Population Neuroscience Beyond the Horizon
Population Neuroscience Beyond the Horizon
Population Neuroscience Beyond the Horizon
From 2014 to 2021, after eight years of academic accumulation and communication at five International Conferences on Human Brain Development, the concept of Developmental Population Neuroscience (DPN) and suggestions for fostering the construction of this discipline were put forward. The DPN research will investigate the laws and mechanisms of human brain development throughout lifespan, promote the transformation and application from fundamental research to education and health, and help satisfy the country’s enormous demands in population quality and national development. The China Brain Project (Brain Science and Brain-Like Intelligence Technology) research on the brain development of children and adolescents has officially begun, and its cohort construction and completion will greatly advance the country’s occupation of the international frontier in the field of DPN.
Topics
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“Population neuroscience: History, present and future”
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“Population neuroscience: Large-scale cohorts”
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“Population neuroscience: Multimodal imaging methods”
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“Population neuroscience: Translational applications”
Call for Abstracts
Participants are encouraged to submit abstracts.
The details on the subject and format of the abstract are here.
The Academic Committee of the conference will review the submitted abstracts, and the reviewed abstracts will be published in the conference manual (inclusion or exclusion of the abstracts will not affect participation in the conference), and oral presentations will be selected. Please send the abstract to deepneuro@bnu.edu.cn by November 30th, 2023 (email subject: name_conference abstract).
Chair: Xi-Nian Zuo (Beijing Normal University, China)
- The 1st ICHBD (2014): A Neuron Perspective, Beijing, China
- The 2nd ICHBD (2015): Beijing, China
- The 3rd ICHBD (2017): A Science Bulletin Research Highlight, Nanning, China
- The 4th ICHBD (2019): Hangzhou, China
- The 5th ICHBD (2021): Beijing, China
Conference e-mail: deepneuro@bnu.edu.cn
Contact: Xinli Luo, 18890058457
Keynote Speakers

Tomas Paus
University of Montreal, Canada
“Population Neuroscience: Past, present and future”
Population neuroscience has been enabled by technological advancements, in genetics and neuroimaging, combined with researchers, from multiple disciplines, working together in a highly cooperative manner on large-scale projects.
Through a personal lens, I will first look back at some of the key projects that guided my path to population neuroscience, including the International Consortium for Brain Mapping, the NIMH Child Psychiatry Branch Project, and the NIH Pediatric Project. I will then provide a brief overview of the first two population-neuroscience studies of brain maturation during adolescence, namely the Saguenay Youth Study (initiated in 2002) and the IMAGEN study (initiated in 2007).
Moving to the present, I will touch on two topics. First, I will illustrate the power of open-science (ABCD study, UK Biobank) and international consortia (CHARGE, ENIGMA) in facilitating discoveries requiring large samples. Second, I will emphasize importance of bridging the gap between MRI-derived metrics and cellular-level neurobiology; I will describe some of our work in this area (virtual histology and virtual ontogeny).
I will conclude my lecture by highlighting a few emerging opportunities for enriching our population-neuroscience toolset in the area of environment, genetics and neuroimaging.

Christian Beckmann
Radboud University Medical Centre Nijmegen, The Netherlands
“Big data for precision neuroscience: Novel approaches for charting resting-state functional connectivity & connectopies”
Large clinical and population cohort neuroimaging resources are increasingly coming online, forming a new field of imaging epidemiology. These offer a unified perspective that links brain structure and connectional organization to behaviour and cognition. Currently, however, the full potential of these resources for understanding advancing clinical and cognitive neuroscience is not being realized. This is due to a lack of suitable analysis tools that explore relationships between and integrate across modalities, are sensitive to subtle changes in individual connectivity profiles and provide a means to move beyond simple case-control analysis towards understanding inter-individual differences in connectivity. In this talk I will outline novel approaches for charting the organisation of structure and functional connectivity and introduce a ‘normative modelling’ strategy for utilising big cohort data for generating individualised predictions with application in clinical neuroimaging studies.

Sha Tao
Beijing Normal University, China
“Beijing Cohort Study of Children School functions and Brain Development(CBD-Beijing Cohort): Progresses”
The CBD-Beijing Cohort was established since 2015, first supported by the national science foundation of China (PI: Qi Dong), and then partially by Beijing Brain Initiative (PI: Sha Tao). It is an ongoing collaboration between researchers from Beijing Normal University (BNU), Peking University (PKU) and Beijing Huilongguan Hospital (BHH). Standardized Brain Imaging Data Acquisition protocols and strategies were carefully developed and have been implementing to ensure high imaging quality and the consistency across three scanning centers at BNU, PKU and BHH. This study is accelerated longitudinal, more than 800 6-12-year-old children have completed baseline brain MRI scan and comprehensive psychological assessments of cognitive, Chinese, and English reading, math, personality, emotional development, and mental health status. The yearly brain scanning and psychological assessments have been continuing. In addition, children’s life events, daily activities, school, and home environment of both physical and psychological features are also quantified yearly. In this presentation, I will share some progresses about school-age children brain development, the longitudinal connection between brain and behavioral development and how school experience may impact brain development.

Chunshui Yu
Tianjin Medical University General Hospital, China
“Neuroimaging exposogenomics“
Neuroimaging exposogenomics (NIMEG) is a new interdisciplinary science and aims to investigate how genome-wide and exposome-wide genetic and environmental factors and their interactions affect the structure and function of the human brain characterized by various neuroimaging techniques based on large-scale multi-dimensional datasets. NIMEG includes five research subfields: neuroimaging genomics, neuroimaging exposomics, and genome-wide gene-gene interactions, exposome-wide environment-environment interactions, and genome-exposome-wide gene-environment interactions of neuroimaging phenotypes. NIMEG will provide a full understanding of causes for individual differences in human behaviors and pathogeneses of neuropsychiatric disorders. In this presentation, I will provide several examples to show how to use NIMEG to investigate individual differences in brain structure and function and behavior.
Invited Speakers

Richard Bethlehem
University of Cambridge, UK
“Putting normative braincharts to use”
For decades, assessment of typical and atypical development has been guided by normative growth charts of anthropometrics. Despite its importance for understanding brain and mind, until recently equivalent normative benchmarks did not exist for the brain, impeding individualised assessment of neurodevelopment. Together with a large international consortium, we established such normative growth charts for structural brain development across the lifespan. This “BrainChart” framework allows for harmonised, and crucially individualised, evaluation of neurodevelopment in much the same way conventional growth charts have served this function for decades on physical growth markers. In my talk I will explore the utility of this framework from two angles. First, I will discuss evidence for it directly clinical utility for prognostication and subgrouping in clinical cohorts across the lifespan. Second, I will discuss how we are using the framework to better understand environmental factor impacting longitudinal brain development.

Xujun Duan
University of Electronic Science and Technology of China, China
“China Autism Brain Imaging Consortium: Charting brain growth in Chinese Autism Children”
Autism spectrum disorder (ASD) is a set of prevalent, complex, and heterogeneous neurodevelopmental conditions characterized by difficulties in social communication and interaction, and repetitive behavior and focused interests. Advances in neuroimaging techniques, as well as the openly sharing large-sample multi-site datasets such as the Autism Brain Imaging Data Exchange (ABIDE), have provided important insights into the neurobiological underpinning of this neurodivergent population. However, those studies have largely focused on measuring brain differences in autistic adolescence and adults, the early brain development at ages closer to clinical diagnosis as well as during a critical period for early intervention was barely known. In addition, the majority of the existing literatures were based on Caucasian participants, little is known on the features of brain development in Chinese autistic children, especially in large samples. Bring together the gaps in the literature, here we introduce the China Autism Brain Imaging Consortium, which is a grassroots effort by researchers across the country to aggregate previously collected multi-site MRI datasets on autistic children and typically developing children, to achieve the large samples necessary to move towards a more comprehensive understanding of the brain development in Chinese autism children, covering a age range from young childhood to adolescence, which might facilitate the utility to provide precise clinical support or educational strategies for autism children with different levels of support needs.

Jianqiao Ge
Peking University, China
“Chinese Human Connectome Project”
The human brains are shaped by our experience, and people’s cultural and ethnic background can exert a significant influence on brain systems responsible for human cognition. Recent advances in multimodal brain imaging and population neuroscience enable the exploration of the large-scale structural and functional connectomic architectures of the human brain and their relationship with behavior. However, most up-to-date large-scale multimodal brain imaging datasets were primarily obtained from people lived in Western culture, missing a crucial contrast with populations living in non-Western culture. In 2017, we launched the Chinese Human Connectome Project (CHCP), which aims to provide large sets of multimodal neuroimaging, behavioral and genetic data on the Chinese population that are comparable to the data of the HCP. A large-scale neuroimaging project such as CHCP in parallel to the HCP but with a focus on the East Asian population would allow direct comparisons of brain-behavior associations across different ethnicities and cultures.

Avram Holmes
Rutgers University, USA
“The cellular underpinnings of the human cortical connectome: from circuitry and networks through psychiatric illness”
The functional properties of the human brain arise, in part, from the complex interactions of biological systems that span across genes, molecules, and cells through large-scale networks. Establishing how neurobiological processes coalesce to contribute to complex human behaviors across the lifespan requires a multi-scale approach, encompassing measures of brain structure and function as well as genetic and cell-specific transcriptional data. Here, I will highlight our recent work integrating densely sampled gene transcriptional atlases with in vivo estimates of brain-network functioning derived through fMRI. In doing so, I will present ongoing research examining the relative influence of inhibitory interneuron subtypes on brain function, cortical specialization, and human behavior. Underscoring the translational potential of multi-scale approaches, I will highlight how this information can be leveraged to understand individual variability in the diverse processing capabilities of the human brain and associated vulnerability for psychiatric illness onset.

Ying Han
Xuanwu Hospital, Capital Medical University, China
“The Sino Longitudinal Study on Cognitive Decline”
The SILCODE was launched in response to the increasing incidence of Alzheimer’s Disease (AD) in China, with the aim of improving prediction of the disease’s course and identifying new markers for early diagnosis. The study was conducted by a multidisciplinary research team led by the National Clinical Research Center for Geriatric Diseases of Xuanwu Hospital of Capital Medical University. The team collected multidimensional data from various sources, including clinical data, blood, urine, gene type, feces, MRI, PET or Near-Infrared.
The SILCODE has yielded significant findings. For instance, it was found that limbic FC, particularly hippocampal connectivity with right insula, was consistently higher in SCD than in controls, and correlated with SCD-plus features. Furthermore, smaller SCD sub-cohorts with PET showed inconsistent amyloid positivity rates and FC–amyloid associations across cohorts. The study also found that the levels of Aβ42 increased gradually across the cognitive continuum, contributing to their diagnoses.
In addition, the study found that both cognitive reserve (CR) and brain reserve (BR) had independent positive effects on multiple cognitive measures in individuals with SCD. Lastly, the study found that compared with controls, individuals with SCD showed decreased total cortical volumes and cortical surface area.
The SILCODE study has also led to the publication of expert consensus on technical specifications of amyloid PET brain imaging and standard of MRI technology of AD. In the future, the study aims to expand its scope through larger samples, longitudinal studies, cross-cultural study, participating in China Brain Project, and combination of multimodal techniques.

Shuyu Li
Beijing Normal University, China
“Dual Long-axis Organization of Hippocampal-Cortical Connectome in Youth”
Understanding the principles of hippocampal-cortical organization remains an ongoing mission in systems human neuroscience. The organization of a single hippocampal long-axis has been predominantly characterized as monotonic, despite recent indications of nonmonotonic features in neuron density and geometric eigenmodes, while the cortical hierarchy has been well recognized for significant developmental and evolutionary advantages. Hippocampus is typically considered an evolutionarily conserved brain structure, leaving unanswered questions about its integrative role of cortical hierarchical processing during development. In this talk, I will introduce the presence and significance of a dual long-axis organization of the human hippocampal connectome and geometry including both linear and quadratic gradients along its long-axis in youth and show the development of the dual long-axis gradients, as well neurodevelopmental variability in spontaneous activities in youth paralleling the gradients of myelin content. Also, I will present that the geometric shape of the hippocampus continues to loosen the constraints on dual long-axis gradients to support the performance of executive function. Neuroactive signaling, stress hormone regulation, and neural growth are related micro-level processes involved in this geometry-function-cognition alignment to enhance the development of the hippocampal dominant long-axis gradient throughout youth. Our findings elucidate the plasticity distribution within the human hippocampus and hold significance for enhancing neurodevelopment and neuropsychiatric healthcare.

Lihui Liu
Science China Press, China
“Science Bulletin”
Science Bulletin (English version) and Chinese Science Bulletin (Chinese version) are multidisciplinary academic journals supervised by the Chinese Academy of Sciences (CAS) and co-sponsored by the CAS and the National Natural Science Foundation of China (NSFC). They publish with Science China Press (in China) and Elsevier (Science Bulletin, outside China), covering a broad range of subjects from natural sciences, medicine, to engineering. Both journals have been the flagship journals of CAS since their establishment in 1950 (Chinese Version) and 1966 (English Version) and have published many high-impact findings including the isolation of artemisinin, a novel therapy against Malaria by Prof. Youyou Tu (the Nobel Prize winner in 2015). Chinese Science Bulletin is indexed by Emerging Sources Citations Index (ESCI), Engineering Index (EI), Scopus, etc. Science Bulletin is a semi-monthly international journal publishing high-caliber peer-reviewed research based on its originality, scientific significance, and whether it is of general interest. In addition, we are committed to serving the scientific community with immediate, authoritative news and valuable insights into upcoming trends around the globe. Science Bulletin is indexed by Science Citation Index (SCI), Engineering Index (EI), Scopus, etc. The JCR 2021 Impact Factor of Science Bulletin is 18.9.

Daniel S. Margulies
University of Paris, France
“Cortical gradients of functional integration: Data-driven and model-based approaches for characterizing individual differences”
Understanding how the cerebral cortex transforms distinct sources of information into cohesive experiences requires knowledge of how functional integration emerges from cortical structure. Insights into functional processing streams indicate that cortical areas are arranged stepwise, representing functional gradients along the cortical surface. Having been largely restricted to describing processing within specific sensory modalities, how do these principles generalize and extend to the surrounding association cortex? Building on work characterizing a principal axis of cortical organization, I will present a line of research that investigates the role of cortical geometry in enabling functional convergence across distinct modalities. By describing how the spatial layout of the cerebral cortex shapes its function, this line of research proposes a framework for understanding structural constraints that contribute to the integrated nature of cognition.

Gunter Schumann
Charité – Universitätsmedizin Berlin, Germany
“environMENTAL – Reducing the impact of major environmental challenges on mental health”
environMENTAL is a Horizon Europe-funded project aimed to investigate how some of the greatest global environmental challenges, climate change, urbanisation, and psychosocial stress caused by the Covid19-pandemic affect brain health during the lifespan, and develop interventions aimed at prevention and early intervention. Leveraging federated cohort data of over 1 million European citizens and patients enriched with deep phenotyping data form large scale behavioural neuroimaging cohorts, such as the IMAGEN and cVEDA cohorts , we will identify brain mechanisms related to environmental adversity underlying symptoms of depression, anxiety, stress and substance abuse. To model how complex, real-life exposure to living in the city relates to brain and mental health, and how this is moderated by genetic factors we used data from UK Biobank to investigate the relationships between urban-living environments and psychiatric symptoms and identified different environmental profiles of urban-living that influence specific psychiatric symptom groups through distinct neurocognitive pathways. By linking population and patient data via geo-location to environmental data derived from remote sensing satellite measures, climate models as well as digital health applications, our interdisciplinary team will develop a neurocognitive model of multimodal environmental influences defined by transdiagnostic symptom groups of mental illness and their brain correlates. We will uncover molecular mechanisms underlying this model using multi-modal omics analyses, 3D-brain organoid aggregates and virtual brain simulations. This work will provide an integrated perspective for each individual that incorporates the genetic and environmental influences on brain systems and psychopathology and behaviour, across the lifespan and spectrum of functioning, which we will apply to develop risk biomarkers and stratification markers for different disease mechanisms. Based on the mechanistic knowledge generated, we will then identify compounds targeting causal mechanisms of disease and develop in close collaborations with stakeholders adapted digital health interventions using virtual reality that target symptom clusters defined by shared brain mechanisms. Together, this project will lead to the development of objective biomarkers and evidence-based interventions that will significantly improve outcomes of environmentally-related mental illness.

Xiaopeng Song
Central Research Institute, United Imaging, Shanghai, China
“Advances in Neuroscience Powered by Innovative MRI technologies”
New technologies such as artificial intelligent (AI), ultra-high field MRI, and multi-modal neuroimaging have been helping scientists to advance their knowledge in brain development, brain aging and relevant diseases. In this talk, Dr. Song will introduce these innovative technologies and their applications in neuroscience, such as AI assisted imaging acceleration, quiet MRI scanning, and automated brain segmentations.

Rui Su
Tibet University, China
“Brain function acclimation to high altitude: cognitive phenotype and exercise interventions”
High altitudes (HA) characteristics with the decrease in atmospheric pressure, humidity, and air temperature, which leads to a limited oxygen supply for HA residents. More than 140 million people live permanently at HA (>2,500 m), and a series of physiological response to hypoxia stress have been well-documented. Especially, In Tibetans, they have successfully settled in the HA, partly due to the genetic changes in HIF pathway connected to adaptation. However, how long-term HA exposure residents adapt to HA in brain function is still unclear. Thus, our team though ERP, fMRI and HDDM to explore brain function acclimatization to hypoxia stress in both chronic and lifelong HA exposure residents. Furthermore, exercise intervention was conducted to improve physiological acclimatization after HA exposure.

Jun Wang
Beijing Normal University, China
“Beijing Aging Brain Rejuvenation Initiative (BABRI): Recent Progress”

Mingrui Xia
Beijing Normal University, China
“Mapping Neurophysiological Subtypes of Depression Using Normative Models of the Functional Connectome”
Major depressive disorder (MDD) is a highly heterogeneous disorder that typically emerges in adolescence and can occur throughout adulthood. Quantitatively uncovering the heterogeneity of individual functional connectome abnormalities in MDD and identifying reproducibly distinct neurophysiological MDD subtypes across the lifespan are still lacking, which could provide promising insights for precise diagnosis and treatment prediction. Leveraging resting-state functional MRI data from 1,148 MDD patients and 1,079 healthy controls (ages 11-93), we first characterized typical lifespan trajectories of functional connectivity strength based on the normative modeling, and quantitatively the research mapped individual functional deviations of each brain network node in depression patients. This approach led to the identification of two reproducible neurophysiological subtypes. Subtype 1 showed severe deviations with positive deviations in the default mode, limbic, and subcortical areas and negative deviations in the sensorimotor and attention areas. Conversely, subtype 2 showed a moderate but converse deviation pattern. More importantly, subtype differences were observed in depressive item scores and predictive ability of baseline deviations for antidepressant treatment outcomes. These findings shed light on our understanding of different neurobiological mechanisms underlying the clinical heterogeneity of MDD and are essential for developing personalized treatments for this disorder.

Chao-Gan Yan
Institute of Psychology, Chinese Academy of Sciences, China
“Research Progress and Blueprint of the Depression Imaging REsearch ConsorTium (DIRECT) Phase III”
Despite a growing neuroimaging literature on the pathophysiology of major depressive disorder (MDD), reproducible findings are lacking, likely reflecting mostly small sample sizes and heterogeneity in analytic approaches. To address these issues, the Depression Imaging REsearch ConsorTium (DIRECT) was launched. DIRECT Phase I pooled 2428 functional brain images processed with a standardized pipeline across all participating sites for the REST-meta-MDD project. DIRECT Phase II used a state-of-the-art, surface-based preprocessing pipeline to improve sensitivity. This time we focused on the subgenual anterior cingulate cortex (sgACC), which plays a central role in the pathophysiology of major depressive disorder (MDD), and its functional interactive profile with the left dorsal lateral prefrontal cortex (DLPFC) is associated with transcranial magnetic stimulation (TMS) treatment outcomes. Leveraging the Phase II large multi-site sample (1660 MDD patients vs. 1341 healthy controls), we systematically delineated case-control difference maps of sgACC-FC. Then, in a sample of 25 individuals with treatment-resistant depression who had received repetitive TMS (rTMS) treatment, we examined the relationship between case-control differences in FCs between sgACC and their specific TMS targets and treatment outcomes. Next, we tested whether the position of the group mean FC-based target (previously determined in healthy participants) differed in MDD patients. Finally, we developed a dual regression (DR) based approach to integrate group-level statistical maps with individual-level spontaneous brain activity to evaluate individualized TMS target localization in MDD. We tested this approach in a sample of 16 individuals who had received rTMS. We found enhanced sgACC-DLPFC FC in MDD patients. The magnitude of case-control differences in FC between sgACC and TMS targets was related to clinical improvement. We found different peak sgACC anticorrelation locations in mean FC maps of MDD patients and HCs. More effective TMS targets were closer to individualized DR-based loci than to group-level targets.
As the proposed individualized approach for TMS targeting has the potential to improve TMS treatment outcome, we are going to launch multi-site prospective clinical trials collaborations for DIRECT Phase III. Through these endeavors, we hope to accelerate the translation of functional neuroimaging findings to clinical utility while building an open repository for the scientific community.

Han Zhang
ShanghaiTech University, China
“Chinese Baby Connectome Project (CBCP): Challenges, Solutions, and Future”
As part of the newly launched Nation-wide China Brain Initiative Projects, Chinese Baby Connectome Project (CBCP) has been aiming to build a large (n > 1000) longitudinal age 0-6 cohort for Healthy China Infant Development. I will introduce the challenges in the infant brain MRI, EEG/ERP, behavioral and environmental data collection, and the new protocols, techniques, and tools that we invented to facilitate fast, high resolution, multiplex infant MRI collection and analysis. I will also cover some preliminary results based on the CBCP data, followed by future perspectives on novel AI techniques toward a better child development cohort with ‘CBCP techniques’.

Juan Helen Zhou
National University of Singapore, Singapore
“Brain network phenotypes relate to cognition and psychopathology in the developing and aging brain”
Under the brain network selective vulnerability hypothesis, multimodal network-sensitive neuroimaging methods such as resting-state fMRI and diffusion MRI can shed light on brain network trajectories in the aging and developing brain and pinpoint network dysfunction in neuropsychiatric disorders. In this talk, I will focus on our recent work on variations in cortical functional gradients relate to dimensions of psychopathology in preschool children. In parallel, brain structural and functional network phenotypes link to distinct disease pathology and lead to cognitive decline over time at pre-dementia stage. Lastly, I will discuss how longitudinal brain age explain future cognitive decline in both children and elderly on top of baseline brain age. I will highlight the challenges in studying brain network phenotypes across the disease spectrum and the potential of machine learning approaches to integrate across modalities and domains. Further developed, multimodal network-specific imaging signatures can help reveal disease mechanisms and facilitate early detection, prognosis, and treatment development of neurological disorders.

Zi-Xuan Zhou
Beijing Normal University, China
“From Brain Charts to Personalized Inference: Pitfalls and Opportunities”

Lusha Zhu
Peking University, China
“A neurocomputational probe into the development of social communicative ability”
The ability to understand what is and is not being said by conservational partners is key to effective communication. However, it remains largely unknown when humans acquire this inferential ability, and how neural and cognitive developments support its maturation. The challenge relates to not only the inherent complexity in human communication, but also the lack of quantitative instruments capable of decomposing the complex mental processes of communication in a principled way to probe relevant neurocognitive underpinnings. In this talk, I will present a novel computational approach to this problem. I will show quantitative evidence for neural and cognitive changes that are correlated with or predictive of communicative ability development, during the transition from childhood through adolescence to adulthood, in both cross-sectional and longitudinal samples. I will also discuss whether and how autistic spectrum traits affects the development of this ability in neurotypical adolescents.

Xi-Nian Zuo
Beijing Normal University, China
“Developmental Population Neuroscience: Recent Progress”
Conference schedule
Friday, 15/12/2023 | Saturday, 16/12/2023 | Sunday, 17/12/2023 |
---|---|---|
- Topic 1: Population neuroscience: History, present and future |
- Topic 3: Population neuroscience: Multimodal imaging methods |
- Courses: Developmental population neuroscience |
- Topic 2: Population neuroscience: Large-scale cohorts |
- Topic 4: Population neuroscience: Translational applications |
- Courses: Developmental population neuroscience |
Friday, 15/12/2023 | Saturday, 16/12/2023 | Sunday, 17/12/2023 |
---|---|---|
- Topic 1: Population neuroscience: History, present and future |
- Topic 3: Population neuroscience: Multimodal imaging methods |
- Courses: Developmental population neuroscience |
- Topic 2: Population neuroscience: Large-scale cohorts |
- Topic 4: Population neuroscience: Translational applications |
- Courses: Developmental population neuroscience |
Registration
Date
September 1, 2023 – December 10, 2023
Rates
There is no registration fee or course fee for this conference, and transportation and accommodation expenses are at your own expense.