Human Cerebellum Research Articles

Within-individual organization of the human cognitive cerebellum: Evidence for closely juxtaposed, functionally specialized regions.

Specific regions in the cognitive cerebellum are connected to distinct cerebral association networks. Do these cerebellar regions exhibit functional specialization similar to the cerebral cortex? Here, we mapped the cerebellum within intensively studied participants (N = 15) first using connectivity to estimate regions linked to specific networks and then prospectively testing functional response properties in task data within each individual's own idiosyncratic anatomy. A large megacluster extending across Crus I/II was consistently found with subregions linked to five higher-order association networks. A more variable smaller association cluster was found in lobule IX. Within the Crus I/II megacluster, specific cerebellar regions responded to domain-flexible cognitive control, while juxtaposed regions differentially responded to language, social, and spatial/episodic task demands. Similarly organized clusters also exist in the caudate consistent with the presence of multiple basal ganglia-cerebellar-cerebral cortical circuits that maintain functional specialization across their entire distributed extents.

Expression pattern of Calbindin-D28k, NeuN, ATOH1 and EN2 genes in the human fetal cerebellum

BackgroundCertain molecules are expressed specific to cerebellar neurons and certain genes play specific role in the development of cerebellum. MethodsThis is a descriptive observational study carried out in human fetal cerebellum, fluorescent immunohistochemistry was used to study the expression of Calbindin-D28k and neuronal nuclease (NeuN), and while the expression of ATOH1 (Atonal homolog 1) and EN2 (Engrailed -2) genes were quantified with the help of qPCR. ResultsCalbindin-D28k was highly immunoreactive in the Purkinje cells and located in their cytoplasm, nucleus and dendrites whereas absent in their axons. NeuN was expressed weakly in the perinuclear cytoplasm and nucleus of granule cells whereas absent in their dendrites and axons. ATOH1 gene was upregulated during third trimester whereas EN2 gene was upregulated during second as well as third trimesters. ConclusionDistribution and intensity of Calbindin-D28k and NeuN proteins in the human fetal cerebellum increased with the increase of fetal age. Expression of ATOH1 and EN2 genes indicated that second and third trimesters are the crucial periods for the proliferation, migration and maturation of granule cells and essential for the establishment of normal morphology of human fetal cerebellum and its development.

Identification and Copy Number Variant Analysis of Enhancer Regions of Genes Causing Spinocerebellar Ataxia.

Currently, routine diagnostics for spinocerebellar ataxia (SCA) look for polyQ repeat expansions and conventional variations affecting the proteins encoded by known SCA genes. However, ~40% of the patients still remain without a genetic diagnosis after routine tests. Increasing evidence suggests that variations in the enhancer regions of genes involved in neurodegenerative disorders can also cause disease. Since the enhancers of SCA genes are not yet known, it remains to be determined whether variations in these regions are a cause of SCA. In this pilot project, we aimed to identify the enhancers of the SCA genes ATXN1, ATXN3, TBP and ITPR1 in the human cerebellum using 4C-seq, publicly available datasets, reciprocal 4C-seq, and luciferase assays. We then screened these enhancers for copy number variants (CNVs) in a cohort of genetically undiagnosed SCA patients. We identified two active enhancers for each of the four SCA genes. CNV analysis did not reveal any CNVs in the enhancers of the four SCA genes in the genetically undiagnosed SCA patients. However, in one patient, we noted a CNV deletion with an unknown clinical significance near one of the ITPR1 enhancers. These results not only reveal elements involved in SCA gene regulation but can also lead to the discovery of novel SCA-causing genetic variants. As enhancer variations are being increasingly recognized as a cause of brain disorders, screening the enhancers of ATXN1, ATXN3, TBP and ITPR1 for variations other than CNVs and identifying and screening enhancers of other SCA genes might elucidate the genetic cause in undiagnosed patients.

RECAPITULATING THE POST-SURGICAL BRAIN MICROENVIRONMENT OF ATYPICAL TERATOID RHABDOID TUMOURS TO IDENTIFY MEMBRANE PROTEINS FOR TARGETED THERAPY

Abstract AIMS Atypical Teratoid Rhabdoid Tumours (AT/RT) are rare aggressive tumours primarily arising in the hind brain of children under three, conferring median survival of <12 months. Surgery remains the only standard treatment; however tumours recur from post-surgical residual disease. Decellularised human brain cerebellum aim to recapitulate AT/RT post-surgical brain microenvironments which retain extracellular matrix (ECM) ligands, and where AT/RT plasma membrane proteins are hypothesised to represent viable molecular therapy targets. METHOD AT/RT, astrocyte and human brain cerebellum (decellularised and non-decellularised) membrane protein fractions were extracted and analysed using liquid chromatography-mass spectrometry. Proteomic analysis tools were integrated to identify differential expressed proteins and identify shared correlations. RESULTS Decellularised cerebellar ECM exhibited an enriched membrane proteome relative to total proteome, evidence of complete removal of intracellular components. Furthermore, decellularised and non-decellularised cerebellar tissue expressed comparable levels of membrane proteins and protein networks, indicative of ECM ligand retention. AT/RT and astrocyte KEGG Pathway analysis revealed specific oncology-based pathway expression in membrane protein compared to total protein, reinforcing membrane proteins as more visible therapeutic targets. Between the top 20 expressed proteins, ATP1A1 was the only membrane protein shared exclusively between all AT/RT cells and astrocytes, suggesting a critical functional role. Membrane proteins showing shared expression when normalised against each AT/RT cell line included ATP1A1, HSPD1, GNA13 and SLC3A2, indicating biological similarities between AT/RT molecular subtypes, which may offer candidate ubiquitous therapy targets. Membrane proteins expressed similarly in AT/RT-MYC molecular subtypes include ATP1A1, SLC7A5 and EEF1A1. STRING membrane pathway analysis also identified shared proteins between AT/RT and astrocyte cell populations. CONCLUSION AT/RT membrane protein pathways provide ideal therapeutic targets directly amenable for drug repurposing. Future work prioritises proteomic analysis utilising 3D AT/RT spheroids and cerebellum brain tissue to maximise accurately recapitulating the AT/RT post-surgical microenvironment. Cerebellum decellularisation still permits retention of essential proteins and ligands.

Advances in the Differentiation of hiPSCs into Cerebellar Neuronal Cells.

The cerebellum has historically been primarily associated with the regulation of precise motor functions. However, recent findings suggest that it also plays a pivotal role in the development of advanced cognitive functions, including learning, memory, and emotion regulation. Pathological changes in the cerebellum, whether congenital hereditary or acquired degenerative, can result in a diverse spectrum of disorders, ranging from genetic spinocerebellar ataxias to psychiatric conditions such as autism, and schizophrenia. While studies in animal models have significantly contributed to our understanding of the genetic networks governing cerebellar development, it is important to note that the human cerebellum follows a protracted developmental timeline compared to the neocortex. Consequently, employing animal models to uncover human-specific molecular events in cerebellar development presents significant challenges. The emergence of human induced pluripotent stem cells (hiPSCs) has provided an invaluable tool for creating human-based culture systems, enabling the modeling and analysis of cerebellar physiology and pathology. hiPSCs and their differentiated progenies can be derived from patients with specific disorders or carrying distinct genetic variants. Importantly, they preserve the unique genetic signatures of the individuals from whom they originate, allowing for the elucidation of human-specific molecular and cellular processes involved in cerebellar development and related disorders. This review focuses on the technical advancements in the utilization of hiPSCs for the generation of both 2D cerebellar neuronal cells and 3D cerebellar organoids.

A hierarchical atlas of the human cerebellum for functional precision mapping

The human cerebellum is activated by a wide variety of cognitive and motor tasks. Previous functional atlases have relied on single task-based or resting-state fMRI datasets. Here, we present a functional atlas that integrates information from seven large-scale datasets, outperforming existing group atlases. The atlas has three further advantages. First, the atlas allows for precision mapping in individuals: the integration of the probabilistic group atlas with an individual localizer scan results in a marked improvement in prediction of individual boundaries. Second, we provide both asymmetric and symmetric versions of the atlas. The symmetric version, which is obtained by constraining the boundaries to be the same across hemispheres, is especially useful in studying functional lateralization. Finally, the regions are hierarchically organized across three levels, allowing analyses at the appropriate level of granularity. Overall, the present atlas is an important resource for the study of the interdigitated functional organization of the human cerebellum in health and disease.

Visuomotor prediction during action planning in the human frontoparietal cortex and cerebellum.

The concept of forward models in the brain, classically applied to describing on-line motor control, can in principle be extended to action planning, i.e. assuming forward sensory predictions are issued during the mere preparation of movements. To test this idea, we combined a delayed movement task with a virtual reality based manipulation of visuomotor congruence during functional magnetic resonance imaging. Participants executed simple hand movements after a delay. During the delay, two aspects of the upcoming movement could be cued: the movement type and the visuomotor mapping (i.e. congruence of executed hand movements and visual movement feedback by a glove-controlled virtual hand). Frontoparietal areas showed increased delay period activity when preparing pre-specified movements (cued > uncued). The cerebellum showed increased activity during the preparation for incongruent > congruent visuomotor mappings. The left anterior intraparietal sulcus showed an interaction effect, responding most strongly when a pre-specified (cued) movement was prepared under expected visuomotor incongruence. These results suggest that motor planning entails a forward prediction of visual body movement feedback, which can be adjusted in anticipation of nonstandard visuomotor mappings, and which is likely computed by the cerebellum and integrated with state estimates for (planned) control in the anterior intraparietal sulcus.

Structural covariation between cerebellum and neocortex intrinsic structural covariation links cerebellum subregions to the cerebral cortex.

The human cerebellum is increasingly recognized to be involved in nonmotor and higher-order cognitive functions. Yet, its ties with the entire cerebral cortex have not been holistically studied in a whole brain exploration with a unified analytical framework. Here, we characterized dissociable cortical-cerebellar structural covariation patterns based on regional gray matter volume (GMV) across the brain in n = 38,527 UK Biobank participants. Our results invigorate previous observations in that important shares of cortical-cerebellar structural covariation are described as 1) a dissociation between the higher-level cognitive system and lower-level sensorimotor system and 2) an anticorrelation between the visual-attention system and advanced associative networks within the cerebellum. We also discovered a novel pattern of ipsilateral, rather than contralateral, cerebral-cerebellar associations. Furthermore, phenome-wide association assays revealed key phenotypes, including cognitive phenotypes, lifestyle, physical properties, and blood assays, associated with each decomposed covariation pattern, helping to understand their real-world implications. This systems neuroscience view paves the way for future studies to explore the implications of these structural covariations, potentially illuminating new pathways in our understanding of neurological and cognitive disorders.NEW & NOTEWORTHY Cerebellum's association with the entire cerebral cortex has not been holistically studied in a unified way. Here, we conjointly characterize the population-level cortical-cerebellar structural covariation patterns leveraging ∼40,000 UK Biobank participants whole brain structural scans and ∼1,000 phenotypes. We revitalize the previous hypothesis of an anticorrelation between the visual-attention system and advanced associative networks within the cerebellum. We also discovered a novel ipsilateral cerebral-cerebellar associations. Phenome-wide association (PheWAS) revealed real-world implications of the structural covariation patterns.

The Human Cerebellum: A Digital Anatomical Atlas at the Level of Individual Folia.

Scientific interest in the cerebellum has surged in the last few decades with an emerging consensus on a multifaceted functionality and intricate, but not yet fully understood, functional topography over the cerebellar cortex. To further refine this structure-function relationship and quantify its inter-subject variability, a high-resolution digital anatomical atlas is fundamental. Using a combination of manual labeling and image processing, we turned a recently published reconstruction of the human cerebellum, the first such reconstruction fine enough to resolve the individual folia, into a digital atlas with both surface and volumetric representations. Its unprecedented granularity (0.16 mm) and detailed expert labeling make the atlas usable as an anatomical ground truth, enabling new ways of analyzing and visualizing cerebellar data through its digital format.

Single-nucleus multiome analysis of human cerebellum in Alzheimer's disease-related dementia.

Although human cerebellum is known to be neuropathologically impaired in Alzheimer's disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes that contribute to this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq and snATAC-seq) analysis of 103,861 nuclei isolated from cerebellum from 9 human cases of AD/ADRD and 8 controls, and with frontal cortex of 6 AD donors for additional comparison. Using peak-to-gene linkage analysis, we identified 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions enriched for candidate cis-regulatory elements (cCREs). These cCREs were associated with AD/ADRD-specific transcriptomic changes and disease-related gene regulatory networks, especially for RAR Related Orphan Receptor A (RORA) and E74 Like ETS Transcription Factor 1 (ELF1) in cerebellar Purkinje cells and granule cells, respectively. Trajectory analysis of granule cell populations further identified disease-relevant transcription factors, such as RORA, and their regulatory targets. Finally, we prioritized two likely causal genes, including Seizure Related 6 Homolog Like 2 (SEZ6L2) in Purkinje cells and KAT8 Regulatory NSL Complex Subunit 1 (KANSL1) in granule cells, through integrative analysis of cCREs derived from snATAC-seq, genome-wide AD/ADRD loci, and Hi-C looping data. This first cell subtype-specific regulatory landscape in the human cerebellum identified here offer novel genomic and epigenomic insights into the neuropathology and pathobiology of AD/ADRD and other neurological disorders if broadly applied.

Proprioceptive engagement of the human cerebellum studied with 7T-fMRI

Abstract Proprioception, the process of perceiving our bodies in space, is a key aspect of self-perception. The cerebellar cortex is believed to play a critical role in proprioception. However, our understanding of the functional involvement of the cerebellum in proprioception remains limited due to the intricate, thin, and highly folded structure of the human cerebellar cortex, which is more challenging to resolve using in-vivo MRI compared to the cerebral cortex. In this study, we employed high-resolution, B1-shimmed, functional magnetic resonance imaging (fMRI) at 7T to investigate proprioceptive involvement of the cerebellum in humans. We used two tasks designed to differentially require proprioceptive information processing: midline-contralateral-finger-touch and simultaneous-unilateral-finger-flexing. We assessed responses to these tasks across three gradient directions inspired by the mesoscale cerebellar functional organisation, akin to laminar and columnar fMRI approaches in the cerebral cortex. Movements requiring higher proprioceptive engagement, in the midline-contralateral-finger-touch task, elicited stronger activations in both anterior and posterior lobe motor areas of the cerebellum (lobules V and VIIIa/b). We identified distinct activation patterns for the two tasks within these cerebellar motor regions, which may reflect differing functional roles of these motor areas. Midline-contralateral-finger-touch responses were found more medial than simultaneous-unilateral-finger-flexing responses in lobule V and deeper into the cerebellar fissures in lobule VIII. These findings contribute to a deeper understanding of cerebellar functional organisation, the cerebellar involvement in proprioception and may offer insights into addressing proprioceptive deficits associated with neurological conditions.

A human fetal cerebellar map of the late second trimester reveals developmental molecular characteristics and abnormality in trisomy 21

Our understanding of human fetal cerebellum development during the late second trimester, a critical period for the generation of astrocytes, oligodendrocytes, and unipolar brush cells (UBCs), remains limited. Here, we performed single-cell RNA sequencing (scRNA-seq) in human fetal cerebellum samples from gestational weeks (GWs) 18-25. We find that proliferating UBC progenitors distribute in the subventricular zone of the rhombic lip (RLSVZ) near white matter (WM), forming a layer structure. We also delineate two trajectories from astrogenic radial glia (ARGs) to Bergmann glial progenitors (BGPs) and recognize oligodendrogenic radial glia (ORGs) as one source of primitive oligodendrocyte progenitor cells (PriOPCs). Additionally, our scRNA-seq analysis of the trisomy 21 fetal cerebellum at this stage reveals abnormal upregulated genes in pathways such as the cell adhesion pathway and focal adhesion pathway, which potentially promote neuronal differentiation. Overall, our research provides valuable insights into normal and abnormal development of the human fetal cerebellum.

The cerebellum computes frequency dynamics for motions with numerical precision and cross-individual uniformity.

Cross-individual variability is considered the essence of biology, preventing precise mathematical descriptions of biological motion1-7 like the physics law of motion. Here we report that the cerebellum shapes motor kinematics by encoding dynamic motor frequencies with remarkable numerical precision and cross-individual uniformity. Using in-vivo electrophysiology and optogenetics in mice, we confirmed that deep cerebellar neurons encoded frequencies via populational tuning of neuronal firing probabilities, creating cerebellar oscillations and motions with matched frequencies. The mechanism was consistently presented in self-generated rhythmic and non-rhythmic motions triggered by a vibrational platform, or skilled tongue movements of licking in all tested mice with cross-individual uniformity. The precision and uniformity allowed us to engineer complex motor kinematics with designed frequencies. We further validated the frequency-coding function of the human cerebellum using cerebellar electroencephalography recordings and alternating-current stimulation during voluntary tapping tasks. Our findings reveal a cerebellar algorithm for motor kinematics with precision and uniformity, the mathematical foundation for brain-computer interface for motor control.

Laminar Architecture and Morphometry of Developing Human Fetal Cerebellum

Abstract Background: One of the organs in the human fetus that starts to differentiate extremely early and keeps doing so throughout the postnatal period is the cerebellum. The goal of this study was to create a nomogram using the chronological events that were occurring and the relationship with progressing gestational age. Granule cells and Purkinje cells play a crucial role in the normal development of the cerebellum. Any disruption at the cellular level can lead to abnormal migration of these cells, potentially resulting in hypoplasia of the cerebellar vermis. Methodology: Tissue specimens from 60 human fetuses were studied for histological changes after being grouped into four from 13th week to 32nd week. Fetuses with any neurological deficit were excluded from the study. Different layers were identified, and the thickness of each layer was noted. Results: The first two groups had three layers, but the composition was different in both. The marginal and mantle layers in the second group disappeared completely. The third group showed presence of five layers, with addition of lamina dissecans, appearing for a transient period. The fourth group had four layers. The thickness of external granular layer and internal granular layer (IGL) increased throughout, except that the IGL made an appearance from the second group only. Lamina dissecans appeared, causing a significant shift between 23 and 27 weeks. The fetus has a four-layered structure near term, with an external granular layer persisting throughout the early postnatal stage of life. Progression of pregnancy was positively connected with the molecular and Purkinje cell layer (PCL) thickness. Conclusion: Progression of pregnancy was positively connected with the molecular and PCL thickness. Age determination and neuropsychiatric disorders of the developing fetus may benefit from such a link.

EPEN-08. MULTI-OMICS PROFILES REVEAL UNIQUE DEFINING MOLECULAR FEATURES OF POSTERIOR FOSSA EPENDYMOMA SUBTYPE A FROM INFANTS

Abstract BACKGROUND Ependymoma is a heterogeneous brain cancer with multiple subgroups based on locations and molecular profiles. Tumours of the methylation class, posterior fossa group A (PF-EPN-A) represent the most common and aggressive neoplasms and have a poor outcome. PF-EPN-A tumours in infants (under three years of age) are understudied; this project aimed to characterise these infant tumours. METHODS We collected DNA methylation (n=570) and gene expression (n=56) profiles of PF-EPN-A tumours, and single-cell RNA sequencing data of human fetal cerebellum from published studies. RESULTS Analysis of copy number profiles derived from DNA methylation arrays showed that infants with PF-EPN-A have relatively quiescent genomes when compared to children aged four to eighteen years (mean fraction of changes in infants (n=300) = 0.018 and children (n=270) = 0.055; p-value < 2.2 × 10-16). No recurrent focal amplifications or losses were detected, however, copy number loss involving chromosome arms, 12q (12%), 7q (9.7%), 5p (8.3%), and 16p (6%) were relatively common in infants, while 1q gain, 6q loss, and 22q loss were more frequent in children. When we stratified PF-EPN-A based on copy number alterations, infants with altered genomes were associated with poor outcomes compared to infants with stable genomes (fraction of changes = 0), which in turn showed poor overall survival compared to children with stable genomes. Gene set enrichment analysis using data from microarrays showed that infant tumours were specifically enriched with genes involved in the extracellular matrix organization, interferon gamma signaling, neuronal system, autophagy, and signaling by Interleukins, VEGF and PDGF. Integration with single-cell data from the human fetal cerebellum revealed that infants in PF-EPN-A had significantly higher proportions of glial progenitor cells and decreased granule cell progenitor subpopulations. CONCLUSIONS Together, our study identifies distinct genetic and transcriptional programs among infants in PF-EPN-A tumours, representing opportunities to refine future treatment.

ATRT-02. RECAPITULATING THE POST-SURGICAL BRAIN MICROENVIRONMENT OF ATYPICAL TERATOID RHABDOID TUMOURS TO IDENTIFY MEMBRANE PROTEIN CANDIDATES FOR TARGETED THERAPY

Abstract BACKGROUND Atypical Teratoid Rhabdoid Tumours – (AT/RT) are rare and aggressive tumours primarily arising in the hind brain of children under three, conferring median survival of <12 months. Surgery remains the only standard treatment; however tumours recur from post-surgical residual disease. The utilisation of PolyEthylene Glycol Diacrylate – (PEGDA) hydrogel and decellularised human brain cerebellum extracellular matrix aim to recapitulate AT/RT post-surgery brain microenvironments, where we hypothesise AT/RT plasma membrane proteins represent viable molecular therapy targets. METHODS AT/RT and astrocyte membrane protein cellular fractions were extracted and analysed using liquid chromatography-mass spectrometry. Proteomic analyses was integrated to identify differentially expressed AT/RT and astrocyte membrane proteins. RESULTS PEGDA and decellularised brain tissue were biocompatible for AT/RT-astrocyte co-cultured spheroid growth. AT/RT and astrocyte KEGG Pathway analysis revealed more specific oncology-based pathway expression in membrane protein than total protein, thus reinforcing membrane proteins as suitable therapeutic targets. Between the top 20 expressed membrane proteins, only ATP1A1 was shared exclusively between all AT/RT cells and astrocytes, suggesting a potential functional role. Membrane proteins showing shared expression when normalised against each AT/RT cell line included ATP1A1, HSPD1, GNA13 and SLC3A2, indicating biological similarities between AT/RT subtypes. Membrane proteins expressed similarly in AT/RT-MYC subtypes include ATP1A1, SLC7A5 and EEF1A1. ATP1A1 network analyses of AT/RT and astrocyte membrane protein pathways displayed strong interactions with ATP1B1, SLC7A5 and SLC3A2, therefore likely to map common expressed shared pathways. CONCLUSIONS AT/RT membrane protein pathways offer novel therapeutic targets directly amenable for drug repurposing. Future work prioritises proteomic analysis utilising 3D AT/RT spheroids and cerebellum brain tissue to maximise accurately recapitulating AT/RT post-surgical microenvironments.

ATRT-01. MODELLING ATYPICAL TERATOID/ RHABDOID TUMOUR AND HEALTHY BRAIN CROSSTALK

Abstract BACKGROUND Atypical Teratoid/Rhabdoid Tumours (ATRT) are aggressive paediatric brain tumours which mostly occur in the first three years of life and which rapidly recur after surgical resection. There has been debate over the use of cytotoxic consolidation therapy due to the severity of off target effects associated with chemo/radiotherapy use in young patients. Astrocytes have previously been shown to support progression and therapy resistance of other brain tumours; however, their role in ATRT pathophysiology is yet to be elucidated. METHODS To better understand how adjacent “healthy” brain tissue may be complicit in ATRT recurrence, we have developed a 3D in vitro model in which ATRT cells are co-cultured with astrocytes within a bespoke decellularized human cerebellum extracellular matrix (ECM) hydrogel. RESULTS Immunofluorescence confirmed that human cerebellar ECM hydrogels retain human brain ECM components (hyaluronic acid, laminin, and fibronectin). ATRT-astrocyte co-culture spheroids were formed within the ECM hydrogel and observed to display a distinctive morphology relative to monoculture controls, with no difference in overall viability. Co-cultured tumour cells were successfully harvested from the model and isolated from astrocyte populations using fluorescence activated cell sorting. In both 2D and 3D culture, we have shown that astrocytes labelled with CM-DiI transfer this cell tracker dye to ATRT-MYC (BT12, BT16) and ATRT-TYR (BT37) cells, potentially indicating intercellular trafficking. Furthermore, in 2D culture ATRT-MYC (BT12 and BT16) cells form actin rich cell-cell processes with astrocytes when co-cultured in vitro. CONCLUSIONS This work represents a comprehensively characterised model of ATRT interaction with the healthy brain. Future work will analyse changes in ATRT cell transcriptomes when astrocytes are present in the model. By understanding how the presence of astrocytes in the tumour microenvironment may promote tumour survival and progression, we aim to use this data to identify candidate therapeutics to inhibit crosstalk and improve patient outcomes.

Expression of transforming growth factor β signalling molecules and their correlations with genes in loci linked to polycystic ovary syndrome in human foetal and adult tissues.

Context Altered signalling of androgens, anti-Müllerian hormone or transforming growth factor beta (TGFβ) during foetal development have been implicated in the predisposition to polycystic ovary syndrome (PCOS) in later life, aside from its genetic predisposition. In foetal ovarian fibroblasts, TGFβ1 has been shown to regulate androgen signalling and seven genes located in loci associated with PCOS. Since PCOS exhibits a myriad of symptoms, it likely involves many different organs. Aims To identify the relationships between TGFβ signalling molecules and PCOS candidate genes in different tissues associated with PCOS. Methods Using RNA sequencing data, we examined the expression patterns of TGFβ signalling molecules in the human ovary, testis, heart, liver, kidney, brain tissue, and cerebellum from 4 to 20weeks of gestation and postnatally. We also examined the correlations between gene expression of TGFβ signalling molecules and PCOS candidate genes. Key results TGFβ signalling molecules were dynamically expressed in most tissues prenatally and/or postnatally. FBN3 , a PCOS candidate gene involved in TGFβ signalling, was expressed during foetal development in all tissues. The PCOS candidate genes HMGA2, YAP1 , and RAD50 correlated significantly (P TGFBR1 in six out of the seven tissues examined. Conclusions This study suggests that possible crosstalk occurs between genes in loci associated with PCOS and TGFβ signalling molecules in multiple tissues, particularly during foetal development. Implications Thus, alteration in TGFβ signalling during foetal development could affect many tissues contributing to the multiple phenotypes of PCOS in later life.

A hierarchical atlas of the human cerebellum for functional precision mapping.

The human cerebellum is activated by a wide variety of cognitive and motor tasks. Previous functional atlases have relied on single task-based or resting-state fMRI datasets. Here, we present a functional atlas that integrates information from 7 large-scale datasets, outperforming existing group atlasses. The new atlas has three further advantages: First, the atlas allows for precision mapping in individuals: The integration of the probabilistic group atlas with an individual localizer scan results in a marked improvement in prediction of individual boundaries. Second, we provide both asymmetric and symmetric versions of the atlas. The symmetric version, which is obtained by constraining the boundaries to be the same across hemispheres, is especially useful in studying functional lateralization. Finally, the regions are hierarchically organized across 3 levels, allowing analyses at the appropriate level of granularity. Overall, the new atlas is an important resource for the study of the interdigitated functional organization of the human cerebellum in health and disease.

Pilot study of the relation between various dynamics of avatar experience and perceptual characteristics

In recent years, due to the prevalence of virtual reality (VR) and human-computer interaction (HCI) research, along with the expectation that understanding the process of establishing sense of ownership, sense of agency, and limb heaviness (in this study, limb heaviness is replaced with comfort level) will contribute to the development of various medical rehabilitation, various studies have been actively conducted in these fields. Previous studies have indicated that each perceptual characteristics decrease in response to positive delay. However, it is still unclear how each perceptual characteristic changes in response to negative delay. Therefore, the purpose of this study was to deduce how changes occur in the perceptual characteristics when certain settings are manipulated using the avatar developed in this study. This study conducted experiments using an avatar system developed for this research that uses electromyography as the interface. Two separate experiments involved twelve participants: a preliminary experiment and a main experiment. As observed in the previous study, it was confirmed that each perceptual characteristics decreased for positive delay. In addition, the range of the preliminary experiment was insufficient for the purpose of this study, which was to confirm the perceptual characteristics for negative delay, thus confirming the validity of conducting this experiment. Meanwhile, the main experiment showed that the sense of ownership, sense of agency, and comfort level decreased gradually as delay time decreased, (i.e., this event is prior to action with intention, which could not be examined in the previous study). This suggests that control by the brain-machine interface is difficult to use when it is too fast. In addition, the distribution of the most strongly perceived settings in human perceptual characteristics was wider in regions with larger delays, suggesting this may lead to the evaluation of an internal model believed to exist in the human cerebellum. The avatar developed for this study may have the potential to create a new experimental paradigm for perceptual characteristics.