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.

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.

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.

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.

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.

Age-associated increase in mnemonic strategy use is linked to prefrontal cortex development.

Memory functioning undergoes dynamic changes between childhood and adulthood. Spontaneous use of elaborative strategies, which can enhance the recall of information, expands with age and contributes to age-associated improvement in memory functioning. Findings from lesion and neuroimaging studies suggest that the ability to use elaborative strategies is dependent upon intact functioning of the prefrontal cortex (PFC), particularly the dorsolateral PFC region. Because the PFC undergoes protracted maturation, we examined whether age difference in the structure of the PFC is correlated with age-associated increase in strategy use. Here, we investigated the relationship between PFC volume and spontaneous strategy use in a sample of 120 participants aged 5-25 years. We assessed semantic clustering during recall with a standardized word-list recall task (California Verbal Learning Task children's version, CVLT-C) and computed PFC regional volumes from participants' structural brain images. We observed an age-associated increase in the use of semantic clustering and an age-associated decrease in volumes of the PFC. Further, we found that smaller PFC volume was linked to increased use of semantic clustering. Importantly, the volume of the right dorsolateral PFC partially explained the relation between age and the use of semantic clustering. These findings suggest that PFC maturation supports the development of strategy use and lends further support for the notion that brain-behavior relations change across development.

Socioeconomic status and hippocampal volume in children and young adults.

An individual's socioeconomic status (SES) is often viewed as a proxy for a host of environmental influences. SES disparities have been linked to variance in brain structures particularly the hippocampus, a neural substrate of learning and memory. However, it is unclear whether the association between SES and hippocampal volume is similar in children and adults. We investigated the relationship between hippocampal volume and SES in a group of children (n = 31, age 8-12 years) and a group of young adults (n = 32, age 18-25 years). SES was assessed with four indicators that loaded on a single factor, therefore a composite SES scores was used in the main analyses. Hippocampal volume was measured using manual demarcation on high resolution structural images. SES was associated with hippocampal volume in the children, but not in adults, suggesting that in childhood, but not adulthood, SES-related environmental factors influence hippocampal volume. In addition, hippocampal volume, but not SES, was associated with scores on a memory task, suggesting that net effects of postnatal environmental factors, captured by SES, are more distal determinants of memory performance than hippocampal volume. Longitudinal investigation of the association between SES, hippocampal volume and cognitive functioning may further our understanding of the putative neural mechanisms underlying SES-related environmental effects on cognitive development.

Optimization and validation of automated hippocampal subfield segmentation across the lifespan.

Automated segmentation of hippocampal (HC) subfields from magnetic resonance imaging (MRI) is gaining popularity, but automated procedures that afford high speed and reproducibility have yet to be extensively validated against the standard, manual morphometry. We evaluated the concurrent validity of an automated method for hippocampal subfields segmentation (automated segmentation of hippocampal subfields, ASHS; Yushkevich et al., ) using a customized atlas of the HC body, with manual morphometry as a standard. We built a series of customized atlases comprising the entorhinal cortex (ERC) and subfields of the HC body from manually segmented images, and evaluated the correspondence of automated segmentations with manual morphometry. In samples with age ranges of 6-24 and 62-79 years, 20 participants each, we obtained validity coefficients (intraclass correlations, ICC) and spatial overlap measures (dice similarity coefficient) that varied substantially across subfields. Anterior and posterior HC body evidenced the greatest discrepancies between automated and manual segmentations. Adding anterior and posterior slices for atlas creation and truncating automated output to the ranges manually defined by multiple neuroanatomical landmarks substantially improved the validity of automated segmentation, yielding ICC above 0.90 for all subfields and alleviating systematic bias. We cross-validated the developed atlas on an independent sample of 30 healthy adults (age 31-84) and obtained good to excellent agreement: ICC (2) = 0.70-0.92. Thus, with described customization steps implemented by experts trained in MRI neuroanatomy, ASHS shows excellent concurrent validity, and can become a promising method for studying age-related changes in HC subfield volumes.

Propofol protects against blood-spinal cord barrier disruption induced by ischemia/reperfusion injury.

Propofol has been shown to exert neuroprotective effects on the injured spinal cord. However, the effect of propofol on the blood-spinal cord barrier (BSCB) after ischemia/reperfusion injury (IRI) is poorly understood. Therefore, we investigated whether propofol could maintain the integrity of the BSCB. Spinal cord IRI (SCIRI) was induced in rabbits by infrarenal aortic occlusion for 30 minutes. Propofol, 30 mg/kg, was intravenously infused 10 minutes before aortic clamping as well as at the onset of reperfusion. Then, 48 hours later, we performed histological and mRNA/protein analyses of the spinal cord. Propofol decreased histological damage to the spinal cord, attenuated the reduction in BSCB permeability, downregulated the mRNA and protein expression levels of matrix metalloprotease-9 (MMP-9) and nuclear factor-κB (NF-κB), and upregulated the protein expression levels of occludin and claudin-5. Our findings suggest that propofol helps maintain BSCB integrity after SCIRI by reducing MMP-9 expression, by inhibiting the NF-κB signaling pathway, and by maintaining expression of tight junction proteins.

Targeting the blood-spinal cord barrier: A therapeutic approach to spinal cord protection against ischemia-reperfusion injury.

One of the principal functions of physical barriers between the blood and central nervous system protects system (i.e., blood brain barrier and blood-spinal cord barrier) is the protection from toxic and pathogenic agents in the blood. Disruption of blood-spinal cord barrier (BSCB) plays a key role in spinal cord ischemia-reperfusion injury (SCIRI). Following SCIRI, the permeability of the BSCB increases. Maintaining the integrity of the BSCB alleviates the spinal cord injury after spinal cord ischemia. This review summarizes current knowledge of the structure and function of the BSCB and its changes following SCIRI, as well as the prevention and cure of SCIRI and the role of the BSCB.

Advance in spinal cord ischemia reperfusion injury: Blood-spinal cord barrier and remote ischemic preconditioning.

The blood-spinal cord barrier (BSCB) is the physiological and metabolic substance diffusion barrier between blood circulation and spinal cord tissues. This barrier plays a vital role in maintaining the microenvironment stability of the spinal cord. When the spinal cord is subjected to ischemia/reperfusion (I/R) injury, the structure and function of the BSCB is disrupted, further destroying the spinal cord homeostasis and ultimately leading to neurological deficit. Remote ischemic preconditioning (RIPC) is an approach in which interspersed cycles of preconditioning ischemia is followed by reperfusion to tissues/organs to protect the distant target tissues/organs against subsequent lethal ischemic injuries. RIPC is an innovation of the treatment strategies that protect the organ from I/R injury. In this study, we review the morphological structure and function of the BSCB, the injury mechanism of BSCB resulting from spinal cord I/R, and the effect of RIPC on it.

The influence of input and output modality on following instructions in working memory.

Following instructions is an important component of learning and has been shown to rely on working memory. This study examined the ability to follow instructions within working memory under varying input and output modalities. In Experiment 1, participants heard, read, or viewed demonstration of short sequences of instructions, and recalled either by oral repetition or physical enactment. There was a significant main effect of encoding, showing superior recall performance when instructions were demonstrated relative to spoken or written presentation. Experiment 2 examined whether recall is further improved when instructions are presented both in spoken and demonstrated form, relative to single modality presentation. The advantage for demonstration over spoken instructions was replicated, and dual input was superior to spoken instructions. However, dual input did not bring extra benefit compared to demonstration of instructions. We also observed a significant enacted-retrieval recall advantage. These findings suggest effects of both input and output modalities on the ability to remember and follow instructions in working memory. Outcomes substantially inform the underexplored but important new area of action-based working memory and its links to embodied cognition, with implications for pedagogic practice.

Rostral medial prefrontal dysfunctions and consummatory pleasure in schizophrenia: a meta-analysis of functional imaging studies.

A large number of imaging studies have examined the neural correlates of consummatory pleasure and anticipatory pleasure in schizophrenia, but the brain regions where schizophrenia patients consistently demonstrate dysfunctions remain unclear. We performed a series of meta-analyses on imaging studies to delineate the regions associated with consummatory and anticipatory pleasure dysfunctions in schizophrenia. Nineteen functional magnetic resonance imaging or positron emission tomography studies using whole brain analysis were identified through a literature search (PubMed and EBSCO; January 1990-February 2014). Activation likelihood estimation was performed using the GingerALE software. The clusters identified were obtained after controlling for the false discovery rate at p<0.05 and applying a minimum cluster size of 200 mm(3). It was found that schizophrenia patients exhibited decreased activation mainly in the rostral medial prefrontal cortex (rmPFC), the right parahippocampus/amygala, and other limbic regions (e.g., the subgenual anterior cingulate cortex, the putamen, and the medial globus pallidus) when consummating pleasure. Task instructions (feeling vs. stimuli) were differentially related to medial prefrontal dysfunction in schizophrenia. When patients anticipated pleasure, reduced activation in the left putamen was observed, despite the limited number of studies. Our findings suggest that the medial prefrontal cortex and limbic regions may play an important role in neural dysfunction underlying deficits in consummatory pleasure in schizophrenia.

A reliable and valid method for manual demarcation of hippocampal head, body, and tail.

There is a growing interest in characterizing functional specialization along the long axis of the hippocampus in humans. Variability in volumetry along the long axis of the hippocampus may be of functional relevance in human development, and in a number of clinical populations. However, there is a lack of consistent definitions for measurements of regional volumetry along the hippocampal long axis. Moreover, there is lack of consistent reliability standards of these measures. Here we describe a protocol for manual demarcation of hippocampal head, body, and tail. The definitions emphasize anatomical landmarks that agree with the extant literature and are visible in children and adults alike. Using this protocol we achieved high reliability of all volumetric measures. We further demonstrate that the protocol can be applied to T2-weighted images optimized for high-resolution scanning of the hippocampus, as well as a more standard T1-weighted image sequence. Third, the protocol is sensitive to detect individual differences in subregion volumes in normally developing children (N=81; ages 8-25 years). This protocol may be of use for researchers studying the hippocampus across the lifespan and in diverse clinical populations.

Protective effect of etomidate on spinal cord ischemia-reperfusion injury induced by aortic occlusion in rabbits.

BACKGROUND: We conducted a randomized controlled study on the neuroprotective effect of a commonly used anesthetic, etomidate, in an ischemia-reperfusion (IR) injury rabbit model. METHODS: We studied 24 white adult Japanese rabbits at the animal facility at the Medical College of Wuhan University. Rabbits were randomly assigned into a sham-operation group (group I), an IR group (group II), and an etomidate-treated IR group (group III). Rabbits in groups II and III were subjected to 45 min of infrarenal aortic cross-clamping to induce spinal cord ischemia, while group I rabbits received the sham operation as a control. Following an initial single-dose intravenous injection at 0.6 mg/kg 10 min before aortic clamping, etomidate was infused intravenously at 3mg/(kg . hr) in group III rabbits until unclamping, while 0.9% saline was given as the control in group II. RESULTS: Changes in neurological function scores, histopathology, electromyography, malondialdehyde levels, superoxide dismutase activities, and the concentrations of Ca(2+), Mg(2+), Cu(2+), and Zn(2+) ions were measured. Compared with the sham-operation group, group II showed significant IR injury-associated changes in all parameters evaluated (p<0.01), whereas these unfavorable changes were significantly reversed in etomidate-treated animals (p<0.05 or p<0.01). No significant differences were observed between group I and group III animals in all parameters. CONCLUSION: Etomidate displayed a potent neuroprotective effect against IR-induced spinal cord injuries. We propose that this effect may be associated with the ability of etomidate to enhance the activities of endogenous antioxidants and maintain the ion balance in IR-affected tissues.

Transplanted neonatal cardiomyocytes as a potential biological pacemaker in pigs with complete atrioventricular block.

BACKGROUND: Sinus node dysfunction and severe heart block are major indications for electronic pacemaker implantation. The aim of the present study was to investigate the feasibility of an alternative approach by using spontaneously excitable cell grafts to serve as a biological pacemaker. METHODS: Enzymatically isolated neonatal atrial cardiomyocytes (including sinus nodal cells) were grafted into the free wall of the left ventricle of 5 male pigs. In the control group (n = 4), the medium was used for injecting. Three weeks after the transplantation the pigs underwent catheter ablation of the atrioventricular (AV) node. Microelectrode technique was used to record the transmembrane action potential of myocytes from cell- and medium-injected preparations. Immunohistochemistry was used to verify the grafted cells and the establishment of the gap junctions between donor and host cardiomyocytes. RESULTS: After the creation of complete AV-block, a higher average idioventricular rate was observed in cell-grafted pigs than that in control pigs (89 +/- 13 vs. 30 +/- 11 bpm, P < 0.05). Administering isoprenaline caused a significant increase in the idioventricular rate from 89 +/- 13 to 120 +/- 18 bpm in the cell-grafted animals (P < 0.05). Microelectrode recordings showed that the spontaneously beating rate was significantly higher in the cell-implanted than that in the control preparations (82 +/- 17 vs. 33 +/- 13 bpm, P < 0.05). Furthermore, the immunofluorescence microscopy identified the DAPI-labeled donor cells, and the connexin-43 and N-cadherin positive junctions between them and host cardiomyocytes. CONCLUSION: Grafted neonatal atrial cardiomyocytes are able to survive and integrate into the host myocardium, and show a pacing function that can be modulated by autonomic agents.