Healthy Adult Human Brain Research Articles

Single-cell atlas of the human brain vasculature across development, adulthood and disease

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell–cell interaction analyses predict substantial endothelial-to-perivascular cell ligand–receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.

Acute effects of (-)-gallocatechin gallate-rich green tea extract on the cerebral hemodynamic response of the prefrontal cortex in healthy humans.

The benefits of long-term consumption of green tea on the brain are well known. However, among many ingredients of green tea, the acute effects of (-)-gallocatechin gallate-rich green tea extract (GCG-GTE), have received comparatively less attention. Herein, we investigated the acute effects of oral ingestion of green tea with GCG-GTE, which contains close replicas of the ingredients of hot green tea, on task-dependent hemodynamics in the prefrontal cortex of healthy adult human brains. In this randomized, double-blind, placebo-controlled, parallel group trial, 35 healthy adults completed computerized cognitive tasks that demand activation of the prefrontal cortex at baseline and 1 h after consumption of placebo and 900 mg of GCG-GTE extract supplement. During cognitive testing, hemodynamic responses (change in HbO2 concentration) in the prefrontal cortex were assessed using functional near-infrared spectroscopy (fNIRS). In fNIRS data, significant group x session interactions were found in the left (p = 0.035) and right (p = 0.036) dorsolateral prefrontal cortex (DLPFC). In behavioral data, despite the numerical increase in the GCG-GTE group and the numerical decrease in the Placebo group, no significant differences were observed in the cognitive performance measure between the groups. The result suggests a single dose of orally administered GCG-GTE can reduce DLPFC activation in healthy humans even with increased task demand. GCG-GTE is a promising functional material that can affect neural efficiency to lower mental workload during cognitively demanding tasks. However, further studies are needed to verify this.

Unfolding the direct connectivity of the occipital cortex with the hypothalamic, septal and BNST nuclei of the human brain

The hypothalamus plays essential roles in the human brain by regulating feeding, fear, aggression, reproductive behaviors, and autonomic activities. The septal nuclei and the bed nucleus of stria terminalis (BNST) are also known to be involved in control of autonomic, motivational, learning, emotional and associative processes in the human brain. Multiple animal dissection studies have revealed direct connectivity between central limbic gray matter nuclei and occipital cortex, particularly from the hypothalamic, septal and BNST nuclei. However, the detailed anatomy of this connectivity in the human brain has yet to be determined. The primary objective of this study was to explore the utility of high spatial and high angular resolution diffusion weighted tractography techniques for mapping the connectivity pathways between the occipital cortex and central limbic gray matter nuclei in the human brain. We studied 30 healthy adult human brains, delineated, and reconstructed the trajectory of the occipito-hypothalamic/septal/BNST for the first time in the human brain.

A systematic review of fMRI studies of healthy adult human brain activation on learning and memory patterns for numerals

This systematic review examines the empirical evidence from previous fMRI studies on brain activation areas for learning and memory patterns for numerals to understand the question of the brain activation areas found from previous fMRI studies on learning and memory patterns for numerals. Relevant articles in the fields of psychology, neuroscience, paediatrics, and education were extracted from the PubMed database. Keyword searches included "learning", "memory", "brain", "digits", "numerals", and "fMRI". The database search was conducted from July 2022 to August 2022. The data collected was limited to English texts, and studies involving animal experiments were excluded. The remaining articles were screened based on the inclusion and exclusion criteria. Articles included in this review were selected from the database search between 1999 to 2022. Ten full-text articles were identified and evaluated. Examination of brain activation regions in learning and memory patterns for numerals revealed that 30% of studies (n=3) found activation in the hippocampus, inferior parietal lobe and parietal lobe. Subsequently, 20% of the studies (n=2) found activation in the anterior cingulate, caudate nucleus, cerebellum, frontal lobe, inferior frontal gyrus, inferior temporal gyrus, medial temporal lobe, occipital lobe, prefrontal cortex, striatum, and thalamus. The frontoparietal network is considered important for working memory, while the limbic areas are essential for learning and memory. Therefore, future studies should look more closely at the brain's functional and structural regions involved in learning and a more specific memory system.

Lipid Adaptations against Oxidative Challenge in the Healthy Adult Human Brain.

It is assumed that the human brain is especially susceptible to oxidative stress, based on specific traits such as a higher rate of mitochondrial free radical production, a high content in peroxidizable fatty acids, and a low antioxidant defense. However, it is also evident that human neurons, although they are post-mitotic cells, survive throughout an entire lifetime. Therefore, to reduce or avoid the impact of oxidative stress on neuron functionality and survival, they must have evolved several adaptive mechanisms to cope with the deleterious effects of oxidative stress. Several of these antioxidant features are derived from lipid adaptations. At least six lipid adaptations against oxidative challenge in the healthy human brain can be discerned. In this work, we explore the idea that neurons and, by extension, the human brain is endowed with an important arsenal of non-pro-oxidant and antioxidant measures to preserve neuronal function, refuting part of the initial premise.

Volumetric measurements of the subcortical structures of healthy adult brains in the Turkish population.

The interest in the morphological development of brain structures during childhood and adolescence arises from discussions on subcortical anomalies and sexual dimorphism, from adolescent changes in cognitive functions supported by cortical and subcortical structures to a wide range of childhood neuropsychiatric diseases. This study aims to investigate the subcortical structures regarding age/gender changes in the healthy adult human brain using web-based volBrain. In this study, 303 normal healthy adults (males and females) were examined using a 1.5 T unit with a 20-channel head coil. The volumes of white matter, grey matter, total brain, cerebrospinal fluid, and total intracranial volume were significantly higher in males than those in females. Our analysis revealed a significantly larger accumbens volume in females. With the age of less than or equal to 50 years, older males were found to have higher total lateral ventricle, putamen, thalamus, amygdala, cerebrum, white matter and grey matter volumes than females. In the age group of 50 years and older mean total volumes of thalamus, globus pallidus and accumbens were higher in females than those in males. Right hemisphere volumes in younger and older age groups were higher except for caudate volume in the older age group; the mean of caudate was significantly higher in females than those in males. These conclusions might be important for the explanation of the effects of gender and age in cross-sectional structural magnetic resonance imaging studies. Also, knowing the volume changes of the subcortical structures can provide convenience about the prevention, diagnosis, and treatment of various neuromental disorders.

Identification of HnRNPC as a novel Tau exon 10 splicing factor using RNA antisense purification mass spectrometry

ABSTRACT Alternative splicing in Tau exon 10 generates 3 R- and 4 R-Tau proteoforms, which have equal abundance in healthy adult human brain. Aberrant alternative splicing in Tau exon 10 leads to distortion of the balanced 3 R- and 4 R-Tau expression levels, which is a causal factor to trigger toxic Tau aggregation, neuron dysfunction and patient death in a group of neurodegenerative diseases known as tauopathies. Hence, identification of regulators upstream of the Tau exon 10 splicing events are crucial to understanding pathogenic mechanisms driving tauopathies. In this study, we used RNA Antisense Purification with Mass Spectrometry (RAP-MS) analysis to identify RNA-binding proteins (RBPs) that interact with the Tau pre-mRNA near exon 10. Among the newly identified RBP candidates, we show that knockdown of hnRNPC induces Tau exon 10 skipping whereas overexpression of hnRNPC promotes Tau exon 10 inclusion. In addition, we show that hnRNPC interacts with the poly-uridine (U-tract) sequences in introns 9 and 10 of Tau pre-mRNA. Mutation of these U-tract motifs abolished binding of hnRNPC with Tau pre-mRNA fragment and blocked its impact on Tau exon 10 inclusion. These findings indicate that hnRNPC binds and utilizes these U-tract motifs located in introns 9 and 10 of Tau pre-mRNA to promote Tau exon 10 inclusion. Intriguingly, high hnRNPC expression level is associated with progressive supranuclear palsy (PSP), a sporadic tauopathy with pathological accumulation of Tau species that contain exon 10, which suggests a putative therapeutic role of hnRNPC for PSP treatment.

Imaging transcriptomics: Convergent cellular, transcriptomic, and molecular neuroimaging signatures in the healthy adult human brain.

The integration of transcriptomic and neuroimaging data, "imaging transcriptomics," has recently emerged to generate hypotheses about potential biological pathways underlying regional variability in neuroimaging features. However, the validity of this approach is yet to be examined in depth. Here, we sought to bridge this gap by performing transcriptomic decoding of the regional distribution of well-known molecular markers spanning different elements of the biology of the healthy human brain. Imaging transcriptomics identifies biological and cell pathways that are consistent with the known biology of a wide range of molecular neuroimaging markers. The extent to which it can capture patterns of gene expression that align well with elements of the biology of the neuroinflammatory axis, at least in healthy controls without a proinflammatory challenge, is inconclusive. Imaging transcriptomics might constitute an interesting approach to improve our understanding of the biological pathways underlying regional variability in a wide range of neuroimaging phenotypes.

Imaging Transcriptomics: Convergent Cellular, Transcriptomic, and Molecular Neuroimaging Signatures in the Healthy Adult Human Brain

Imaging Transcriptomics: Convergent Cellular, Transcriptomic, and Molecular Neuroimaging Signatures in the Healthy Adult Human Brain

Folding drives cortical thickness variations

The cortical thickness is a characteristic biomarker for a wide variety of neurological disorders. While the structural organization of the cerebral cortex is tightly regulated and evolutionarily preserved, its thickness varies widely between 1.5 and 4.5 mm across the healthy adult human brain. It remains unclear whether these thickness variations are a cause or consequence of cortical development. Recent studies suggest that cortical thickness variations are primarily a result of genetic effects. Previous studies showed that a simple homogeneous bilayered system with a growing layer on an elastic substrate undergoes a unique symmetry breaking into a spatially heterogeneous system with discrete gyri and sulci. Here, we expand on that work to explore the evolution of cortical thickness variations over time to support our finding that cortical pattern formation and thickness variations can be explained – at least in part – by the physical forces that emerge during cortical folding. Strikingly, as growth progresses, the developing gyri universally thicken and the sulci thin, even in the complete absence of regional information. Using magnetic resonance images, we demonstrate that these naturally emerging thickness variations agree with the cortical folding pattern in n = 9 healthy adult human brains, in n = 564 healthy human brains ages 7–64, and in n = 73 infant brains scanned at birth, and at ages one and two. Additionally, we show that cortical organoids develop similar patterns throughout their growth. Our results suggest that genetic, geometric, and physical events during brain development are closely interrelated. Understanding regional and temporal variations in cortical thickness can provide insight into the evolution and causative factors of neurological disorders, inform the diagnosis of neurological conditions, and assess the efficacy of treatment options.

Multi-speckle diffuse correlation spectroscopy to measure cerebral blood flow.

We present a multi-speckle diffuse correlation spectroscopy (DCS) system for measuring cerebral blood flow in the healthy adult human brain. In contrast to the need for a high frame rate camera to measure the multi-speckle intensity auto-correlation, we employ a low frame rate camera to measure the auto-correlation using the recently introduced multi-step volterra integral method (MVIM). The results are validated by comparison against the blood flow measured using standard DCS system.

Uncovering the Dorsal Thalamo-hypothalamic Tract of the Human Limbic System

As a non-limbic structure, the human thalamus is the most important modulator of the limbic system. The hypothalamus plays vital roles in the survival of species by regulating fear, learning, feeding behavior, circadian rhythm, sociosexual and reproductive activities of the limbic system through connections with the thalamus. The detailed anatomy of the pathways responsible for mediating these responses, however, is yet to be determined. The mammillothalamic tract is known as the major direct thalamo-hypothalamic connection in the primates including the human brain connecting the ventral thalamus to the dorsal hypothalamus. Multiple dissection animal studies revealed additional connections specially from the dorsal thalamus to the ventral hypothalamic nuclei. Diffusion weighted imaging may be helpful in better visualizing the surgical anatomy of this additional connectivity noninvasively. This study aimed to investigate the utility of high spatial and high angular resolution diffusion weighted tractography technique for mapping the trajectory of this dorsal thalamic connectivity with the ventral hypothalamus in the human brain. We studied 30 healthy human subjects. Using a high-resolution diffusion weighted tractography technique, for the first time, we were able to delineate and reconstruct the trajectory of the dorsal thalamo-hypothalamic tract (DTH). We further revealed the close relationship of the DTH, fornix and hippocampus in healthy adult human brain.

Development of a Competition-Binding Assay to Determine Binding Affinity of Molecules to Neuromelanin via Fluorescence Spectroscopy.

Neuromelanin, the polymeric form of dopamine which accumulates in aging neuronal tissue, is increasingly recognized as a functional and critical component of a healthy and active adult human brain. Notorious in plant and insect literature for their ability to bind and retain amines for long periods of time, catecholamine polymers known colloquially as ‘melanins’ are nevertheless curiously absent from most textbooks regarding biochemistry, neuroscience, and evolution. Recent research has brought attention to the brain pigment due to its possible role in neurodegeneration. This linkage is best illustrated by Parkinson’s disease, which is characterized by the loss of pigmented dopaminergic neurons and the ‘white brain’ pathological state. As such, the ability to determine the binding affinity of neurotoxic agents, as well as any potential specific endogenous ligands to neuromelanin are of interest and potential value. Neuromelanin has been shown to have saturable binding interactions with nicotine as monitored by a fluorimeter. This interaction provides a signal to allow for a competition-binding assay with target molecules which do not themselves produce signal. The current report establishes the viability of this competition assay toward three compounds with central relevance to Parkinson’s disease. The Kd of binding toward neuromelanin by methyl-phenyl-pyridinium ion (MPP+), dopamine, and 6-hydroxydopamine were found to be 1 mM, 0.05 mM, and 0.1 mM, respectively in the current study. In addition, we demonstrate that 6-hydroxydopamine polymerizes to form neuromelanin granules in cultured dopaminergic neurons that treated with 2,4,5-trihydroxy-l-phenylalanine. Immunohistochemical analysis using fluor-tagged anti-dopamine antibodies suggests that the incorporation of 6-hydroxydopamine (following internalization and decarboxylation analogous to levodopa and dopamine) alters the localized distribution of bound dopamine in these cells.

Mapping the trajectory of the amygdalothalamic tract in the human brain.

Although the thalamus is not considered primarily as a limbic structure, abundant evidence indicates the essential role of the thalamus as a modulator of limbic functions indirectly through the amygdala. The amygdala is a central component of the limbic system and serves an essential role in modulating the core processes including the memory, decision-making, and emotional reactions. The amygdalothalamic pathway is the largest direct amygdalo-diencephalic connection in the primates including the human brain. Given the crucial role of the amygdalothalamic tract (ATT) in memory function and diencephalic amnesia in stroke patients, diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of this pathway noninvasively. To date, few diffusion-weighted studies have focused on the amygdala, yet the fine neuronal connection of the amygdala and thalamus known as the ATT has yet to be elucidated. This study aimed to investigate the utility of high spatial resolution diffusion tensor tractography for mapping the trajectory of the ATT in the human brain. We studied 15 healthy right-handed human subjects (12 men and 3 women with age range of 24-37 years old). Using a high-resolution diffusion tensor tractography technique, for the first time, we were able to reconstruct and measure the trajectory of the ATT. We further revealed the close relationship of the ATT with the temporopontine tract and the fornix bilaterally in 15 healthy adult human brains.

Specific Metabolomics Adaptations Define a Differential Regional Vulnerability in the Adult Human Cerebral Cortex.

Brain neurons offer diverse responses to stresses and detrimental factors during development and aging, and as a result of both neurodegenerative and neuropsychiatric disorders. This multiplicity of responses can be ascribed to the great diversity among neuronal populations. Here we have determined the metabolomic profile of three healthy adult human brain regions—entorhinal cortex, hippocampus, and frontal cortex—using mass spectrometry-based technologies. Our results show the existence of a lessened energy demand, mitochondrial stress, and lower one-carbon metabolism (particularly restricted to the methionine cycle) specifically in frontal cortex. These findings, along with the better antioxidant capacity and lower mTOR signaling also seen in frontal cortex, suggest that this brain region is especially resistant to stress compared to the entorhinal cortex and hippocampus, which are more vulnerable regions. Globally, our results show the presence of specific metabolomics adaptations in three mature, healthy human brain regions, confirming the existence of cross-regional differences in cell vulnerability in the human cerebral cortex.

Revealing the ventral amygdalofugal pathway of the human limbic system using high spatial resolution diffusion tensor tractography.

The amygdala is known to have a role in core processes regulated by the limbic system such as motivation, memory, emotion, social behavior, self-awareness as well as certain primitive instincts. Several functional studies have investigated some of these brain tasks of the human limbic system. However, the underlying neuronal fiber connectivity of the amygdalo-diencephalon, as part of the limbic system, has not been delineated separately by prior diffusion-weighted imaging studies. The ability to trace the underlying fiber connections individually will be helpful in understanding the neurophysiology of these tracts in different functions. To date, few diffusion-weighted studies have focused on the amygdala, yet the fine connections of the amygdala, hypothalamus, septum or other adjacent limbic structures have yet to be elucidated by diffusion-weighted tractography studies. We therefore aimed to further investigate these fine neuronal connections using fiber tractography and high spatial resolution diffusion tensor imaging on 3T on 15 healthy right-handed male human subjects (age range 24-37years). The ventral amygdalofugal pathway, anterior commissure and stria terminalis are the three main efferent pathways of the amygdala. We delineated the detailed trajectories of the ventral amygdalofugal tract, anterior commissure and their connections bilaterally in 15 normal adult human brains. Using a high-resolution diffusion tensor tractography technique, for the first time, we were able to demonstrate the trajectory of amygdalofugal tract and its connections to the hypothalamic and septal nuclei. We further revealed, for the first time, the close relationship of the amygdalofugal tract and anterior commissure with the fornix, stria terminalis and uncinate fasciculus bilaterally in 15 healthy adult human brains.

4D hyperspherical harmonic (HyperSPHARM) representation of surface anatomy: a holistic treatment of multiple disconnected anatomical structures.

Image-based parcellation of the brain often leads to multiple disconnected anatomical structures, which pose significant challenges for analyses of morphological shapes. Existing shape models, such as the widely used spherical harmonic (SPHARM) representation, assume topological invariance, so are unable to simultaneously parameterize multiple disjoint structures. In such a situation, SPHARM has to be applied separately to each individual structure. We present a novel surface parameterization technique using 4D hyperspherical harmonics in representing multiple disjoint objects as a single analytic function, terming it HyperSPHARM. The underlying idea behind HyperSPHARM is to stereographically project an entire collection of disjoint 3D objects onto the 4D hypersphere and subsequently simultaneously parameterize them with the 4D hyperspherical harmonics. Hence, HyperSPHARM allows for a holistic treatment of multiple disjoint objects, unlike SPHARM. In an imaging dataset of healthy adult human brains, we apply HyperSPHARM to the hippocampi and amygdalae. The HyperSPHARM representations are employed as a data smoothing technique, while the HyperSPHARM coefficients are utilized in a support vector machine setting for object classification. HyperSPHARM yields nearly identical results as SPHARM, as will be shown in the paper. Its key advantage over SPHARM lies computationally; HyperSPHARM possess greater computational efficiency than SPHARM because it can parameterize multiple disjoint structures using much fewer basis functions and stereographic projection obviates SPHARM's burdensome surface flattening. In addition, HyperSPHARM can handle any type of topology, unlike SPHARM, whose analysis is confined to topologically invariant structures.

Decoding the superior parietal lobule connections of the superior longitudinal fasciculus/arcuate fasciculus in the human brain

The temporo-parietal (TP) white matter connections between the inferior parietal lobule and superior temporal gyrus as part of the superior longitudinal fasciculus/arcuate fasciculus (SLF/AF) or middle longitudinal fasciculus (MdLF) have been studied in prior diffusion tensor tractography (DTT) studies. However, few studies have been focusing on the higher TP connections of the superior parietal lobule with the temporal lobe. These higher TP connections have been shown to have a role in core processes such as attention, memory, emotions, and language. Our most recent study, for the first time, hinted to the possibility of a long white matter connection interconnecting the superior parietal lobule (SPL) with the posterior temporal lobe in human brain which we call the SLF/AF TP-SPL and for a shorter abbreviation, the TP-SPL. We decided to further investigate this white matter connection using fiber assignment by continuous tracking deterministic tractography and high spatial resolution diffusion tensor imaging on 3T. Five healthy right-handed men (age range 24–37years) were studied. We delineated the SPL connections of the SLF/AF TP bilaterally in five normal adult human brains. Using a high resolution DTT technique, we demonstrate for the first time, the trajectory of a long fiber bundle connectivity between the SPL and posterior temporal lobe, called the SLF/AF TP-SPL (or the TP-SPL), bilaterally in five healthy adult human brains. We also demonstrate the trajectory of the vertically oriented posterior TP connections, interconnecting the inferior parietal lobule (IPL) with the posterior temporal lobe (TP-IPL) in relation to the TP-SPL, arcuate fasciculus and other major language pathways. In the current study, for the first time, we categorized the TP connections into the anterior and posterior connectivity groups and subcategorized each one into the SPL or IPL connections.

A Scaffold for Efficiency in the Human Brain

The comprehensive relations between healthy adult human brain white matter (WM) microstructure and gray matter (GM) function, and their joint relations to cognitive performance, remain poorly understood. We investigated these associations in 27 younger and 28 older healthy adults by linking diffusion tensor imaging (DTI) with functional magnetic resonance imaging (fMRI) data collected during an n-back working memory task. We present a novel application of multivariate Partial Least Squares (PLS) analysis that permitted the simultaneous modeling of relations between WM integrity values from all major WM tracts and patterns of condition-related BOLD signal across all GM regions. Our results indicate that greater microstructural integrity of the major WM tracts was negatively related to condition-related blood oxygenation level-dependent (BOLD) signal in task-positive GM regions. This negative relationship suggests that better quality of structural connections allows for more efficient use of task-related GM processing resources. Individuals with more intact WM further showed greater BOLD signal increases in typical "task-negative" regions during fixation, and notably exhibited a balanced magnitude of BOLD response across task-positive and -negative states. Structure-function relations also predicted task performance, including accuracy and speed of responding. Finally, structure-function-behavior relations reflected individual differences over and above chronological age. Our findings provide evidence for the role of WM microstructure as a scaffold for the context-relevant utilization of GM regions.

Function in the human connectome: Task-fMRI and individual differences in behavior

The primary goal of the Human Connectome Project (HCP) is to delineate the typical patterns of structural and functional connectivity in the healthy adult human brain. However, we know that there are important individual differences in such patterns of connectivity, with evidence that this variability is associated with alterations in important cognitive and behavioral variables that affect real world function. The HCP data will be a critical stepping-off point for future studies that will examine how variation in human structural and functional connectivity play a role in adult and pediatric neurological and psychiatric disorders that account for a huge amount of public health resources. Thus, the HCP is collecting behavioral measures of a range of motor, sensory, cognitive and emotional processes that will delineate a core set of functions relevant to understanding the relationship between brain connectivity and human behavior. In addition, the HCP is using task-fMRI (tfMRI) to help delineate the relationships between individual differences in the neurobiological substrates of mental processing and both functional and structural connectivity, as well as to help characterize and validate the connectivity analyses to be conducted on the structural and functional connectivity data. This paper describes the logic and rationale behind the development of the behavioral, individual difference, and tfMRI batteries and provides preliminary data on the patterns of activation associated with each of the fMRI tasks, at both group and individual levels.