Postnatal Development of Glutamate and GABA Transcript Expression in Monkey Visual, Parietal, and Prefrontal Cortices.

Visuospatial working memory (vsWM) requires information transfer among multiple cortical regions, from primary visual (V1) to prefrontal (PFC) cortices. This information is conveyed via layer 3 glutamatergic neurons whose activity is regulated by gamma-aminobutyric acid (GABA)ergic interneurons. In layer 3 of adult human neocortex, molecular markers of glutamate neurotransmission were lowest in V1 and highest in PFC, whereas GABA markers had the reverse pattern. Here, we asked if these opposite V1-visual association cortex (V2)-posterior parietal cortex (PPC)-PFC gradients across the vsWM network are present in layer 3 of monkey neocortex, when they are established during postnatal development, and if they are specific to this layer. We quantified transcript levels of glutamate and GABA markers in layers 3 and 6 of four vsWM cortical regions in a postnatal developmental series of 30 macaque monkeys. In adult monkeys, glutamate transcript levels in layer 3 increased across V1-V2-PPC-PFC regions, whereas GABA transcripts showed the opposite V1-V2-PPC-PFC gradient. Glutamate transcripts established adult-like expression patterns earlier during postnatal development than GABA transcripts. These V1-V2-PPC-PFC gradients and developmental patterns were less evident in layer 6. These findings demonstrate that expression of glutamate and GABA transcripts differs across cortical regions and layers during postnatal development, revealing potential molecular substrates for vsWM functional maturation.

Neuron-derived VEGF contributes to cortical and hippocampal development independently of VEGFR1/2-mediated neurotrophism.

Vascular endothelial growth factor (VEGF) is a potent mitogen critical for angiogenesis and organogenesis. Deletion or inhibition of VEGF during development not only profoundly suppresses vascular outgrowth, but significantly affects the development and function of various organs. In the brain, VEGF is thought to not only promote vascular growth, but also directly act on neurons as a neurotrophic factor by activating VEGF receptors. In the present study, we demonstrated that deletion of VEGF using hGfap-Cre line, which recombines genes specifically in cortical and hippocampal neurons, severely impaired brain organization and vascularization of these regions. The mutant mice had motor deficits, with lethality around the time of weaning. Multiple reporter lines indicated that VEGF was highly expressed in neurons, but that its cognate receptors, VEGFR1 and 2 were exclusive to endothelial cells in the brain. In accordance, mice lacking neuronal VEGFR1 and VEGFR2 did not exhibit neuronal deformities or lethality. Taken together, our data suggest that neuron-derived VEGF contributes to cortical and hippocampal development likely through angiogenesis independently of direct neurotrophic effects mediated by VEGFR1 and 2.

The longitudinal relationship between BOLD signal variability changes and white matter maturation during early childhood.

Intra-individual transient temporal fluctuations in brain signal, as measured by fMRI blood oxygenation level dependent (BOLD) variability, is increasingly considered an important signal rather than measurement noise. Evidence from computational and cognitive neuroscience suggests that signal variability is a good proxy-measure of brain functional integrity and information processing capacity. Here, we sought to explore across-participant and longitudinal relationships between BOLD variability, age, and white matter structure in early childhood. We measured standard deviation of BOLD signal, total white matter volume, global fractional anisotropy (FA) and mean diffusivity (MD) during passive movie viewing in a sample of healthy children (aged 2-8 years; N = 83). We investigated how age and white matter development related to changes in BOLD variability both across- and within-participants. Our across-participant analyses using behavioural partial least squares (bPLS) revealed that the influence of age and white matter maturation on BOLD variability was highly interrelated. BOLD variability increased in widespread frontal, temporal and parietal regions, and decreased in the hippocampus and parahippocampal gyrus with age and white matter development. Our longitudinal analyses using linear mixed effects modelling revealed significant associations between BOLD variability, age and white matter microstructure. Analyses using artificial neural networks demonstrated that BOLD variability and white matter micro and macro-structure at earlier ages were strong predictors of BOLD variability at later ages. By characterizing the across-participant and longitudinal features of the association between BOLD variability and white matter micro- and macrostructure in early childhood, our results provide a novel perspective to understand structure-function relationships in the developing brain.

Preterm birth leads to impaired rich-club organization and fronto-paralimbic/limbic structural connectivity in newborns.

Prematurity disrupts brain development during a critical period of brain growth and organization and is known to be associated with an increased risk of neurodevelopmental impairments. Investigating whole-brain structural connectivity alterations accompanying preterm birth may provide a better comprehension of the neurobiological mechanisms related to the later neurocognitive deficits observed in this population. Using a connectome approach, we aimed to study the impact of prematurity on neonatal whole-brain structural network organization at term-equivalent age. In this cohort study, twenty-four very preterm infants at term-equivalent age (VPT-TEA) and fourteen full-term (FT) newborns underwent a brain MRI exam at term age, comprising T2-weighted imaging and diffusion MRI, used to reconstruct brain connectomes by applying probabilistic constrained spherical deconvolution whole-brain tractography. The topological properties of brain networks were quantified through a graph-theoretical approach. Furthermore, edge-wise connectivity strength was compared between groups. Overall, VPT-TEA infants' brain networks evidenced increased segregation and decreased integration capacity, revealed by an increased clustering coefficient, increased modularity, increased characteristic path length, decreased global efficiency and diminished rich-club coefficient. Furthermore, in comparison to FT, VPT-TEA infants had decreased connectivity strength in various cortico-cortical, cortico-subcortical and intra-subcortical networks, the majority of them being intra-hemispheric fronto-paralimbic and fronto-limbic. Inter-hemispheric connectivity was also decreased in VPT-TEA infants, namely through connections linking to the left precuneus or left dorsal cingulate gyrus - two regions that were found to be hubs in FT but not in VPT-TEA infants. Moreover, posterior regions from Default-Mode-Network (DMN), namely precuneus and posterior cingulate gyrus, had decreased structural connectivity in VPT-TEA group. Our finding that VPT-TEA infants' brain networks displayed increased modularity, weakened rich-club connectivity and diminished global efficiency compared to FT infants suggests a delayed transition from a local architecture, focused on short-range connections, to a more distributed architecture with efficient long-range connections in those infants. The disruption of connectivity in fronto-paralimbic/limbic and posterior DMN regions might underlie the behavioral and social cognition difficulties previously reported in the preterm population.

Modular segregation of task-dependent brain networks contributes to the development of executive function in children.

Executive function (EF) refers as to a set of high-level cognitive abilities that are critical to many aspects of daily life. Despite its importance in human daily life, the neural networks responsible for the development of EF in childhood are not well understood. The present study thus aimed to examine the development of task-dependent brain network organization and its relationship to age-related improvements in EF. To address this issue, we recruited eighty-eight Chinese children ranging in age from 7 to 12 years old, and collected their functional magnetic resonance imaging (fMRI) data when they performed an EF task. By utilizing graph theory, we found that the task-dependent brain network modules became increasingly segregated with age. Specifically, the intra-module connections within the default-mode network (DMN), frontal-parietal network (FPN) and sensorimotor network (SMN) increased significantly with age. In contrast, the inter-module connections of the visual network to both the FPN/SMN decreased significantly with age. Most importantly, modular segregation of the FPN significantly mediated the relationship between age and EF performance. These findings add to our growing understanding of how development changes in task-dependent brain network organization support vast behavioral improvements in EF observed during childhood.

The Lifespan Trajectory of the Encoding-Retrieval Flip: A Multimodal Examination of Medial Parietal Cortex Contributions to Episodic Memory.

The formation of episodic memories is associated with deactivation during encoding and activation during retrieval in the posteromedial cortex (PMC). We hypothesized that the encoding/retrieval (E/R) flip is a critical component of episodic memory across the lifespan because structural and metabolic changes in the PMC coincide with the fine tuning of the episodic memory system in development and the reductions of memory performance in aging. The aims of the present study were, first, to describe lifespan trajectories of PMC encoding and retrieval activity in 270 human participants (167 females) from 6 to 80 years of age. Our second goal was to construct a model for episodic memory development in which contributions from brain activity, cortical thickness (CT), and structural connectivity are accounted for. We found that modulation of neural activity in response to memory encoding and retrieval demands was not fully developed until adolescence and decreased from adulthood through old age. The magnitude of the E/R flip was related to source memory and 55% of the age-related variance in source memory performance during childhood and adolescence could be accounted for by the E/R flip, CT, and mean diffusivity together. However, only CT and the E/R flip provided unique contributions with which to explain memory performance. The results suggest that neural dynamics in the PMC is related to the development of episodic memory during childhood and adolescence. The similar trajectories of the E/R flip and episodic memory emergence and decline through development and aging further suggests that a lifelong relationship exists.SIGNIFICANCE STATEMENT Modulation of neural activity in the posteromedial cortex (PMC) in response to memory encoding/retrieval (E/R) demands (E/R flip) does not reach its peak until adolescence and decreases from adulthood through old age. The magnitude of the E/R flip is related to source memory and 55% of the age-related variance in source memory performance during childhood and adolescence can be accounted for by the E/R flip and brain structure together. The results suggest that neural dynamics in the PMC is related to the development of episodic memory function during childhood and adolescence and the similar trajectories of the E/R flip and episodic memory performance through development and aging suggests that a lifelong relationship exists.

Functional Organization of the Temporal-Parietal Junction for Theory of Mind in Preverbal Infants: A Near-Infrared Spectroscopy Study.

Successful human social life requires imagining what others believe or think to understand and predict behavior. This ability, often referred to as theory of mind (ToM), reliably engages a specialized network of temporal and prefrontal brain regions in older children and adults, including selective recruitment of the temporal-parietal junction (TPJ). To date, how and when this specialized brain organization for ToM arises is unknown due to limitations in functional neuroimaging at younger ages. Here, we used the emerging technique of functional near-infrared spectroscopy to measure the functional brain response across parietal, temporal, and prefrontal regions in 7-month-old male and female infants as they viewed different video scenarios of a person searching for a hidden object. Over different conditions, we manipulated whether the person held an accurate (true) or inaccurate (false) belief about the location of the hidden object in the videos. In two separate experiments, we observed that activity from the TPJ, but not other temporal and prefrontal regions, spontaneously tracked with the beliefs of the other person, responding more during scenarios when the other person's belief regarding the location of the object was false compared with scenarios when her belief was true. These results mirror those obtained with adults to show that the TPJ already shows some functional organization relevant to high-level social cognition by around 7 months of age. Furthermore, these results suggest that infants may draw on similar core mechanisms to implicitly track beliefs, as adults do when reasoning explicitly about them.SIGNIFICANCE STATEMENT Humans selectively engage a network of brain regions, including the temporal-parietal junction (TPJ), to track what others think, an ability referred to as theory of mind. How and when this specialized brain organization for high-level social cognition arises is unknown. Using the emerging technique of near-infrared spectroscopy with 7-month-old infants, we observed that activity of the TPJ, but not other temporal and frontal regions, distinguished between scenarios when another person's belief about the location of the object was false compared with scenarios when the belief was true. These results suggest that a basic neural architecture to understand and predict the actions of others based on their beliefs may be present from the first year of life.

Developmental Maturation of the Precuneus as a Functional Core of the Default Mode Network.

Efforts to map the functional architecture of the developing human brain have shown that connectivity between and within functional neural networks changes from childhood to adulthood. Although prior work has established that the adult precuneus distinctively modifies its connectivity during task versus rest states [Utevsky, A. V., Smith, D. V., & Huettel, S. A. Precuneus is a functional core of the default-mode network. Journal of Neuroscience, 34, 932-940, 2014], it remains unknown how these connectivity patterns emerge over development. Here, we use fMRI data collected at two longitudinal time points from over 250 participants between the ages of 8 and 26 years engaging in two cognitive tasks and a resting-state scan. By applying independent component analysis to both task and rest data, we identified three canonical networks of interest-the rest-based default mode network and the task-based left and right frontoparietal networks (LFPN and RFPN, respectively)-which we explored for developmental changes using dual regression analyses. We found systematic state-dependent functional connectivity in the precuneus, such that engaging in a task (compared with rest) resulted in greater precuneus-LFPN and precuneus-RFPN connectivity, whereas being at rest (compared with task) resulted in greater precuneus-default mode network connectivity. These cross-sectional results replicated across both tasks and at both developmental time points. Finally, we used longitudinal mixed models to show that the degree to which precuneus distinguishes between task and rest states increases with age, due to age-related increasing segregation between precuneus and LFPN at rest. Our results highlight the distinct role of the precuneus in tracking processing state, in a manner that is both present throughout and strengthened across development.

Charting shared developmental trajectories of cortical thickness and structural connectivity in childhood and adolescence.

The cortex is organised into broadly hierarchical functional systems with distinct neuroanatomical characteristics reflected by macroscopic measures of cortical morphology. Diffusion-weighted magnetic resonance imaging allows the delineation of areal connectivity, changes to which reflect the ongoing maturation of white matter tracts. These developmental processes are intrinsically linked with timing coincident with the development of cognitive function. In this study, we use a data-driven multivariate approach, nonnegative matrix factorisation, to define cortical regions that co-vary together across a large paediatric cohort (n = 456) and are associated with specific subnetworks of cortical connectivity. We find that age between 3 and 21 years is associated with accelerated cortical thinning in frontoparietal regions, whereas relative thinning of primary motor and sensory regions is slower. Together, the subject-specific weights of the derived set of cortical components can be combined to predict chronological age. Structural connectivity networks reveal a relative increase in strength in connection within, as opposed to between hemispheres that vary in line with cortical changes. We confirm our findings in an independent sample.

The developmental neural substrates of item and serial order components of verbal working memory.

Behavioral and developmental studies have made a critical distinction between item and serial order processing components of verbal working memory (WM). This functional magnetic resonance imaging (fMRI) study determined the extent to which item and serial order WM components are characterized by specialized neural networks already in young children or whether this specialization emerges at a later developmental stage. Total of 59 children aged 7-12 years performed item and serial order short-term probe recognition tasks in an fMRI experiment. While a left frontoparietal network was recruited in both item and serial order WM conditions, the right intraparietal sulcus was selectively involved in the serial order WM condition. This neural segregation was modulated by age, with both networks becoming increasingly separated in older children. Our results indicate a progressive specialization of networks involved in item and order WM processes during cognitive development.

Aspects of excitatory/inhibitory synapses in multiple brain regions are correlated with levels of brain-derived neurotrophic factor/neurotrophin-3.

Appropriate synapse formation during development is necessary for normal brain function, and synapse impairment is often associated with brain dysfunction. Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are key factors in regulating synaptic development. We previously reported that BDNF/NT-3 secretion was enhanced by calcium-dependent activator protein for secretion 2 (CADPS2). Although BDNF/NT-3 and CADPS2 are co-expressed in various brain regions, the effect of Cadps2-deficiency on brain region-specific BDNF/NT-3 levels and synaptic development remains elusive. Here, we show developmental changes of BDNF/NT-3 levels and we assess disruption of excitatory/inhibitory synapses in multiple brain regions (cerebellum, hypothalamus, striatum, hippocampus, parietal cortex and prefrontal cortex) of Cadps2 knockout (KO) mice compared with wild-type (WT) mice. Compared with WT, BDNF levels in KO mice were reduced in young/adult hippocampus, but increased in young hypothalamus, while NT-3 levels were reduced in adult cerebellum and young hippocampus, but increased in adult parietal cortex. Immunofluorescence of vGluT1, an excitatory synapse marker, and vGAT, an inhibitory synapse marker, in adult KO showed that vGluT1 was higher in the cerebellum and parietal cortex but lower in the hippocampus, whereas vGAT was lower in the hippocampus and parietal cortex compared with WT. Immunolabeling for both vGluT1 and vGAT was increased in the parietal cortex but vGAT was decreased in the cerebellum in adult KO compared with WT. These data suggest that CADPS2-mediated secretion of BDNF/NT-3 may be involved in development and maturation of synapses and in the balance between inhibitory and excitatory synapses.

The relationship between biological and psychosocial risk factors and resting-state functional connectivity in 2-month-old Bangladeshi infants: A feasibility and pilot study.

Childhood poverty has been associated with structural and functional alterations in the developing brain. However, poverty does not alter brain development directly, but acts through associated biological or psychosocial risk factors (e.g. malnutrition, family conflict). Yet few studies have investigated risk factors in the context of infant neurodevelopment, and none have done so in low-resource settings such as Bangladesh, where children are exposed to multiple, severe biological and psychosocial hazards. In this feasibility and pilot study, usable resting-state fMRI data were acquired in infants from extremely poor (n = 16) and (relatively) more affluent (n = 16) families in Dhaka, Bangladesh. Whole-brain intrinsic functional connectivity (iFC) was estimated using bilateral seeds in the amygdala, where iFC has shown susceptibility to early life stress, and in sensory areas, which have exhibited less susceptibility to early life hazards. Biological and psychosocial risk factors were examined for associations with iFC. Three resting-state networks were identified in within-group brain maps: medial temporal/striatal, visual, and auditory networks. Infants from extremely poor families compared with those from more affluent families exhibited greater (i.e. less negative) iFC in precuneus for amygdala seeds; however, no group differences in iFC were observed for sensory area seeds. Height-for-age, a proxy for malnutrition/infection, was not associated with amygdala/precuneus iFC, whereas prenatal family conflict was positively correlated. Findings suggest that it is feasible to conduct infant fMRI studies in low-resource settings. Challenges and practical steps for successful implementations are discussed.

Atypical Structural Asymmetry of the Planum Temporale is Related to Family History of Dyslexia.

Research on the neural correlates of developmental dyslexia indicates atypical anatomical lateralization of the planum temporale, a higher-order cortical auditory region. Yet whether this atypical lateralization precedes reading acquisition and is related to a familial risk for dyslexia is not currently known. In this study, we address these questions in 2 separate cohorts of young children and adolescents with and without a familial risk for dyslexia. Planum temporale surface area was manually labeled bilaterally, on the T1-weighted MR brain images of 54 pre-readers (mean age: 6.2 years, SD: 3.2 months; 33 males) and 28 adolescents (mean age: 14.7 years, SD: 3.3 months; 11 males). Half of the pre-readers and adolescents had a familial risk for dyslexia. In both pre-readers and adolescents, group comparisons of left and right planum temporale surface area showed a significant interaction between hemisphere and family history of dyslexia, with participants who had no family risk for dyslexia showing greater leftward asymmetry of the planum temporale. This effect was confirmed when analyses were restricted to normal reading participants. Altered planum temporale asymmetry thus seems to be related to family history of dyslexia.

Altered brain cortical maturation is found in adolescents with a family history of alcoholism.

Substance-naïve offspring from high-density alcohol use disorder (AUD) families exhibit altered subcortical brain volumes structurally and altered executive-functioning and emotion-processing functionally, compared with their peers. However, there is a dearth of literature exploring alterations of cortical thickness (CTh) in this population. T1-weighted structural brain MRI was acquired in 75 substance-naïve male offspring of treatment-seeking early onset (<25 years) AUD patients with high familial loading of AUDs (≥2 affected relatives) (FHP) and 65 age-matched substance-naïve male controls with negative family history from the community. Surface-based CTh reconstruction was done using FreeSurfer. Univariate general linear models were implemented at each vertex using SurfStat, controlling for age (linear and quadratic effects), and head size, to examine the main effect of familial AUD risk on CTh and its relationship with externalizing symptom score (ESS). A Johnson-Neyman procedure revealed that the main effect of familial AUD risk on CTh was seen during adolescence, where the FHP group had thicker cortices involving bilateral precentral gyri, left caudal middle frontal gyrus (MFG), bilateral temporo-parietal junction, left inferior-frontal gyrus and right inferior-temporal gyrus. Thicker cortices in left MFG and inferior-parietal lobule were also associated with greater ESS within both groups. More importantly, these group differences diminished with age by young adulthood. Familial AUD risk is associated with age-related differences in maturation of several higher order association cortices that are critical to ongoing development in executive function, emotion regulation and social cognition during adolescence. Early supportive intervention for a delay in alcohol initiation during this critical phase may be crucial for this at-risk population.

Immediate and Delayed Effects of Food Restriction on Some Parameters of Brain Development in Rats.

The effects of 15-day restriction diet (from 1 to 1.5 months of age) on some parameters of brain development were studied in rats. The immediate and delayed (15 days after transfer to normal ration) effects were evaluated. The immediate effects included a significant decrease of the absolute weights of the brain and hemispheres. The relative weight of the brain was significantly higher. The thickness of the cortex of the parietal lobe proper and its layer I decreased. The absolute weights of the brain and hemispheres were less than in the control 15 days after the rats were transferred to ad libitum feeding, while the relative weight of the brain was higher than in controls. The thickness of the parietal and anterior parietal cortex and the numerical density of neurons in layers II and V did not differ from the control. In the neurons of layers II and V of the anterior parietal and parietal lobe proper the nuclei were larger, while the nucleoli were enlarged in the neurons of these locations and the hippocampus, the shifts being significant in the anterior parietal layer V. The concentrations of RNA in the parietal, anterior parietal, and hippocampal lobe neurons in different groups were similar directly and 15 days after the diet. Changes in the gravimetric and morphometric parameters of the brain were paralleled by the development of oxidative stress.

Neural Tuning to Numerosity Relates to Perceptual Tuning in 3-6-Year-Old Children.

Neural representations of approximate numerical value, or numerosity, have been observed in the intraparietal sulcus (IPS) in monkeys and humans, including children. Using functional magnetic resonance imaging, we show that children as young as 3-4 years old exhibit neural tuning to cardinal numerosities in the IPS and that their neural responses are accounted for by a model of numerosity coding that has been used to explain neural responses in the adult IPS. We also found that the sensitivity of children's neural tuning to number in the right IPS was comparable to their numerical discrimination sensitivity observed behaviorally, outside of the scanner. Children's neural tuning curves in the right IPS were significantly sharper than in the left IPS, indicating that numerical representations are more precise and mature more rapidly in the right hemisphere than in the left. Further, we show that children's perceptual sensitivity to numerosity can be predicted by the development of their neural sensitivity to numerosity. This research provides novel evidence of developmental continuity in the neural code underlying numerical representation and demonstrates that children's neural sensitivity to numerosity is related to their cognitive development. SIGNIFICANCE STATEMENT: Here we test for the existence of neural tuning to numerosity in the developing brain in the youngest sample of children tested with fMRI to date. Although previous research shows evidence of numerical distance effects in the intraparietal sulcus of the developing brain, those effects could be explained by patterns of neural activity that do not represent neural tuning to numerosity. These data provide the first robust evidence that from as early as 3-4 years of age there is developmental continuity in how the intraparietal sulcus represents the values of numerosities. Moreover, the study goes beyond previous research by examining the relation between neural tuning and perceptual tuning in children.

Specialization of the Right Intraparietal Sulcus for Processing Mathematics During Development.

Mathematical ability, especially perception of numbers and performance of arithmetics, is known to rely on the activation of intraparietal sulcus (IPS). However, reasoning ability and working memory, 2 highly associated abilities also activate partly overlapping regions. Most studies aimed at localizing mathematical function have used group averages, where individual variability is averaged out, thus confounding the anatomical specificity when localizing cognitive functions. Here, we analyze the functional anatomy of the intraparietal cortex by using individual analysis of subregions of IPS based on how they are structurally connected to frontal, parietal, and occipital cortex. Analysis of cortical thickness showed that the right anterior IPS, defined by its connections to the frontal lobe, was associated with both visuospatial working memory, and mathematics in 6-year-old children. This region specialized during development to be specifically related to mathematics, but not visuospatial working memory in adolescents and adults. This could be an example of interactive specialization, where interacting with the environment in combination with interactions between cortical regions leads from a more general role of right anterior IPS in spatial processing, to a specialization of this region for mathematics.

Development of Right-hemispheric Dominance of Inferior Parietal Lobule in Proprioceptive Illusion Task.

Functional lateralization can be an indicator of brain maturation. We have consistently shown that, in the adult brain, proprioceptive processing of muscle spindle afferents generating illusory movement of the right hand activates inferior frontoparietal cortical regions in a right-side dominant manner in addition to the cerebrocerebellar motor network. Here we provide novel evidence regarding the development of the right-dominant use of the inferior frontoparietal cortical regions in humans using this task. We studied brain activity using functional magnetic resonance imaging while 60 right-handed blindfolded healthy children (8-11 years), adolescents (12-15 years), and young adults (18-23 years) (20 per group) experienced the illusion. Adult-like right-dominant use of the inferior parietal lobule (IPL) was observed in adolescents, while children used the IPL bilaterally. In contrast, adult-like lateralized cerebrocerebellar motor activation patterns were already observable in children. The right-side dominance progresses during adolescence along with the suppression of the left-sided IPL activity that emerges during childhood. Therefore, the neuronal processing implemented in the adult's right IPL during the proprioceptive illusion task is likely mediated bilaterally during childhood, and then becomes right-lateralized during adolescence at a substantially later time than the lateralized use of the cerebrocerebellar motor system for kinesthetic processing.

Ageing-related changes in the cortical processing of otolith information in humans.

Acoustic short tone bursts (STB) trigger ocular and cervical vestibular-evoked myogenic potentials (oVEMPs/cVEMPs) by activating irregular otolith afferents. Simultaneously, STBs introduce an artificial net acceleration signal of otolith origin into the vestibular network. VEMP parameters as diagnostic otolith processing markers have been shown to decline after the age of thirty. To delineate the differential effects of healthy ageing on the cortical vestibular subnetwork processing otolith information, we measured cVEMPs and the differential effects of unilateral STB in three age groups (20-40, 40-60 and 60+; n = 42) using functional neuroimaging. STB evoked responses in the main vestibular hubs in the parieto-opercular cortex. Whereas cVEMP amplitudes declined linearly with age, analysis of the BOLD response size depicted a u-shaped curve. Vestibular perception of the otolith stimulus on the other hand remained unchanged with age. Therefore, we propose that the comparably larger BOLD responses past the age of sixty could reflect a mechanism of central sensitisation for otolith perception to counterbalance the concurrent peripheral vestibular and somatosensory function decline.

Sleep/wake movement velocities, trajectories and micro-arousals during maturation in rats.

BACKGROUND: Sleep is regulated by two main processes. The circadian process provides a 24-h rhythm and the homeostatic process reflects sleep pressure, which increases in the course of wakefulness and decreases during sleep. Both of these processes undergo major changes during development. For example, sleep homeostasis, measured by means of electroencephalogram (EEG) slow-wave activity (SWA, EEG power between 0.5 and 4.5 Hz), peaks around puberty and decreases during adolescence. In humans and rats these changes have been related to cortical maturation. We aimed to explore whether additional parameters as state dynamic (dynamic of sleep/wake behavior) parameters of movement velocity, trajectories and micro-arousals provide markers of rat maturation. The state dynamics reflect the stability of sleep within a specific sleep stage. We applied a state space technique (SST), a quantitative and unbiased method, based on frequency band ratios of the EEG to analyze the development of different sleep/wake states and state dynamics between vigilance states. EEG of recording electrodes at the frontal and parietal lobe were analyzed using conventional scoring criteria and SST. RESULTS: We found that movement velocity, trajectories between sleep states and micro-arousals changed as an inverse U-shaped curve across maturation. At all ages, movement velocity over the frontal lobe is higher compared to the parietal lobe, while the number of trajectories and micro-arousals are reduced. Furthermore, we showed that SWA correlates negatively with movement velocity and the number of micro-arousals. The velocity in the parietal lobe correlates positively with the number of micro-arousals. As for SWA, trajectories seem primarily to depend on sleep homeostasis regulatory mechanisms while the movement velocity seems to be modulated by other sleep regulators like the circadian rhythms. CONCLUSIONS: New insights in sleep/wake state dynamics are established with the SST, because trajectories, micro-arousals and velocities are not evident by traditional scoring methods. These dynamic measures may represent new indicators for changes in sleep regulatory processes across maturation.