Cortical and white matter substrates supporting visuospatial working memory.

OBJECTIVE: In tasks involving new visuospatial information, we rely on working memory, supported by a distributed brain network. We investigated the dynamic interplay between brain regions, including cortical and white matter structures, to understand how neural interactions change with different memory loads and trials, and their subsequent impact on working memory performance. METHODS: Patients undertook a task of immediate spatial recall during intracranial EEG monitoring. We charted the dynamics of cortical high-gamma activity and associated functional connectivity modulations in white matter tracts. RESULTS: Elevated memory loads were linked to enhanced functional connectivity via occipital longitudinal tracts, yet decreased through arcuate, uncinate, and superior-longitudinal fasciculi. As task familiarity grew, there was increased high-gamma activity in the posterior inferior-frontal gyrus (pIFG) and diminished functional connectivity across a network encompassing frontal, parietal, and temporal lobes. Early pIFG high-gamma activity was predictive of successful recall. Including this metric in a logistic regression model yielded an accuracy of 0.76. CONCLUSIONS: Optimizing visuospatial working memory through practice is tied to early pIFG activation and decreased dependence on irrelevant neural pathways. SIGNIFICANCE: This study expands our knowledge of human adaptation for visuospatial working memory, showing the spatiotemporal dynamics of cortical network modulations through white matter tracts.

From vision to memory: How scene-sensitive regions support episodic memory formation during child development.

Previous brain imaging studies have identified three brain regions that selectively respond to visual scenes, the parahippocampal place area (PPA), the occipital place area (OPA), and the retrosplenial cortex (RSC). There is growing evidence that these visual scene-sensitive regions process different types of scene information and may have different developmental timelines in supporting scene perception. How these scene-sensitive regions support memory functions during child development is largely unknown. We investigated PPA, OPA and RSC activations associated with episodic memory formation in childhood (5-7 years of age) and young adulthood, using a subsequent scene memory paradigm and a functional localizer for scenes. PPA, OPA, and RSC subsequent memory activation and functional connectivity differed between children and adults. Subsequent memory effects were found in activations of all three scene regions in adults. In children, however, robust subsequent memory effects were only found in the PPA. Functional connectivity during successful encoding was significant among the three regions in adults, but not in children. PPA subsequently memory activations and PPA-RSC subsequent memory functional connectivity correlated with accuracy in adults, but not children. These age-related differences add new evidence linking protracted development of the scene-sensitive regions to the protracted development of episodic memory.

KIBRA single nucleotide polymorphism is associated with hippocampal subfield volumes and cognition across development.

The hippocampus (Hc) consists of cytoarchitectonically and functionally distinct subfields: dentate gyrus (DG), cornu ammonis (CA1-3), and subiculum. In adults, a single nucleotide polymorphism (rs17070145, C→ T) in KIBRA, a gene encoding the eponymous (KIdney-BRAin) protein, is associated with variability in Hc subfield volumes and episodic memory. T-allele carriers have larger DG and CA volumes and better episodic memory compared to C-homozygotes. Little is known, however, about KIBRA's role in the development of the brain and cognition. In a sample of children, adolescents, and young adults (N = 176, ages 5- 25 years), we replicated the adult association between KIBRA T-allele and larger DG and CA volumes but observed no relationship between KIBRA rs17070145 polymorphism and episodic memory. We noted, however, that a general cognitive performance index (IQ) differed across the allelic groups, with the lowest scores among T-homozygotes and the highest among C-homozygotes. Thus, in this developmental sample, KIBRA appears to have opposing effects on regional brain volume and cognition. These influences of KIBRA SNP may stem from associations between developmental reduction in brain volume and gains in cognitive performance-a hypothesis to be tested in longitudinal studies.

Neurophysiological mechanisms of cognition in the developing brain: Insights from intracranial EEG studies.

The quest to understand how the development of the brain supports the development of complex cognitive functions is fueled by advances in cognitive neuroscience methods. Intracranial EEG (iEEG) recorded directly from the developing human brain provides unprecedented spatial and temporal resolution for mapping the neurophysiological mechanisms supporting cognitive development. In this paper, we focus on episodic memory, the ability to remember detailed information about past experiences, which improves from childhood into adulthood. We review memory effects based on broadband spectral power and emphasize the importance of isolating narrowband oscillations from broadband activity to determine mechanisms of neural coordination within and between brain regions. We then review evidence of developmental variability in neural oscillations and present emerging evidence linking the development of neural oscillations to the development of memory. We conclude by proposing that the development of oscillations increases the precision of neural coordination and may be an essential factor underlying memory development. More broadly, we demonstrate how recording neural activity directly from the developing brain holds immense potential to advance our understanding of cognitive development.

Age-related differences in hippocampal subfield volumes across the human lifespan: A meta-analysis.

The human hippocampus (Hc) is critical for memory function across the lifespan. It is comprised of cytoarchitectonically distinct subfields: dentate gyrus (DG), cornu ammonis sectors (CA) 1-4, and subiculum, each of which may be differentially susceptible to neurodevelopmental and neurodegenerative mechanisms. Identifying age-related differences in Hc subfield volumes can provide insights into neural mechanisms of memory function across the lifespan. Limited evidence suggests that DG and CA3 volumes differ across development while other regions remain relatively stable, and studies of adulthood implicate a downward trend in all subfield volumes with prominent age effects on CA1. Due to differences in methods and limited sampling for any single study, the magnitude of age effects on Hc subfield volumes and their probable lifespan trajectories remain unclear. Here, we conducted a meta-analysis on cross-sectional studies (n = 48,278 participants, ages = 4-94 years) to examine the association between age and Hc subfield volumes in development (n = 11 studies), adulthood (n = 30 studies), and a combined lifespan sample (n = 41 studies) while adjusting estimates for sample sizes. In development, age was positively associated with DG and CA3-4 volumes, whereas in adulthood a negative association was observed with all subfield volumes. Notably, the observed age effects were not different across subfield volumes within each age group. All subfield volumes showed a nonlinear age pattern across the lifespan with DG and CA3-4 volumes showing a more distinct age trajectory as compared to the other subfields. Lastly, among all the study-level variables, only female percentage of the study sample moderated the age effect on CA1 volume: a higher female-to-male ratio in the study sample was linked to the greater negative association between age and CA1 volume. These results document that Hc subfield volumes differ as a function of age offering broader implications for constructing theoretical models of lifespan memory development.

Household socioeconomic status relates to specific hippocampal subfield volumes across development.

The hippocampus is composed of cytoarchitecturally distinct subfields that support specific memory functions. Variations in total hippocampal volume across development have been linked to socioeconomic status (SES), a proxy for access to material resources, medical care, and quality education. High childhood household SES is associated with greater cognitive abilities in adulthood. Currently, it is not known whether household SES differentially impacts specific hippocampal subfield volumes. We assessed susceptibility of subfields to variations in household SES across development in a sample of 167 typically developing 5- to 25-year-old. Bilateral cornu ammonis (CA) 1-2, combined CA3-dentate gyrus (DG), and subiculum (Sub) volumes were measured by highly reliable manual segmentation of high-resolution T2-weighted images and adjusted for intracranial volume. A summary component score of SES measures (paternal education, maternal education, and income-to-needs ratio) was used to examine variability in volumes across ages. We did not identify age-related differences in any of the regional volumes, nor did age modify SES-related effects. Controlling for age, larger volumes of CA3-DG and CA1-2 were associated with lower SES, while Sub volume was not. Overall, these findings support the specific impact of SES on CA3-DG and CA1-2 and highlight the importance of considering environmental influences on hippocampal subfield development.

Meta-Analysis of Hippocampal Volume and Episodic Memory in Preterm and Term Born Individuals.

Preterm birth (< 37 weeks gestation) has been associated with memory deficits, which has prompted investigation of possible alterations in hippocampal volume in this population. However, existing literature reports varying effects of premature birth on hippocampal volume. Specifically, it is unclear whether smaller hippocampal volume in preterm-born individuals is merely reflective of smaller total brain volume. Further, it is not clear if hippocampal volume is associated with episodic memory functioning in preterm-born individuals. Meta-analysis was used to investigate the effects of premature birth on hippocampal volume and episodic memory from early development to young adulthood (birth to 26). PubMed, PsychINFO, and Web of Science were searched for English peer-reviewed articles that included hippocampal volume of preterm and term-born individuals. Thirty articles met the inclusion criteria. Separate meta-analyses were used to evaluate standardized mean differences between preterm and term-born individuals in uncorrected and corrected hippocampal volume, as well as verbal and visual episodic memory. Both uncorrected and corrected hippocampal volume were smaller in preterm-born compared to term-born individuals. Although preterm-born individuals had lower episodic memory performance than term-born individuals, the limited number of studies only permitted a qualitative review of the association between episodic memory performance and hippocampal volume. Tested moderators included mean age, pre/post-surfactant era, birth weight, gestational age, demarcation method, magnet strength, and slice thickness. With this meta-analysis, we provide novel evidence of the effects of premature birth on hippocampal volume.

Development of the neural correlates of recollection.

Recollection of past events has been associated with the core recollection network comprising the posterior medial temporal lobe and parietal regions, as well as the medial prefrontal cortex (mPFC). The development of the brain basis for recollection is understudied. In a sample of adults (n = 22; 18-25 years) and children (n = 23; 9-13 years), the present study aimed to address this knowledge gap using a cued recall paradigm, known to elicit recollection experience. Successful recall was associated with activations in regions of the core recollection network and frontoparietal network. Adults exhibited greater successful recall activations compared with children in the precuneus and right angular gyrus. In contrast, similar levels of successful recall activations were observed in both age groups in the mPFC. Group differences were also seen in the hippocampus and lateral frontal regions. These findings suggest that the engagement of the mPFC in episodic retrieval may be relatively early maturing, whereas the contribution to episodic retrieval of more posterior regions such as the precuneus and angular gyrus undergoes more protracted maturation.

Lifespan differences in background functional connectivity of core cognitive large-scale brain networks.

Large-scale brain networks undergo functional reorganization over the course of the lifespan, with concurrent implications for cognition. Characterizing network connectivity during a task may provide complementary insight into cognitive development and aging, to that provided by resting-state. We assessed network background connectivity, which refers to connectivity that remains after task effects have been regressed out, during a visual memory-encoding task in a lifespan sample. More specifically we assessed the within- and between-network background connectivity of the default mode, salience, and frontoparietal networks. Within-network background connectivity of salience and frontoparietal networks differed between age groups, with late-life adults showing lower connectivity. We did not find an effect of age group in default mode network background connectivity, contrary to previous findings using resting-state. However, default mode between-network background connectivity with salience and frontoparietal networks was greater in mid-life and late-life adults than in younger age groups. Overall, our findings in a lifespan sample are in line with previous observations of age-related network de-differentiation. However, the lack of age effect in default mode network background connectivity suggests that background connectivity indeed represents a complementary measure to resting-state connectivity, providing a differential glance of network connectivity during a particular state.

Dissociable oscillatory theta signatures of memory formation in the developing brain.

Understanding complex human brain functions is critically informed by studying such functions during development. Here, we addressed a major gap in models of human memory by leveraging rare direct electrophysiological recordings from children and adolescents. Specifically, memory relies on interactions between the medial temporal lobe (MTL) and prefrontal cortex (PFC), and the maturation of these interactions is posited to play a key role in supporting memory development. To understand the nature of MTL-PFC interactions, we examined subdural recordings from MTL and PFC in 21 neurosurgical patients aged 5.9-20.5 years as they performed an established scene memory task. We determined signatures of memory formation by comparing the study of subsequently recognized to forgotten scenes in single trials. Results establish that MTL and PFC interact via two distinct theta mechanisms, an ∼3-Hz oscillation that supports amplitude coupling and slows down with age and an ∼7-Hz oscillation that supports phase coupling and speeds up with age. Slow and fast theta interactions immediately preceding scene onset further explained age-related differences in recognition performance. Last, with additional diffusion imaging data, we linked both functional mechanisms to the structural maturation of the cingulum tract. Our findings establish system-level dynamics of memory formation and suggest that MTL and PFC interact via increasingly dissociable mechanisms as memory improves across development.

Reliability of subsequent memory effects in children and adults: The good, the bad, and the hopeful.

Functional MRI (fMRI) is a key tool for investigating neural underpinnings of cognitive development. Yet, in recent years, the reliability of fMRI effects has come into question and with it, the feasibility of using task-based fMRI to identify developmental changes related to cognition. Here, we investigated the reliability of task-based fMRI activations with a widely used subsequent memory paradigm using two developmental samples: a cross-sectional sample (n = 85, age 8-25 years) and a test-retest sample (n = 24, one-month follow up, age 8-20 years). In the large cross-sectional sample, we found good to excellent group-level reliability when assessing activation patterns related to the encoding task and subsequent memory effects. In the test-retest sample, while group-level reliability was excellent, the consistency of activation patterns within individuals was low, particularly for subsequent memory effects. We observed consistent activation patterns in frontal, parietal, and occipital cortices, but comparatively lower test-retest reliability in subcortical regions and the hippocampus. Together, these findings highlight the limitations of interpreting task-based fMRI effects and the importance of incorporating reliability analyses in developmental studies. Leveraging larger and densely collected longitudinal data may help contribute to increased reproducibility and the accumulation of knowledge in developmental sciences.

Test-retest reliability of hippocampal subfield volumes in a developmental sample: Implications for longitudinal developmental studies.

The hippocampus (Hc) is composed of cytoarchitectonically distinct subfields: dentate gyrus (DG), cornu ammonis sectors 1-3 (CA1-3), and subiculum. Limited evidence suggests differential maturation rates across the Hc subfields. While longitudinal studies are essential in demonstrating differential development of Hc subfields, a prerequisite for interpreting meaningful longitudinal effects is establishing test-retest consistency of Hc subfield volumes measured in vivo over time. Here, we examined test-retest consistency of Hc subfield volumes measured from structural MR images in two independent developmental samples. Sample One (n = 28, ages 7-20 years, M = 12.64, SD = 3.35) and Sample Two (n = 28, ages 7-17 years, M = 11.72, SD = 2.88) underwent MRI twice with a 1-month and a 2-year delay, respectively. High-resolution PD-TSE-T2 -weighted MR images (0.4 × 0.4 × 2 mm3 ) were collected and manually traced using a longitudinal manual demarcation protocol. In both samples, we found excellent consistency of Hc subfield volumes between the two visits, assessed by two-way mixed intraclass correlation (ICC (3) single measures ≥ 0.87), and no difference between children and adolescents. The results further indicated that discrepancies between repeated measures were not related to Hc subfield volumes, or visit number. In addition to high consistency, with the applied longitudinal protocol, we detected significant variability in Hc subfield volume changes over the 2-year delay, implying high sensitivity of the method in detecting individual differences. Establishing unbiased, high longitudinal consistency of Hc subfield volume measurements optimizes statistical power of a hypothesis test and reduces standard error of the estimate, together improving external validity of the measures in constructing theoretical models of memory development.

An fMRI investigation of neural activation predicting memory formation in children with fetal alcohol spectrum disorders.

Prenatal alcohol exposure (PAE) is associated with physical anomalies, growth restriction, and a range of neurobehavioral deficits. Although declarative memory impairment has been documented extensively in individuals with fetal alcohol spectrum disorders (FASD), this cognitive process has been examined in only one functional magnetic resonance imaging (fMRI) study, and mechanisms underlying this impairment are not well understood. We used an event-related fMRI design to examine neural activations during visual scene encoding that predict subsequent scene memory in 51 right-handed children (age range = 10-14 years, M = 11.3, SD = 1.3) whose mothers had been recruited and interviewed prospectively about their alcohol use during pregnancy. Following examination by expert dysmorphologists, children were assigned to one of three FASD diagnostic groups: FAS/PFAS (nFAS = 7; nPFAS = 4), nonsyndromal heavily exposed (HE; n = 14), and Controls (n = 26). Subsequent memory was assessed in a post-scan recognition test, and subsequent memory activations were examined by contrasting activations during encoding of scenes that were subsequently remembered (hits) to those for incorrectly judged as 'new' (misses). Recognition accuracy did not differ between groups. Pooled across groups, we observed extensive bilateral subsequent memory effects in regions including the hippocampal formation, posterior parietal cortex, and occipital cortex-a pattern consistent with previous similar studies of typically developing children. Critically, in the group of children with FAS or PFAS, we observed activations in several additional regions compared to HE and Control groups. Given the absence of between-group differences in recognition accuracy, these data suggest that in achieving similar memory compared to children in the HE and Control groups, children with FAS and PFAS recruit more extensive neural resources to achieve successful memory formation.

Age moderation of the association between negative subsequent memory effects and episodic memory performance.

Negative subsequent memory effects in functional MRI studies of memory formation have been linked to individual differences in memory performance, yet the effect of age on this association is currently unclear. To provide insight into the brain systems related to memory across the lifespan, we examined functional neuroimaging data acquired during episodic memory formation and behavioral performance from a memory recognition task in a sample of 109 participants, including three developmental age groups (8-12, 13-17, 18-25 year-olds) and one additional group of older adults (55-85 year-olds). Young adults showed the highest memory performance and strongest negative subsequent memory effects, while older adults showed reduced negative subsequent memory effects relative to young adults. Across the sample, negative subsequent memory effects were associated with better memory performance, and there was a significant interaction between negative subsequent memory effects and memory performance by age group. Posthoc analyses revealed that this moderation effect was driven by a stronger association between negative subsequent memory effects and memory performance in young adults than children, and that neither children nor older adults showed a significant association. These findings suggest that negative subsequent memory effects may differentially support memory performance across a lifespan trajectory characterized by developmental maturation and support further investigation of this effect in aging.

Microstructure of Human Corpus Callosum across the Lifespan: Regional Variations in Axon Caliber, Density, and Myelin Content.

The myeloarchitecture of the corpus callosum (CC) is characterized as a mosaic of distinct differences in fiber density of small- and large-diameter axons along the anterior-posterior axis; however, regional and age differences across the lifespan are not fully understood. Using multiecho T2 magnetic resonance imaging combined with multi-T2 fitting, the myelin water fraction (MWF) and geometric-mean of the intra-/extracellular water T2 (geomT2IEW) in 395 individuals (7-85 years; 41% males) were examined. The approach was validated where regional patterns along the CC closely resembled the histology; MWF matched mean axon diameter and geomT2IEW mirrored the density of large-caliber axons. Across the lifespan, MWF exhibited a quadratic association with age in all 10 CC regions with evidence of a positive linear MWF-age relationship among younger participants and minimal age differences in the remainder of the lifespan. Regarding geomT2IEW, a significant linear age × region interaction reflected positive linear age dependence mostly prominent in the regions with the highest density of small-caliber fibers-genu and splenium. In all, these two indicators characterize distinct attributes that are consistent with histology, which is a first. In addition, these results conform to rapid developmental progression of CC myelination leveling in middle age as well as age-related degradation of axon sheaths in older adults.

Direct brain recordings reveal occipital cortex involvement in memory development.

Processing of low-level visual information shows robust developmental gains through childhood and adolescence. However, it is unknown whether low-level visual processing in the occipital cortex supports age-related gains in memory for complex visual stimuli. Here, we examined occipital alpha activity during visual scene encoding in 24 children and adolescents, aged 6.2-20.5 years, who performed a subsequent memory task while undergoing electrocorticographic recording. Scenes were classified as high- or low-complexity by the number of unique object categories depicted. We found that recognition of high-complexity, but not low-complexity, scenes increased with age. Age was associated with decreased alpha power and increased instantaneous alpha frequency during the encoding of subsequently recognized high- compared to low-complexity scenes. Critically, decreased alpha power predicted improved recognition of high-complexity scenes in adolescents. These findings demonstrate how the functional maturation of the occipital cortex supports the development of memory for complex visual scenes.

Differential Functional Connectivity in Anterior and Posterior Hippocampus Supporting the Development of Memory Formation.

Neuroimaging evidence suggests that the development of the hippocampus, a brain structure critical for memory function, contributes to the improvements of episodic memory between middle childhood to adulthood. However, investigations on age differences in hippocampal activation and functional connectivity and their contributions to the development of memory have yielded mixed results. Given the known structural and functional heterogeneity along the long axis of the hippocampus, we investigated age differences in the activation and functional connectivity in hippocampal subregions with a cross-sectional sample of 96 participants ages 8-25 years. We found that anterior and posterior hippocampus supported memory formation, and there was overall stability in memory-related hippocampal activation with age. Without taking account of memory outcome, direct contrast between subregions showed higher functional connectivity of anterior, compared to the posterior hippocampus, with regions in the inferior frontal and lateral temporal lobes, and higher functional connectivity of posterior, compared to the anterior hippocampus, with regions in the medial and superior frontal, inferior parietal, and occipital lobes. A direct contrast between the memory-related connectivity patterns of anterior and posterior hippocampus identified a region in the medial frontal cortex, with which anterior and posterior hippocampus was differentially functionally connected. Finally, we identified age differences in memory-related differential hippocampal functional connectivity with several frontal and visual/sensory cortices, underscoring the importance of examining age differences in the patterns of hippocampal connectivity. Moreover, the specific patterns of differential anterior and posterior functional connectivity indicate an increase in the functional specialization along the long axis of the hippocampus and a dynamic shift in hippocampal connectivity patterns that supports memory development.

Cumulative Antenatal Risk and Kindergarten Readiness in Preterm-Born Preschoolers.

A suboptimal intrauterine environment is thought to increase the probability of deviation from the typical neurodevelopmental trajectory, potentially contributing to the etiology of learning disorders. Yet the cumulative influence of individual antenatal risk factors on emergent learning skills has not been sufficiently examined. We sought to determine whether antenatal complications, in aggregate, are a source of variability in preschoolers' kindergarten readiness, and whether specific classes of antenatal risk play a prominent role. We recruited 160 preschoolers (85 girls; ages 3-4 years), born ≤336/7 weeks' gestation, and reviewed their hospitalization records. Kindergarten readiness skills were assessed with standardized intellectual, oral-language, prewriting, and prenumeracy tasks. Cumulative antenatal risk was operationalized as the sum of complications identified out of nine common risks. These were also grouped into four classes in follow-up analyses: complications associated with intra-amniotic infection, placental insufficiency, endocrine dysfunction, and uteroplacental bleeding. Linear mixed model analyses, adjusting for sociodemographic and medical background characteristics (socioeconomic status, sex, gestational age, and sum of perinatal complications) revealed an inverse relationship between the sum of antenatal complications and performance in three domains: intelligence, language, and prenumeracy (p = 0.003, 0.002, 0.005, respectively). Each of the four classes of antenatal risk accounted for little variance, yet together they explained 10.5%, 9.8%, and 8.4% of the variance in the cognitive, literacy, and numeracy readiness domains, respectively. We conclude that an increase in the co-occurrence of antenatal complications is moderately linked to poorer kindergarten readiness skills even after statistical adjustment for perinatal risk.

Progress update from the hippocampal subfields group.

INTRODUCTION: Heterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence. METHODS: Our international working group, funded by the EU Joint Programme-Neurodegenerative Disease Research (JPND), is working toward the production of a reliable, validated, harmonized protocol for segmentation of medial temporal lobe regions. The working group uses a novel postmortem data set and online consensus procedures to ensure validity and facilitate adoption. RESULTS: This progress report describes the initial results and milestones that we have achieved to date, including the development of a draft protocol and results from the initial reliability tests and consensus procedures. DISCUSSION: A harmonized protocol will enable the standardization of segmentation methods across laboratories interested in medial temporal lobe research worldwide.

Memory and the developing brain: From description to explanation with innovation in methods.

Recent advances in human cognitive neuroscience show great promise in extending our understanding of the neural basis of memory development. We briefly review the current state of knowledge, highlighting that most work has focused on describing the neural correlates of memory in cross-sectional studies. We then delineate three examples of the application of innovative methods in addressing questions that go beyond description, towards a mechanistic understanding of memory development. First, structural brain imaging and the harmonization of measurements across laboratories may uncover ways in which the maturation of the brain constrains the development of specific aspects of memory. Second, longitudinal designs and sophisticated modeling of the data may identify age-driven changes and the factors that determine individual developmental trajectories. Third, recording memory-related activity directly from the developing brain presents an unprecedented opportunity to examine how distinct brain structures support memory in real time. Finally, the growing prevalence of data sharing offers additional means to tackle questions that demand large-scale datasets, ambitious designs, and access to rare samples. We propose that the use of such innovative methods will move our understanding of memory development from a focus on describing trends to explaining the causal factors that shape behavior.