Spatiotemporal dynamics of cortical somatosensory network in typically developing children.

Sense of touch is essential for our interactions with external objects and fine control of hand actions. Despite extensive research on human somatosensory processing, it is still elusive how involved brain regions interact as a dynamic network in processing tactile information. Few studies probed temporal dynamics of somatosensory information flow and reported inconsistent results. Here, we examined cortical somatosensory processing through magnetic source imaging and cortico-cortical coupling dynamics. We recorded magnetoencephalography signals from typically developing children during unilateral pneumatic stimulation. Neural activities underlying somatosensory evoked fields were mapped with dynamic statistical parametric mapping, assessed with spatiotemporal activation analysis, and modeled by Granger causality. Unilateral pneumatic stimulation evoked prominent and consistent activations in the contralateral primary and secondary somatosensory areas but weaker and less consistent activations in the ipsilateral primary and secondary somatosensory areas. Activations in the contralateral primary motor cortex and supramarginal gyrus were also consistently observed. Spatiotemporal activation and Granger causality analysis revealed initial serial information flow from contralateral primary to supramarginal gyrus, contralateral primary motor cortex, and contralateral secondary and later dynamic and parallel information flows between the consistently activated contralateral cortical areas. Our study reveals the spatiotemporal dynamics of cortical somatosensory processing in the normal developing brain.

Sensory Coding of Limb Kinematics in Motor Cortex across a Key Developmental Transition.

Primary motor cortex (M1) undergoes protracted development in mammals, functioning initially as a sensory structure. Throughout the first postnatal week in rats, M1 is strongly activated by self-generated forelimb movements-especially by the twitches that occur during active sleep. Here, we quantify the kinematic features of forelimb movements to reveal receptive-field properties of individual units within the forelimb region of M1. At postnatal day 8 (P8), nearly all units were strongly modulated by movement amplitude, especially during active sleep. By P12, only a minority of units continued to exhibit amplitude tuning, regardless of behavioral state. At both ages, movement direction also modulated M1 activity, though to a lesser extent. Finally, at P12, M1 population-level activity became more sparse and decorrelated, along with a substantial alteration in the statistical distribution of M1 responses to limb movements. These findings reveal a transition toward a more complex and informationally rich representation of movement long before M1 develops its motor functionality.SIGNIFICANCE STATEMENT Primary motor cortex (M1) plays a fundamental role in the generation of voluntary movements and motor learning in adults. In early development, however, M1 functions as a prototypical sensory structure. Here, we demonstrate in infant rats that M1 codes for the kinematics of self-generated limb movements long before M1 develops its capacity to drive movements themselves. Moreover, we identify a key transition during the second postnatal week in which M1 activity becomes more informationally complex. Together, these findings further delineate the complex developmental path by which M1 develops its sensory functions in support of its later-emerging motor capacities.

Parallel and Serial Sensory Processing in Developing Primary Somatosensory and Motor Cortex.

It is generally supposed that primary motor cortex (M1) receives somatosensory input predominantly via primary somatosensory cortex (S1). However, a growing body of evidence indicates that M1 also receives direct sensory input from the thalamus, independent of S1; such direct input is particularly evident at early ages before M1 contributes to motor control. Here, recording extracellularly from the forelimb regions of S1 and M1 in unanesthetized rats at postnatal day (P)8 and P12, we compared S1 and M1 responses to self-generated (i.e., reafferent) forelimb movements during active sleep and wake, and to other-generated (i.e., exafferent) forelimb movements. At both ages, reafferent responses were processed in parallel by S1 and M1; in contrast, exafferent responses were processed in parallel at P8 but serially, from S1 to M1, at P12. To further assess this developmental difference in processing, we compared exafferent responses to proprioceptive and tactile stimulation. At both P8 and P12, proprioceptive stimulation evoked parallel responses in S1 and M1, whereas tactile stimulation evoked parallel responses at P8 and serial responses at P12. Independent of the submodality of exafferent stimulation, pairs of S1-M1 units exhibited greater coactivation during active sleep than wake. These results indicate that S1 and M1 independently develop somatotopy before establishing the interactive relationship that typifies their functionality in adults.SIGNIFICANCE STATEMENT Learning any new motor task depends on the ability to use sensory information to update motor outflow. Thus, to understand motor learning, we must also understand how animals process sensory input. Primary somatosensory cortex (S1) and primary motor cortex (M1) are two interdependent structures that process sensory input throughout life. In adults, the functional relationship between S1 and M1 is well established; however, little is known about how S1 and M1 begin to transmit or process sensory information in early life. In this study, we investigate the early development of S1 and M1 as a sensory processing unit. Our findings provide new insights into the fundamental principles of sensory processing and the development of functional connectivity between these important sensorimotor structures.

Development of Individual Variability in Brain Functional Connectivity and Capability across the Adult Lifespan.

Individual variability exists in both brain function and behavioral performance. However, changes in individual variability in brain functional connectivity and capability across adult development and aging have not yet been clearly examined. Based on resting-state functional magnetic resonance imaging data from a large cohort of participants (543 adults, aged 18-88 years), brain functional connectivity was analyzed to characterize the spatial distribution and differences in individual variability across the adult lifespan. Results showed high individual variability in the association cortex over the adult lifespan, whereas individual variability in the primary cortex was comparably lower in the initial stage but increased with age. Individual variability was also negatively correlated with the strength/number of short-, medium-, and long-range functional connections in the brain, with long-range connections playing a more critical role in increasing global individual variability in the aging brain. More importantly, in regard to specific brain regions, individual variability in the motor cortex was significantly correlated with differences in motor capability. Overall, we identified specific patterns of individual variability in brain functional structure during the adult lifespan and demonstrated that functional variability in the brain can reflect behavioral performance. These findings advance our understanding of the underlying principles of the aging brain across the adult lifespan and suggest how to characterize degenerating behavioral capability using imaging biomarkers.

Primary hand motor representation areas in healthy children, preadolescents, adolescents, and adults.

The development of the organization of the motor representation areas in children and adolescents is not well-known. This cross-sectional study aimed to provide an understanding for the development of the functional motor areas of the upper extremity muscles by studying healthy right-handed children (6-9 years, n = 10), preadolescents (10-12 years, n = 13), adolescents (15-17 years, n = 12), and adults (22-34 years, n = 12). The optimal representation site and resting motor threshold (rMT) for the abductor pollicis brevis (APB) were assessed in both hemispheres using navigated transcranial magnetic stimulation (nTMS). Motor mapping was performed at 110% of the rMT while recording the EMG of six upper limb muscles in the hand and forearm. The association between the motor map and manual dexterity (box and block test, BBT) was examined. The mapping was well-tolerated and feasible in all but the youngest participant whose rMT exceeded the maximum stimulator output. The centers-of-gravity (CoG) for individual muscles were scattered to the greatest extent in the group of preadolescents and centered and became more focused with age. In preadolescents, the CoGs in the left hemisphere were located more laterally, and they shifted medially with age. The proportion of hand compared to arm representation increased with age (p = 0.001); in the right hemisphere, this was associated with greater fine motor ability. Similarly, there was less overlap between hand and forearm muscles representations in children compared to adults (p<0.001). There was a posterior-anterior shift in the APB hotspot coordinate with age, and the APB coordinate in the left hemisphere exhibited a lateral to medial shift with age from adolescence to adulthood (p = 0.006). Our results contribute to the elucidation of the developmental course in the organization of the motor cortex and its associations with fine motor skills. It was shown that nTMS motor mapping in relaxed muscles is feasible in developmental studies in children older than seven years of age.

The maturation and cognitive relevance of structural brain network organization from early infancy to childhood.

The interactions of brain regions with other regions at the network level likely provide the infrastructure necessary for cognitive processes to develop. Specifically, it has been theorized that in infancy brain networks become more modular, or segregated, to support early cognitive specialization, before integration across networks increases to support the emergence of higher-order cognition. The present study examined the maturation of structural covariance networks (SCNs) derived from longitudinal cortical thickness data collected between infancy and childhood (0-6 years). We assessed modularity as a measure of network segregation and global efficiency as a measure of network integration. At the group level, we observed trajectories of increasing modularity and decreasing global efficiency between early infancy and six years. We further examined subject-based maturational coupling networks (sbMCNs) in a subset of this cohort with cognitive outcome data at 8-10 years, which allowed us to relate the network organization of longitudinal cortical thickness maturation to cognitive outcomes in middle childhood. We found that lower global efficiency of sbMCNs throughout early development (across the first year) related to greater motor learning at 8-10 years. Together, these results provide novel evidence characterizing the maturation of brain network segregation and integration across the first six years of life, and suggest that specific trajectories of brain network maturation contribute to later cognitive outcomes.

Development and plasticity of complex movement representations.

The mammalian motor cortex is topographically organized into representations of discrete body parts (motor maps). Studies in adult rats using long-duration intracortical microstimulation (LD-ICMS) reveal that forelimb motor cortex is functionally organized into several spatially distinct areas encoding complex, multijoint movement sequences: elevate, advance, grasp, and retract. The topographical arrangement of complex movements during development and the influence of skilled learning are unknown. Here, we determined the emergence and topography of complex forelimb movement representations in rats between postnatal days (PND) 13 and 60. We further investigated the expression of the maps for complex movements under conditions of reduced cortical inhibition and whether skilled forelimb motor training could alter their developing topography. We report that simple forelimb movements are first evoked at PND 25 and are confined to the caudal forelimb area (CFA), whereas complex movements first reliably appear at PND 30 and are observed in both the caudal and rostral forelimb areas (RFA). During development, the topography of complex movement representations undergoes reorganization with "grasp" and "elevate" movements predominantly observed in the RFA and all four complex movements observed in CFA. Under reduced cortical inhibition, simple and complex movements were first observed in the CFA on PND 15 and 20, respectively, and the topography is altered relative to a saline control. Further, skilled motor learning was associated with increases in "grasp" and "retract" representations specific to the trained limb. Our results demonstrate that early-life motor experience during development can modify the topography of complex forelimb movement representations.NEW & NOTEWORTHY The motor cortex is topographically organized into maps of different body parts. We used to think that the function of motor cortex was to drive individual muscles, but more recently we have learned that it is also organized to make complex movements. However, the development and plasticity of those complex movements is completely unknown. In this paper, the emergence and topography of complex movement representation, as well as their plasticity during development, is detailed.

Transient expansion of the expression region of Hsd11b1, encoding 11ß-hydroxysteroid dehydrogenase type 1, in the developing mouse neocortex.

Corticosteroids are stress-related hormones that maintain homeostasis. The most effective corticosteroids are corticosterone (CORT) in rodents and cortisol in primates. 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1; EC 1.1.1.146), encoded by Hsd11b1, is a key regulator of the local concentration of CORT/cortisol. Hsd11b1 expression in layer 5 of the primary somatosensory cortex has been shown in adult mice. However, its localization in the entire neocortex, especially during development, has not been fully addressed. Here, we established robust and dynamic expression profiles of Hsd11b1 in the developing mouse neocortex. Hsd11b1 was found mostly in pyramidal neurons. By retrograde tracing, we observed that some Hsd11b1-positive cells were projection neurons, indicating that at least some were excitatory. At postnatal day 0 (P0), Hsd11b1 was expressed in the deep layer of the somatosensory cortex. Then, from P3 to P8, the expression area expanded broadly; it was observed in layers 4 and 5, spanning the whole neocortex, including the primary motor cortex (M1) and the primary visual cortex (V1). The positive region gradually narrowed from P14 onwards and was ultimately limited to layer 5 of the somatosensory cortex at P26 and later. Furthermore, we administered CORT to nursing dams to increase the systemic CORT level of their pups. Here, we observed a reduced number of Hsd11b1-positive cells in the neocortex of these pups. Our observation suggests that Hsd11b1 expression in the developing neocortex is affected by systemic CORT levels. It is possible that stress on mothers influences the neocortical development of their children.

A Lifespan fMRI Study of Neurodevelopment Associated with Reading Chinese.

We used functional magnetic resonance imaging (fMRI) to map the neural systems involved in reading Chinese in 125 participants 6-74 years old to examine two theoretical issues: how brain structure and function are related in the context of the lifetime neural development of human cognition and whether the neural network for reading is universal or different across languages. Our findings showed that a common network of left frontal and occipital regions typically involved in reading Chinese was recruited across all participants. Crucially, activation in left mid-inferior frontal regions, fusiform and striate-extrastriate sites, premotor cortex, right inferior frontal gyrus, bilateral insula, and supplementary motor area all showed linearly decreasing changes with age. These findings differ from previous findings on alphabetic reading development and suggest that early readers at age 6-7 are already using the same cortical network to process printed words as adults, though the connections among these regions are modulated by reading proficiency, and cortical regions for reading are tuned by experience toward reduced and more focused activation. This fMRI study has demonstrated, for the first time, the neurodevelopment of reading across the lifespan and suggests that learning experience, instead of pre-existing brain structures, determines reading acquisition.

Loss-of-Huntingtin in Medial and Lateral Ganglionic Lineages Differentially Disrupts Regional Interneuron and Projection Neuron Subtypes and Promotes Huntington's Disease-Associated Behavioral, Cellular, and Pathological Hallmarks.

Emerging studies are providing compelling evidence that the pathogenesis of Huntington's disease (HD), a neurodegenerative disorder with frequent midlife onset, encompasses developmental components. Moreover, our previous studies using a hypomorphic model targeting huntingtin during the neurodevelopmental period indicated that loss-of-function mechanisms account for this pathogenic developmental component (Arteaga-Bracho et al., 2016). In the present study, we specifically ascertained the roles of subpallial lineage species in eliciting the previously observed HD-like phenotypes. Accordingly, we used the Cre-loxP system to conditionally ablate the murine huntingtin gene (Httflx) in cells expressing the subpallial patterning markers Gsx2 (Gsx2-Cre) or Nkx2.1 (Nkx2.1-Cre) in Httflx mice of both sexes. These genetic manipulations elicited anxiety-like behaviors, hyperkinetic locomotion, age-dependent motor deficits, and weight loss in both Httflx;Gsx2-Cre and Httflx;Nkx2.1-Cre mice. In addition, these strains displayed unique but complementary spatial patterns of basal ganglia degeneration that are strikingly reminiscent of those seen in human cases of HD. Furthermore, we observed early deficits of somatostatin-positive and Reelin-positive interneurons in both Htt subpallial null strains, as well as early increases of cholinergic interneurons, Foxp2+ arkypallidal neurons, and incipient deficits with age-dependent loss of parvalbumin-positive neurons in Httflx;Nkx2.1-Cre mice. Overall, our findings indicate that selective loss-of-huntingtin function in subpallial lineages differentially disrupts the number, complement, and survival of forebrain interneurons and globus pallidus GABAergic neurons, thereby leading to the development of key neurological hallmarks of HD during adult life. Our findings have important implications for the establishment and deployment of neural circuitries and the integrity of network reserve in health and disease.SIGNIFICANCE STATEMENT Huntington's disease (HD) is a progressive degenerative disorder caused by aberrant trinucleotide expansion in the huntingtin gene. Mechanistically, this mutation involves both loss- and gain-of-function mechanisms affecting a broad array of cellular and molecular processes. Although huntingtin is widely expressed during adult life, the mutant protein only causes the demise of selective neuronal subtypes. The mechanisms accounting for this differential vulnerability remain elusive. In this study, we have demonstrated that loss-of-huntingtin function in subpallial lineages not only differentially disrupts distinct interneuron species early in life, but also leads to a pattern of neurological deficits that are reminiscent of HD. This work suggests that early disruption of selective neuronal subtypes may account for the profiles of enhanced regional cellular vulnerability to death in HD.

Individual differences in motor development during early childhood: An MEG study.

In a previous study, we reported the first measurements of pre-movement and sensorimotor cortex activity in preschool age children (ages 3-5 years) using a customized pediatric magnetoencephalographic system. Movement-related activity in the sensorimotor cortex differed from that typically observed in adults, suggesting that maturation of cortical motor networks was still incomplete by late preschool age. Here we compare these earlier results to a group of school age children (ages 6-8 years) including seven children from the original study measured again two years later, and a group of adults (mean age 31.1 years) performing the same task. Differences in movement-related brain activity were observed both longitudinally within children in which repeated measurements were made, and cross-sectionally between preschool age children, school age children, and adults. Movement-related mu (8-12 Hz) and beta (15-30 Hz) oscillations demonstrated linear increases in amplitude and mean frequency with age. In contrast, movement-evoked gamma synchronization demonstrated a step-like transition from low (30-50 Hz) to high (70-90 Hz) narrow-band oscillations, and this occurred at different ages in different children. Notably, pre-movement activity ('readiness fields') observed in adults was absent in even the oldest children. These are the first direct observations of brain activity accompanying motor responses throughout early childhood, confirming that maturation of this activity is still incomplete by mid-childhood. In addition, individual children demonstrated markedly different developmental trajectories in movement-related brain activity, suggesting that individual differences need to be taken into account when studying motor development across age groups.

Early Excitatory Activity-Dependent Maturation of Somatostatin Interneurons in Cortical Layer 2/3 of Mice.

GABAergic interneurons perform distinct functions during cortical development in the mouse brain. Among the diverse GABAergic neurons present in the brain, early-born somatostatin (SST)-expressing inhibitory interneurons, which are innervated by other interneurons and local pyramidal cells (PCs), act in a neural computational role in circuitry regulation. The synapses between the SST+ interneurons and other cells form gradually during development. Here, we traced the developmental course of the electrophysiological properties of SST+ interneurons at layer 2/3 of the neocortical secondary motor area (M2) in mouse, and the synaptic connectivity between SST+ interneurons and PCs. Also, we used toxin-mediated and genetic method to suppress the activities of PCs, and demonstrate that decreasing excitatory input at early stage (before P1) rather than late stage (after P8) would delay the functional maturation of SST+ interneurons. In conclusion, our results indicate that early functional activity of PCs is crucial for the intrinsic maturation of SST+ interneurons, following which these interneurons participate in local circuitry.

Structural and Functional Maturation of Rat Primary Motor Cortex Layer V Neurons.

Rodent neocortical neurons undergo prominent postnatal development and maturation. The process is associated with structural and functional maturation of the axon initial segment (AIS), the site of action potential initiation. In this regard, cell size and optimal AIS length are interconnected. In sensory cortices, developmental onset of sensory input and consequent changes in network activity cause phasic AIS plasticity that can also control functional output. In non-sensory cortices, network input driving phasic events should be less prominent. We, therefore, explored the relationship between postnatal functional maturation and AIS maturation in principal neurons of the primary motor cortex layer V (M1LV), a non-sensory area of the rat brain. We hypothesized that a rather continuous process of AIS maturation and elongation would reflect cell growth, accompanied by progressive refinement of functional output properties. We found that, in the first two postnatal weeks, cell growth prompted substantial decline of neuronal input resistance, such that older neurons needed larger input current to reach rheobase and fire action potentials. In the same period, we observed the most prominent AIS elongation and significant maturation of functional output properties. Alternating phases of AIS plasticity did not occur, and changes in functional output properties were largely justified by AIS elongation. From the third postnatal week up to five months of age, cell growth, AIS elongation, and functional output maturation were marginal. Thus, AIS maturation in M1LV is a continuous process that attunes the functional output of pyramidal neurons and associates with early postnatal development to counterbalance increasing electrical leakage due to cell growth.

Effects of Aging on Cortical Neural Dynamics and Local Sleep Homeostasis in Mice.

Healthy aging is associated with marked effects on sleep, including its daily amount and architecture, as well as the specific EEG oscillations. Neither the neurophysiological underpinnings nor the biological significance of these changes are understood, and crucially the question remains whether aging is associated with reduced sleep need or a diminished capacity to generate sufficient sleep. Here we tested the hypothesis that aging may affect local cortical networks, disrupting the capacity to generate and sustain sleep oscillations, and with it the local homeostatic response to sleep loss. We performed chronic recordings of cortical neural activity and local field potentials from the motor cortex in young and older male C57BL/6J mice, during spontaneous waking and sleep, as well as during sleep after sleep deprivation. In older animals, we observed an increase in the incidence of non-rapid eye movement sleep local field potential slow waves and their associated neuronal silent (OFF) periods, whereas the overall pattern of state-dependent cortical neuronal firing was generally similar between ages. Furthermore, we observed that the response to sleep deprivation at the level of local cortical network activity was not affected by aging. Our data thus suggest that the local cortical neural dynamics and local sleep homeostatic mechanisms, at least in the motor cortex, are not impaired during healthy senescence in mice. This indicates that powerful protective or compensatory mechanisms may exist to maintain neuronal function stable across the life span, counteracting global changes in sleep amount and architecture.SIGNIFICANCE STATEMENT The biological significance of age-dependent changes in sleep is unknown but may reflect either a diminished sleep need or a reduced capacity to generate deep sleep stages. As aging has been linked to profound disruptions in cortical sleep oscillations and because sleep need is reflected in specific patterns of cortical activity, we performed chronic electrophysiological recordings of cortical neural activity during waking, sleep, and after sleep deprivation from young and older mice. We found that all main hallmarks of cortical activity during spontaneous sleep and recovery sleep after sleep deprivation were largely intact in older mice, suggesting that the well-described age-related changes in global sleep are unlikely to arise from a disruption of local network dynamics within the neocortex.

The developmental trajectory of sensorimotor cortical oscillations.

Numerous studies of motor control have confirmed beta and gamma oscillations in the primary motor cortices during basic movements. These responses include a robust beta decrease that precedes and extends through movement onset, a transient gamma response that coincides with the movement, and a post-movement beta rebound (PMBR) response that occurs after movement offset. While the existence of these responses has been confirmed by many studies, very few studies have examined their developmental trajectory. In the current study, we utilized magnetoencephalography (MEG) to investigate age-related changes in sensorimotor cortical oscillations in a large cross-section of children and adolescents (n = 94; age range = 9 -15 years-old). All participants performed a stimulus detection task with their right finger and the resulting MEG data were examined using oscillatory analysis methods and imaged using a beamformer. Consistent with adult studies, these youth participants exhibited characteristic beta (16-24 Hz) decreases prior to and during movement, as well as PMBR responses following movement offset, and a transient gamma (74-84 Hz) response during movement execution. Our primary findings were that the strength of the PMBR increased with age, while the strength of the gamma synchronization decreased with chronological age. In addition, the strength of each motor-related oscillatory response was significantly correlated with the power of spontaneous activity in the same frequency range and same voxel. This was the case for all three oscillatory responses. In conclusion, we investigated motor-related oscillatory activity in the largest cohort of children and adolescents reported to date, and our results indicated that beta and gamma cortical oscillations continue to develop as children transition into adolescents, and that these responses may not be fully matured until young to middle adulthood.

Differential developmental changes in cortical representations of auditory-vocal stimuli in songbirds.

Procedural skill learning requires iterative comparisons between feedback of self-generated motor output and a goal sensorimotor pattern. In juvenile songbirds, neural representations of both self-generated behaviors (each bird's own immature song) and the goal motor pattern (each bird's adult tutor song) are essential for vocal learning, yet little is known about how these behaviorally relevant stimuli are encoded. We made extracellular recordings during song playback in anesthetized juvenile and adult zebra finches ( Taeniopygia guttata) in adjacent cortical regions RA (robust nucleus of the arcopallium), AId (dorsal intermediate arcopallium), and RA cup, each of which is well situated to integrate auditory-vocal information: RA is a motor cortical region that drives vocal output, AId is an adjoining cortical region whose projections converge with basal ganglia loops for song learning in the dorsal thalamus, and RA cup surrounds RA and receives inputs from primary and secondary auditory cortex. We found strong developmental differences in neural selectivity within RA, but not in AId or RA cup. Juvenile RA neurons were broadly responsive to multiple songs but preferred juvenile over adult vocal sounds; in addition, spiking responses lacked consistent temporal patterning. By adulthood, RA neurons responded most strongly to each bird's own song with precisely timed spiking activity. In contrast, we observed a complete lack of song responsivity in both juvenile and adult AId, even though this region receives song-responsive inputs. A surprisingly large proportion of sites in RA cup of both juveniles and adults did not respond to song playback, and responsive sites showed little evidence of song selectivity. NEW & NOTEWORTHY Motor skill learning entails changes in selectivity for behaviorally relevant stimuli across cortical regions, yet the neural representation of these stimuli remains understudied. We investigated how information important for vocal learning in zebra finches is represented in regions analogous to infragranular layers of motor and auditory cortices during vs. after the developmentally regulated learning period. The results provide insight into how neurons in higher level stages of cortical processing represent stimuli important for motor skill learning.

Endothelial cells promote excitatory synaptogenesis and improve ischemia-induced motor deficits in neonatal mice.

Brain microvascular endothelial cells (BMEC) are highly complex regulatory cells that communicate with other cells in the neurovascular unit. Cerebral ischemic injury is known to produce detectable synaptic dysfunction. This study aims to investigate whether endothelial cells in the brain regulate postnatal synaptic development and to elucidate their role in functional recovery after ischemia. Here, we found that in vivo engraftment of endothelial cells increased synaptic puncta and excitatory postsynaptic currents in layers 2/3 of the motor cortex. This pro-synaptogenic effect was blocked by the depletion of VEGF in the grafted BMEC. The in vitro results showed that BMEC conditioned medium enhanced spine and synapse formation but conditioned medium without VEGF had no such effects. Moreover, under pathological conditions, transplanted endothelial cells were capable of enhancing angiogenesis and synaptogenesis and improved motor function in the ischemic injury model. Collectively, our findings suggest that endothelial cells promote excitatory synaptogenesis via the paracrine factor VEGF during postnatal development and exert repair functions in hypoxia-ischemic neonatal mice. This study highlights the importance of the endothelium-neuron interaction not only in regulating neuronal development but also in maintaining healthy brain function.

Anticipatory postural adjustments and spatial organization of motor cortex: evidence of adaptive compensations in healthy older adults.

During anticipated postural perturbations induced by limb movement, the central nervous system generates anticipatory postural adjustments (APAs) in the trunk and hip musculature to minimize disturbances to equilibrium. Age-related changes in functional organization of the nervous system may contribute to changes in APAs in healthy older adults. Here we examined if altered APAs of trunk/hip musculature in older adults are accompanied by changes in the representation of these muscles in motor cortex. Twelve healthy older adults, 5 with a history of falls and 7 nonfallers, were compared with 13 young adults. APAs were assessed during a mediolateral arm raise task in standing. Temporal organization of postural adjustments was quantified as latency of APAs in the contralateral external oblique, lumbar paraspinals, and gluteus medius relative to activation of the deltoid. Spatial organization was quantified as extent of synergistic coactivation between muscles. Volume and location of the muscle representations in motor cortex were mapped using transcranial magnetic stimulation. We found that older adults demonstrated significantly delayed APAs in the gluteus medius muscle. Spatial organization of the three muscles in motor cortex differed between groups, with the older adults demonstrating more lateral external oblique representation than the other two muscles. Separate comparisons of the faller and nonfaller subgroups with young adults indicated that nonfallers had the greatest delay in gluteus medius APAs and a reduced distance between the representational areas of the lumbar paraspinals and gluteus medius. This study indicates that altered spatial organization of motor cortex accompanies altered temporal organization of APA synergies in older adults. NEW & NOTEWORTHY Anticipatory postural adjustments are a critical component of postural control. Here we demonstrate that, in healthy older adults with and without a history of falls, delayed anticipatory postural adjustments in the hip musculature during mediolateral perturbations are accompanied by altered organization of trunk/hip muscle representation in motor cortex. The largest adaptations are evident in older adults with no history of falls.

A critical period of corticomuscular and EMG-EMG coherence detection in healthy infants aged 9-25 weeks.

KEY POINTS: The early postnatal development of functional corticospinal connections in human infants is not fully clarified. Corticospinal drive to upper and lower limb muscle shows developmental changes with an increased functional coupling in infants between 9 and 25 weeks in the beta frequency band. The changes in functional coupling coincide with the developmental period where fidgety movements are present in healthy infants. Data support a possible sensitive period where functional connections between corticospinal tract fibres and spinal motoneurones undergo activity-dependent reorganization. ABSTRACT: The early postnatal development of functional corticospinal connections in human infants is not fully clarified. We used EEG and EMG to investigate the development of corticomuscular and intramuscular coherence as indicators of functional corticospinal connectivity in healthy infants aged 1-66 weeks. EEG was recorded over leg and hand area of motor cortex. EMG recordings were made from right ankle dorsiflexor and right wrist extensor muscles. Quantification of the amount of corticomuscular coherence in the 20-40 Hz frequency band showed a significantly larger coherence for infants aged 9-25 weeks compared to younger and older infants. Coherence between paired EMG recordings from tibialis anterior muscle in the 20-40 Hz frequency band was also significantly larger for the 9-25 week age group. A low-amplitude, broad-duration (40-50 ms) central peak of EMG-EMG synchronization was observed for infants younger than 9 weeks, whereas a short-lasting (10-20 ms) central peak was observed for EMG-EMG synchronization in older infants. This peak was largest for infants aged 9-25 weeks. These data suggest that the corticospinal drive to lower and upper limb muscles shows significant developmental changes with an increase in functional coupling in infants aged 9-25 weeks, a period which coincides partly with the developmental period of normal fidgety movements. We propose that these neurophysiological findings may reflect the existence of a sensitive period where the functional connections between corticospinal tract fibres and spinal motoneurones undergo activity-dependent reorganization. This may be relevant for the timing of early therapy interventions in infants with pre- and perinatal brain injury.

Characterization of infant mu rhythm immediately before crawling: A high-resolution EEG study.

Crawling is an important milestone in infant motor development. However, infants with developmental motor disorders can exhibit delays, or even miss, in the acquisition of crawling skill. And little information is available from the neurodevelopmental domain about the changes in brain function with intervention. The mu rhythm can potentially play a substantial role in understanding human motor development at early ages in infants, as it has in adults. Studies about the mu rhythm in infants were in coarse temporal resolution with longitudinal samples taken months or years apart. Details about the infant mu rhythm at a fine age resolution has not been fully revealed, which leads to contradictory evidence about its formulation and developmental changes of its spectral origins and, therefore, impedes the full understanding of motor brain development before crawling skill acquisition. The present study aims to expand knowledge about the infant mu rhythm and its spatio-spectral pattern shifts along maturation immediately before crawling. With high-density EEG data recorded on a weekly basis and simultaneous characterization of spatio-spectral patterns of the mu rhythm, subtle developmental changes in its spectral peak, frequency range, and scalp topography are revealed. This mu rhythm further indicates a significant correlation to the crawling onset while powers from other frequency bands do not show such correlations. These details of developmental changes about the mu rhythm provide an insight of rapid changes in the human motor cortex in the first year of life. Our results are consistent with previous findings about the peak frequency shifting of the mu rhythm and further depict detailed developmental curves of its frequency ranges and spatial topographies. The infant mu rhythm could potentially be used to assess motor brain deficiencies at early ages and to evaluate intervention effectiveness in children with neuromotor disorders.