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Liu, Z.-Q.

Publications and source records attributed to Liu, Z.-Q..

At least 19 recordsLinked to original sources

EigenBrain maps cortical molecular architecture from functional, geometric, and structural eigenmodes

Neurotransmitter receptor and transporter distributions shape neural communication across the cortex and underpin mechanistic interpretations of brain function. Magnetic resonance imaging (MRI)-derived eigenmodes, low-dimensional spatial patterns that capture the principal axes of cortical organization, are increasingly used to reconstruct brain maps and offer a potential route to approximating molecular topographies in large cohorts where direct measurements are unavailable. Yet whether the type of MRI data used to derive these eigenmodes determines which receptor and transporter distributions can be approximated, and which molecular systems are accessible through this approach at all, remains unknown. Using a spatial reconstruction framework applied to 23 molecular systems spanning neurotransmitter, metabolic, and pathological markers, we show that eight receptor and transporter maps, spanning serotonin, dopamine, histamine, cholinergic, and opioid markers, can be selectively approximated from functional eigenmodes but not structural or geometric ones. This selectivity also reveals that functional brain organization encodes a specific subset of neuromodulatory topographies that structural and geometric organization does not. To illustrate translational potential in clinical cohorts where molecular imaging is unavailable, we applied individual-level eigenmode decompositions of MRI data projected onto the eight validated molecular systems and detected cross-sectional differences in autism and longitudinal changes in schizophrenia. Together, these findings reveal a difference in how geometric, structural, and functional brain organization relate to molecular architecture, offering a method for approximating validated molecular profiles in population neuroimaging cohorts that lack direct molecular imaging.

neuroscience↗

Cerebral vasculature shapes the spatial patterning of brain metastases

Primary cancer cells that originate in diverse tissues in the body can spread to the brain through various physiological pathways and form metastatic tumors. The spatial patterning of brain metastases is highly stereotyped across individuals, but the physiological factors that confer regional vulnerability to tumor colonization are poorly understood. Here we map the brain metastases associated with primary breast cancer, lung cancer, and malignant melanoma to the multiscale organization of the brain. We analyze structural magnetic resonance imaging (MRI) data from more than 2, 300 cancer patients with approximately 10, 000 brain metastases to estimate metastatic frequency maps. We then examine whether transcriptional (microarray profiling), functional (functional MRI), and vascular (arterial spin labeling) features can predict the spatial pattern of each brain metastasis type. Our analyses highlight vascular anatomy as an integral determinant of metastatic patterning, particularly in breast and lung cancers. We find arterial border-zones as sites of elevated vulnerability to metastatic invasion. These areas, characterized by slow flow and small-caliber vessels, create a hemodynamic environment that favors the arrest and extravasation of circulating tumor cells. Together, these results provide quantitative support for the long-standing hypothesis that vascular architecture and its biomechanical properties constrain metastatic seeding in the brain. Identifying vascular topology as a key determinant of metastatic patterning suggests that systemic vascular and metabolic factors may contribute to metastatic risk.

neuroscience↗

Generalisable signatures of anaesthesia in the large-scale functional organisation of the marmoset brain

How the activity and connectivity of the brain support consciousness remains a central question in neuroscience. Recent progress driven by the use of functional MRI has seen growing recognition that large-scale distributed functional organisation of the human and non-human primate brain are systematically and consistently reshaped by anaesthetic-induced unconsciousness, across anaesthetics and across human and macaque. Here, we generalise these results to a different primate species that is gaining traction as model organism in neuroscience, the marmoset (Callithrix jacchus). We also generalise results to an additional anaesthetic, isoflurane, which we compare with propofol and sevoflurane. We report that under anaesthesia with propofol, sevoflurane, or isoflurane, distributed brain activity from functional MRI is increasingly constrained by the underlying structural connectivity across scales. Anaesthesia also induces a collapse of the principal gradient and intrinsic functional geometry of the marmoset brain, coinciding with a breakdown of hierarchical integration. Altogether, the present results indicate generalisable signatures of anaesthesia in the large-scale organisation of the primate brain.

neuroscience↗

The blueprint of human functional architecture shifts from cognition to anatomy during perturbations of consciousness

Consciousness and cognition arise from the ongoing interactions between brain regions. Synchronous fluctuations of fMRI signals may indicate that two brain regions perform similar cognitive functions, but neural interactions are also constrained by anatomical connectivity and regions molecular, cytoarchitectonic, and metabolic profiles. Here we disentangle the respective contributions of ongoing cognition and multimodal neurobiological constraints in shaping functional connectivity. We jointly contextualise haemodynamic FC against eight distinct multimodal representations of the human connectome: (i) structural connectivity from diffusion tractography; (ii) spatial embedding; (iii) similarity of transcriptional profiles from gene expression; (iv) similarity of receptor profiles from Positron Emission Tomography; (v) laminar profile similarity from histology; (vi) correlated electrophysiological activity from magnetoencephalography; (vii) correlated metabolic activity from PET glucose uptake; (viii) coordinated activation across 123 cognitive operations from the NeuroSynth meta-analytic engine. We demonstrate that cognitive co-activation is the dominant predictor of inter-regional fMRI synchrony in the awake human brain, even when quantified using intracranial electrical stimulation. Crucially, this predominance of cognitive co-activation for shaping functional connectivity is systematically obliterated across five datasets of pharmacological and pathological perturbations of consciousness (chronic disorders of consciousness; anaesthesia with sevoflurane, propofol, or ketamine) when cognition is disconnected from the environment or altogether abolished. Altogether, we show that multimodal predictors of functional architecture shift away from cognitive co-activation and toward anatomicalmolecular constraints during pharmacological and pathological perturbations of consciousness.

neuroscience↗

Homophily-informed generative models of brain maps

The structural and functional organization of the brain can be studied across multiple scales, yielding richly detailed topographic brain maps of biological features. What are the underlying forces that shape their spatial patterning? Here we introduce a simple generative model of multiscale brain maps based on the concept of inter-regional homophily: the tendency for regions that are proximal in a given physical, molecular or functional space to display similar biological features. We evaluate the model with respect to six definitions of inter-regional homophily, including physical proximity, structural and functional connectivity, and laminar, receptor and transcriptional similarity, and across 43 empirical brain maps estimated using multiple imaging, electrophysiological and histological technologies. We show that homophilic principles are sufficient to accurately reconstruct many maps, with biological similarity and functional connectivity often contributing more than the brains geometry. We also identify consistent patterns of unexplained variation in maps with low homophily, revealing axes of cortical organization not captured by canonical inter-regional relationships. Finally, we show that homophily-informed generative models can be used to disentangle complex relationships between brain features and make new inferences on how they fit together. Collectively, this work highlights the fundamental contribution of homophily to the topographic layout of numerous biological features of the brain.

neuroscience↗

Symptom Dimension-Specific Neurotransmitter Correlates of Psychopathology and Cognition in Early Psychosis

Extended duration of under-treated psychosis (DUP) is among the strongest predictors of poor outcome, yet diagnostic heterogeneity impedes treatment matching, with approximately 50% of patients failing to respond to first-line antipsychotics. Negative symptoms and cognitive impairment are particularly refractory, lacking effective pharmacological treatments. Identifying neurotransmitter systems associated with specific symptom dimensions could accelerate targeted therapeutic development and reduce DUP. We applied Partial Least Squares correlation (PLSc) to derive whole-brain resting-state functional connectivity (RSFC) and anatomical (cortical thickness and subcortical volume) signatures associated with five psychopathology dimensions (positive symptoms, negative symptoms, general psychopathology, mania, and cognition) in a transdiagnostic sample from the Human Connectome Project-Early Psychosis (HCP-EP; n=124). We tested associations with potential confounds including antipsychotic medication dosage and substance use. Signatures were spatially correlated with 21 Positron Emission Tomography (PET)-derived receptor and transporter maps across 9 neurotransmitter systems using the neuromaps toolbox. Significant RSFC signatures emerged for positive symptoms, negative symptoms, general psychopathology, and cognition, but not mania. The negative symptom RSFC signature correlated with norepinephrine transporter (NET; {rho}=.40, q=.030) and vesicular acetylcholine transporter (VAChT; {rho}=.38, q=.048) distributions. The cognition signature similarly correlated with VAChT ({rho}=.48, q=.025). Anatomical signatures were associated with positive symptoms, general psychopathology, and cognition, but were more susceptible to confounding by medication and substance use. No significant receptor associations were detected for anatomical signatures. These findings implicate cholinergic and noradrenergic systems as molecular targets for negative symptoms and cognitive impairment, supporting prioritization of these systems in pharmacotherapy development in early psychosis.

neuroscience↗

Structure-function coupling in the human brainstem

The nuclei of the brainstem fundamentally modulate neuronal activity throughout the central nervous system. Yet connectome reconstructions typically do not include the brainstem because it is notoriously difficult to image. As a result, the influence of the brainstem on structure-function coupling in the brain is unknown. Here we use high-resolution 7 Tesla magnetic resonance imaging (MRI) to reconstruct structural and functional brain connectomes encompassing cortex and 58 brainstem nuclei spanning the midbrain, pons, and medulla. We identify structural connectional profiles of individual brainstem nuclei to the cortex and find that they align with a spectrum of functions, spanning sensory and motor processing to higher-order cognition. Structural and functional connectivity in brainstem-augmented connectomes are positively correlated, and pairs of regions with direct anatomical projections display greater functional connectivity than pairs without. Structure-function coupling is heterogeneous across brainstem nuclei, with greatest coupling in both modulatory and relay nuclei. Collectively, this work presents an initial step towards understanding how the brainstem shapes structure-function relationships in the brain.

neuroscience↗

Spatial organization of AQP4 channels in the human brain: links with perfusion, edema, and disease vulnerability

Aquaporin-4 (AQP4) water channels support the glymphatic system, a brain-wide pathway that clears cerebral waste products. Despite its importance, the whole-brain organization of this system in humans remains underexplored. Here we use AQP4 gene expression as a molecular anchor to reconstruct a whole-brain glymphatic-related topography and link it to vascular physiology, edema, and neurode-generative vulnerability. We find that AQP4 expression is highly organized across the brain, peaking in subcortical, ventral, and periventricular territories, consistent with a clearance axis near cerebrospinal fluid reservoirs and perivascular interfaces. Linking AQP4 expression to vascular organization, we find that AQP4-enriched regions show lower normative blood perfusion and lower vein density, suggesting that this axis is not simply explained by vascular supply or large-vessel anatomy. Turning to neurodegeneration, we find that atrophy patterns across multiple neurodegenerative diseases co-localize with AQP4 expression--most strongly for tau and TDP-43 proteinopathies--and high-atrophy regions lie close to AQP4 hotspots in both anatomical space and structural connectome space. Furthermore, incorporating normative PET markers of neuroinflammation typically strengthens the spatial alignment between AQP4 expression and disease atrophy, suggesting that inflammatory tone and glymphatic-related architecture jointly shape vulnerability. Finally, we show that peritumoral edema is most frequent in AQP4-enriched regions and is further shaped by regional inflammatory tone. Collectively, this work highlights a whole-brain glymphatic organization that relates to diverse aspects of brain physiology and vulnerability.

neuroscience↗

netneurotools: a trainee-oriented approach to network neuroscience

Brain imaging is an increasingly inter-disciplinary field, encompassing multiple data types and multiple analytic traditions. Projects typically involve many moving parts, such as building customized preprocessing pipelines, transforming between data formats, preparing datasets for analysis, and ultimately displaying results. The field is conventionally built on highly specialized software packages that solve these individual challenges well, but are not necessarily designed to be interoperable. Trainees new to the field are therefore often left to come up with isolated heuristics and workarounds to complete a project. Here we present a way to navigate the increasingly complex informatics ecosystem of brain imaging. netneurotools is our labs internal Python toolkit that has been continuously developed and maintained by the labs trainees. The philosophy of the toolkit is that it should be the Swiss army knife of the lab: functions and routines that we often use but that are not part of any established pipeline or package. Since its inception, the toolkit has been open and welcomes contribution from neuroscientists across the globe. netneurotools presents a necessary counterweight to out-of-the-box software packages and highlights the importance of smaller, ad hoc functions for implementing projects. By opening a window into the inner workings of a lab, netneurotools also presents an opportunity to begin a new type of discourse among groups and establish tangible links within the community.

neuroscience↗

Multivariate Resting-State Functional Connectivity Features Linked to Transdiagnostic Psychopathology in Early Psychosis

BackgroundEarly psychosis (EP) is characterized by neurobiological changes, including alterations in resting-state functional connectivity (RSFC). We now understand that symptoms and neural changes may overlap across EP diagnostic categories. However, the relationship between RSFC patterns and transdiagnostic symptom dimensions remains poorly understood. MethodsWe employed Partial Least Squares correlation to examine multivariate relationships between whole-brain RSFC and clinical symptoms in 124 EP patients (aged 16-35 years) diagnosed with schizophrenia, schizoaffective disorder, or a psychotic mood disorder. RSFC was computed among 216 cortical and subcortical regions. Clinical assessment included 41 symptom measures spanning positive, negative, general psychopathology, and manic dimensions. ResultsAnalysis revealed one significant latent component (p<0.001) capturing 41.6% of the RSFC-symptom covariance. This component was characterized by increased between-network connectivity, particularly involving sensory-motor, default mode, and subcortical regions including the amygdala and thalamus. The associated symptom profile included cognitive rigidity and arousal dysregulation (stereotyped thinking, anxiety, and somatic concerns), rather than traditional positive or negative symptoms. This brain-behavior relationship was consistent across diagnoses and independent of medication and substance use. The clinical relevance was validated through significant correlations with standardized measures of hostility (r=0.23), negative affect (r=0.25), and perceived stress (r=0.22). ConclusionsOur findings reveal a distinct transdiagnostic phenotype in EP characterized by cognitive inflexibility and arousal dysregulation that is associated with altered integration between sensory, default mode, and subcortical networks. This work suggests that specific patterns of network-level functional connectivity may relate to symptom dimensions that cut across conventional diagnostic boundaries, potentially informing more targeted therapeutic approaches.

neuroscience↗

Comprehensive profiling of anaesthetised brain dynamics across phylogeny

Intrinsic dynamics of neuronal circuits shape information processing. Combining neuroimaging with causal perturbation offers the opportunity to understand how local dynamics mediate the link between neurobiology and functional repertoire. We compile a unique dataset of multi-scale neural activity during wakefulness and anaesthetic-induced suppression of information processing encompassing human, macaque, marmoset, mouse, zebrafish and nematode. Applying massive feature extraction, we comprehensively characterise local neural dynamics across >6,000 time-series features. Using dynamics as a common space for cross-species comparison reveals a conserved dynamical profile of anaesthesia across species, characterised by shorter intrinsic timescales of neural activity and dampened interregional synchrony. This dynamical regime is experimentally reversed in vivo by deep-brain stimulation of the macaque centromedian thalamus, restoring behavioural responsiveness. Spatially, this conserved dynamical phenotype covaries with conserved transcriptional profiles of excitatory and inhibitory neurotransmission across human, macaque, marmoset and mouse cortex. Biophysical modelling provides a mechanistic link between the macroscale dynamical phenotype of anaesthesia, and microscale effects of key molecular targets on the timescales of synaptic excitation and inhibition. Altogether, comprehensive dynamical phenotyping reveals a shared neural endpoint of anaesthesia: across species and scales, anaesthetics induce spatio-temporal isolation of local neural activity.

neuroscience↗

Cerebral blood perfusion across biological systems and the human lifespan

Blood perfusion delivers oxygen and nutrients to all cells, making it a fundamental feature of brain organization. How cerebral blood perfusion maps onto micro-, meso- and macro-scale brain structure and function is therefore a key question in neuroscience. Here we analyze pseudo-continuous arterial spin labeling (ASL) data from 1 305 healthy individuals in the HCP Lifespan studies (5-100 years) to reconstruct a high-resolution normative cerebral blood perfusion map. At the cellular and molecular level, cerebral blood perfusion co-localizes with granular layer IV, biological pathways for maintenance of cellular relaxation potential and mitochondrial organization, and with neurotransmitter and neuropeptide receptors involved in vasomodulation. At the regional level, blood perfusion aligns with cortical arealization and is greatest in regions with high metabolic demand and resting-state functional hubs. Looking across individuals, blood perfusion is dynamic throughout the lifespan, follows microarchitectural changes in development, and maps onto individual differences in physiological changes in aging. In addition, we find that cortical atrophy in multiple neurodegenerative diseases (late-onset Alzheimers disease, TDP-43C, and dementia with Lewy bodies) is most pronounced in regions with lower perfusion, highlighting the utility of perfusion topography as an indicator of transdiagnostic vulnerability. Finally, we show that ASL-derived perfusion can be used to delineate arterial territories in a data-driven manner, providing insights into how the vascular system is linked to human brain function. Collectively, this work highlights how cerebral blood perfusion is central to, and interlinked with, multiple structural and functional systems in the brain.

neuroscience↗

Lethal effects of phyllosphere fungi associated with local plants on invasive plant Ageratina adenophora seedlings

Native community resistance to plant invasion may reflect microbial effects on invader establishment. Here, we compared the effects of the aboveground and belowground microbes and leaf functional traits of 25 native plant species on the germination and survival of invader Ageratina adenophora. Results show that leaf physical and chemical traits vary among plant species and shape the aboveground microbial community. Local plants more phylogenetically close to A. adenophora harbour more similar pathogen communities to those A. adenophora. The aboveground tissue inoculations had more adverse effects on A. adenophora establishment by delaying germination time and decreasing the germination rate and seedling survival than did soil inoculations; aboveground tissues from local plants, which are more closely related to A. adenophora, cause longer germination times and greater seedling mortality of A. adenophora. Moreover, local plant aboveground fungi, rather than bacteria, adversely impact seedling survival, and most of the detrimental fungal pathogen ASVs are specialists. Several strains isolated from dead seedlings caused by aboveground tissue inoculations belonging to Alternaria, Fusarium and Stagonosporopsis were verified to kill more than 60% of A. adenophora seedlings and thus have great potential as biocontrol agents for A. adenophora. This is the first study to provide evidence for the effects of phylogenetic relatedness and leaf traits (both functional and microbial) on local community resistance to invaders through the regulation of germination and seedling survival.

ecology↗

The effect of spherical projection on spin tests for brain maps

Statistical comparison between brain maps is a standard procedure in neuroimaging. Numerous inferential methods have been developed to account for the effect of spatial autocorrelation when evaluating map-to-map similarity. A popular method to generate surrogate maps with preserved spatial autocorrelation is the spin test. Here we show that a key component of the procedure -- projecting brain maps to a spherical surface -- distorts distance relationships between vertices. These distortions result in surrogate maps that imperfectly preserve spatial autocorrelation, yielding inflated false positive rates. We then confirm that targeted removal of individual spins with high distortion reduces false positive rates. Collectively, this work highlights the importance of accurately representing and manipulating cortical geometry when generating surrogate maps for use in map-to-map comparisons.

neuroscience↗

Mapping neuropeptide sigaling in the human brain

Neuropeptides are functionally diverse signaling molecules in the brain, regulating a wide range of basal bodily and cognitive processes. Despite their importance, the distribution and function of neu-ropeptides in the human brain remains underexplored. Here we comprehensively map the organization of human whole-brain neuropeptide receptors across multiple levels of description; from molecular and cellular embedding to mesoscale connectivity and macroscale cognitive specialization. Using gene transcription as a proxy, we reconstruct a topographic cortical and subcortical atlas of neuropeptide receptors for 38 neuropeptide receptors, across 14 different neuropeptide families. We find that most neuropeptide receptors are highly expressed either in cortex or subcortex, delineating an anatomical cortical-subcortical gradient. Neuropeptides preferentially co-localize with metabotropic neurotrans-mitters, suggesting a system-wide correspondence between slow-acting molecular signaling mechanisms. Mapping neuropeptide receptors and their cognate ligands onto white-matter connectomes, we demonstrate that specific neuropeptides families shape electrophysiological and haemodynamic interregional connectivity. To investigate the behavioural consequences of distributed neuropeptide systems, we apply meta-analytic decoding to neuropeptide maps and show a gradient of functions, from sensory-cognitive to reward and bodily functions. Finally, evolutionary analysis indicates extended positive selection for neuropeptides in early mammals, suggesting that refinement of neuropeptides coincides with the emergence of neocortex and higher cognitive function. Collectively, these results show that the neuropeptide receptors are highly organized across the human brain and closely intertwined with multiple features of brain structure and function.

neuroscience↗

Benchmarking methods for mapping functional connectivity in the brain

The networked architecture of the brain promotes synchrony among neuronal populations and the emergence of coherent dynamics. These communication patterns can be comprehensively mapped using noninvasive functional imaging, resulting in functional connectivity (FC) networks. Despite its popularity, FC is a statistical construct and its operational definition is arbitrary. While most studies use zero-lag Pearsons correlations by default, there exist hundreds of pairwise interaction statistics in the broader scientific literature that can be used to estimate FC. How the organization of the FC matrix varies with the choice of pairwise statistic is a fundamental methodological question that affects all studies in this rapidly growing field. Here we comprehensively benchmark the topological and geometric organization, neurobiological associations, and cognitive-behavioral relevance of FC matrices computed using a large library of 239 pairwise interaction statistics. We comprehensively investigate how canonical features of FC networks vary with the choice of pairwise statistic, including (1) hub mapping, (2) weight-distance trade-offs, (3) structure-function coupling, (4) correspondence with other neurophysiological networks, (5) individual fingerprinting, and (6) brain-behavior prediction. We find substantial quantitative and qualitative variation across FC methods. Throughout, we observe that measures such as covariance (full correlation), precision (partial correlation) and distance display multiple desirable properties, including close correspondence with structural connectivity, the capacity to differentiate individuals and to predict individual differences in behavior. Using information flow decomposition, we find that differences among FC methods may arise from differential sensitivity to the underlying mechanisms of inter-regional communication, with some more sensitive to redundant and some to synergistic information flow. In summary, our report highlights the importance of tailoring a pairwise statistic to a specific neurophysiological mechanism and research question, providing a blueprint for future studies to optimize their choice of FC method.

neuroscience↗

Glutamate as a co-agonist for acid-sensing ion channels to aggravate ischemic brain damage

Glutamate is traditionally viewed as the first messenger to activate N-methyl-D-aspartate receptors (NMDARs) and downstream cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other NMDAR-independent mechanisms3-7. Here we show that glutamate and its structural analogs, including NMDAR antagonist L-AP5 (or APV), robustly potentiated currents mediated by acid-sensing ion channels (ASICs) which are known for driving acidosis-induced neurotoxicity in stroke4. Glutamate increased the proton affinity and open probability of ASICs, aggravating ischemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis and structure-based in silico molecular docking and simulations uncovered a novel glutamate binding cavity in the extracellular domain of ASIC1a. Computational drug screening of NMDAR competitive antagonist analogs identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs, providing strong neuroprotection efficacy comparable to that in ASIC1a or other cation ion channel knockout mouse models4-7. We conclude that glutamate serves as the first messenger for ASICs to exacerbate neurotoxicity, and that selective blockage of glutamate binding sites on ASICs without affecting NMDARs may be of strategic importance for developing effective stroke therapeutics devoid of the psychotic side effects of NMDAR antagonists.

neuroscience↗

Distinct effects of phyllosphere and rhizosphere microbes on invader Ageratina adenophora during its early life stages

Microbes strongly affect invasive plant growth. However, how the phyllosphere and rhizosphere soil microbes distinctively affect seedling mortality and the growth of invasive plants across ontogeny under varying soil nutrient levels remains unclear. In this study, we used the invader Ageratina adenophora to evaluate these effects in plant growth chambers. We found that leaf litter harboured more potential pathogens and thus had more adverse effects on seed germination and seedling survival than soil inoculation. Microbial inoculation at different growth stages altered the microbial community and microbial functions of seedlings, and earlier inoculation had a more adverse effect on seedling survival and growth. In most cases, the soil nutrient level did not affect microbe-mediated seedling growth and the relative abundance of the microbial community and functions involved in seedling growth. The effects of some microbial genera on seedling survival are distinct from those on growth. Moreover, the A. adenophora seedling-killing effects of fungal strains isolated from dead seedlings by nonsterile leaf inoculation litter exhibited significant phylogenetic signals, by which strains of Allophoma and Alternaria generally caused high seedling mortality. Our study stresses the essential role of A. adenophora litter microbes in population establishment by regulating seedling density and growth.

plant biology↗