18 years). Participants performed a relational matching task in which they viewed arrays of four visual stimuli and determined whether two stimuli shared a particular feature (a first-order relational judgment) or whether two pairs of stimuli matched according to the same feature (a second-order relational judgment). fMRI results provide evidence for increased functional selectivity across ages 6-18 years in RLPFC and IPL. Specifically, young children engaged RLPFC and IPL indiscriminately for first-order and second-order relational judgments, and activation for first-order relations diminished with age whereas activation for second-order relations stayed elevated. Examination of cortical thickness revealed that increased functional selectivity in RLPFC could be partly accounted for by cortical thinning in IPL.

Transitive inference: distinct contributions of rostrolateral prefrontal cortex and the hippocampus.

The capacity to reason about complex information is a central characteristic of human cognition. An important component of many reasoning tasks is the need to integrate multiple mental relations. Several researchers have argued that rostrolateral prefrontal cortex (RLPFC) plays a key role in relational integration. If this hypothesis is correct, then RLPFC should play a key role in transitive inference, which requires the integration of multiple relations to reach a conclusion. Thus far, however, neuroscientific research on transitive inference has focused primarily on the hippocampus. In this fMRI study, we sought to compare the roles of RLPFC and the hippocampus on a novel transitive inference paradigm. Four relations between colored balls were presented on the screen together with a target relation. Participants were asked to decide whether the target relation was correct, given the other indicated relations between balls. RLPFC, but not the hippocampus, exhibited stronger activation on trials that required relational integration as compared with trials that involved relational encoding without integration. In contrast, the hippocampus exhibited a pattern consistent with a role in relational encoding, with stronger activation on trials requiring encoding of relational predicate-argument structure as compared with trials requiring encoding of item-item associations. Functional connectivity analyses give rise to the hypothesis that RLPFC draws on hippocampal representations of mental relations during the process of relational integration.

Stimulus and response conflict processing during perceptual decision making.

Encoding and dealing with conflicting information is essential for successful decision making in a complex environment. In the present fMRI study, stimulus conflict and response conflict are contrasted in the context of a perceptual decision-making dot-motion discrimination task. Stimulus conflict was manipulated by varying dot-motion coherence along task-relevant and task-irrelevant dimensions. Response conflict was manipulated by varying whether or not competing stimulus dimensions provided evidence for the same or different responses. The right inferior frontal gyrus was involved specifically in the resolution of stimulus conflict, whereas the dorsal anterior cingulate cortex was shown to be sensitive to response conflict. Additionally, two regions that have been linked to perceptual decision making with dot-motion stimuli in monkey physiology studies were differentially engaged by stimulus conflict and response conflict. The middle temporal area, previously linked to processing of motion, was strongly affected by the presence of stimulus conflict. On the other hand, the superior parietal lobe, previously associated with accumulation of evidence for a response, was affected by the presence of response conflict. These results shed light on the neural mechanisms that support decision making in the presence of conflict, a cognitive operation fundamental to both basic survival and high-level cognition.

A functional and structural study of emotion and face processing in children with autism.

Children with autism exhibit impairment in the processing of socioemotional information. The amygdala, a core structure centrally involved in socioemotional functioning, has been implicated in the neuropathology of autism. We collected structural and functional magnetic resonance images (MRI) in children 8 to 12 years of age with high-functioning autism (n=12) and typical development (n=15). The functional MRI experiment involved matching facial expressions and people. Volumetric analysis of the amygdala was also performed. The results showed that children with autism exhibited intact emotion matching, while showing diminished activation of the fusiform gyrus (FG) and the amygdala. Conversely, the autism group showed deficits in person matching amidst some FG and variable amygdala activation. No significant between-group differences in the volume of the left or right amygdala were found. There were associations between age, social anxiety and amygdala volume in the children with autism such that smaller volumes were generally associated with more anxiety and younger age. In summary, the data are consistent with abnormalities in circuits involved in emotion and face processing reported in studies of older subjects with autism showing reductions in amygdala activation related to emotion processing and reduced fusiform activation involved in face processing.