Brain Organoids: Tools for Understanding the Uniqueness and Individual Variability of the Human Brain.

How well do brain organoids capture your brain?

Mapping neuronal network dynamics in developing cerebral organoids

For decades, insight into fundamental principles of human biology and disease has been obtained primarily by experiments in animal models. While this has allowed researchers to understand many human biological processes in great detail, some developmental and disease mechanisms have proven difficult to study due to inherent species differences. The advent of organoid technology more than 10 years ago has established laboratory-grown organ tissues as an additional model system to recapitulate human-specific aspects of biology. The use of human 3D organoids, as well as other advances in single-cell technologies, has revealed unprecedented insights into human biology and disease mechanisms, especially those that distinguish humans from other species. This review highlights novel advances in organoid biology with a focus on how organoid technology has generated a better understanding of human-specific processes in development and disease.

Clinical and lifestyle related factors influencing whole blood metabolite levels – A comparative analysis of three large cohorts

Editorial: Categories and dimensions: reflections on obsessive-compulsive disorder (OCD)

Brain Organoids, the Path Forward?

Towards systemic and individualized brain markers for learning difficulties

There is increasing awareness of interindividual variability in brain function, with potentially major implications for repetitive transcranial magnetic stimulation (rTMS) efficacy. We perform a secondary analysis using data from a double-blind randomized controlled 4-week trial of 20 Hz active versus sham rTMS to dorsolateral prefrontal cortex (DLPFC) during a working memory task in participants with schizophrenia. We hypothesized that rTMS would change local functional activity and variability in the active group compared with sham. 83 participants were randomized in the original trial, and offered neuroimaging pre- and post-treatment. Of those who successfully completed both scans (n = 57), rigorous quality control left n = 42 (active/sham: n = 19/23), who were included in this analysis. Working memory-evoked activity during an N-Back (3-Back vs 1-Back) task was contrasted. Changes in local brain activity were examined from an 8 mm ROI around the rTMS coordinates. Individual variability was examined as the mean correlational distance (MCD) in brain activity pattern from each participant to others within the same group. We observed an increase in task-evoked left DLPFC activity in the active group compared with sham (F1,36 = 5.83, False Discovery Rate (FDR))-corrected P = .04). Although whole-brain activation patterns were similar in both groups, active rTMS reduced the MCD in activation pattern compared with sham (F1,36 = 32.57, P < .0001). Reduction in MCD was associated with improvements in attention performance (F1,16 = 14.82, P = .0014, uncorrected). Active rTMS to DLPFC reduces individual variability of brain function in people with schizophrenia. Given that individual variability is typically higher in schizophrenia patients compared with controls, such reduction may "normalize" brain function during higher-order cognitive processing.

The recent emergence of three-dimensional organoids and their utilization as in vitro disease models confirmed the complexities behind organ-specific functions and unravelled the importance of establishing suitable human models for various applications. Also, in light of persistent challenges associated with their use, researchers have been striving to establish more advanced structures (i.e. assembloids) that can help address the limitations presented in the current organoids. In this review, we discuss the distinct organoid types that are available to date, with a special focus on retinal and brain organoids, and highlight their importance in disease modelling. We refer to published research to explore the extent to which retinal and brain organoids can serve as potential alternatives to organ/cell transplants and direct our attention to the topic of photostimulation in retinal organoids. Additionally, we discuss the advantages of incorporating microfluidics and organ-on-a-chip devices for boosting retinal organoid performance. The challenges of organoids leading to the subsequent development of assembloid fusion models are also presented. In conclusion, organoid technology has laid the foundation for generating upgraded models that not only better replicate in vivo systems but also allow for a deeper comprehension of disease pathophysiology.

Understanding the fundamental processes of human brain development and diseases is of great importance for our health. However, existing research models such as non-human primate and mouse models remain limited due to their developmental discrepancies compared with humans. Over the past years, an emerging model, the "brain organoid" integrated from human pluripotent stem cells, has been developed to mimic developmental processes of the human brain and disease-associated phenotypes to some extent, making it possible to better understand the complex structures and functions of the human brain. In this review, we summarize recent advances in brain organoid technologies and their applications in brain development and diseases, including neurodevelopmental, neurodegenerative, psychiatric diseases, and brain tumors. Finally, we also discuss current limitations and the potential of brain organoids.

This special review issue on Neurological and Psychiatric Diseases and Traits focuses upon a number of phenotypes which, while very diVerent, result from impairment of, or variation in, some aspect of brain function. The brain is widely regarded as one of the most challenging subjects for biomedical research. Its anatomical organization is highly complex, its functional organization is poorly understood, and notwithstanding advances in neuroimaging, it remains relatively inaccessible to direct study in vivo. Moreover, whereas the wider functions of most organs can be understood in basic biochemical and/or physical terms, this is not often the case for the brain. For example, the genesis of the higher order brain functions that are often central to brain disorders such as self-awareness, perception, thought, mood, and volition cannot be readily understood in terms of fundamental molecular mechanisms. In many cases, to these diYculties can be added a deWciency of relevant molecular and phenotypic model systems, the beneWts of which are illustrated herein by the review of Down syndrome (Patterson 2009). While brain disorders are undeniably challenging targets for biomedical research, they are also amongst the most important, the brain being central to every aspect of human life. With its role in human adaptability and survival, it would be remarkable if traits that result from variation in brain function were not inXuenced in part by genes. However, even in fairly recent times, the hypothesis that genes contribute to variation in normal cognitive and behavioural traits has been controversial. As illustrated by the articles on human intelligence (Deary et al. 2009) and on aggression (Craig and Halton 2009), there is now convincing evidence (some of it old) that genes are involved, and the same is true for many other cognitive and behavioural traits. Genetic methods, therefore, oVer one possible route to trying to understand normal variation in brain function. The other reviews have as their subjects heritable brain-related phenotypes that are generally thought of as ‘disorders’; like intelligence and aggression, some of these can alternatively be conceptualized as quantitative traits, as illustrated in the review of ADHD by Franke and colleagues. In addition to the general diYculties alluded to above, many of the disorders reviewed herein also have features that make genetic studies problematic. Discussed in detail in the review of psychosis (O’Donovan et al. 2009), often the disorders cannot be classiWed based upon any biologically validated methodology. Consequently, the power of genetic studies is likely to be compromised by sub-optimal phenotypic deWnitions and extensive heterogeneity. In some cases, it has been possible to overcome this by identifying relatively homogenous groups based upon the presence of other syndromic features and/or by studying large single families co-segregating major genes, as exempliWed in the reviews of epilepsy (Andrade 2009) and migraine (de Vries et al. 2009). However, such approaches are not currently applicable to the majority of people with those disorders, or to individuals with other common neurological and psychiatric phenotypes. Another approach that has met with considerable success in identifying genes that contribute to Mental Retardation has been the study of balanced translocations (Vandeweyer and Kooy 2009) and other chromosomal abnormalities. Such gross abnormalities may not contribute substantially to typical forms of common disorders. However, studies of smaller chromosomal abnormalities in the form of rare copy number variants are beginning M. C. O’Donovan (&) · M. J. Owen Department of Psychological Medicine and Neurology, School of Medicine, MRC Centre for Neuropsychiatric Genetics and Genomics, Heath Park, CardiV CF23 6BQ, UK e-mail: odonovanmc@cf.ac.uk

<p indent="0mm">Brain organoids are <italic>in vitro</italic> three-dimensional neural cultures with similar cellular diversities, spatial organizations, and physiological functions of the human brain. Since its establishment, brain organoid technology has provided valuable tools for investigating the human brain development and functionality, disease etiology, drug discovery, and many other biological and medical questions. The progress of region-specific brain organoids has furthered the frontiers of brain organoid technology. In this article, we briefly review the development of brain organoid technology, including region-specific brain organoids. In particular, we focus on the technologies and applications of brain organoids in modeling human brain development. We also discuss the progress and challenges of various pivotal technologies in brain organoid studies, including vascularization, gene editing, single-cell sequencing, and other engineering approaches.

Understanding etiology of human neurological and psychiatric diseases is challenging. Genomic changes, protracted development, and histological features unique to human brain development limit the disease aspects that can be investigated using model organisms. Hence, in order to study phenotypes associated with human brain development, function, and disease, it is necessary to use alternative experimental systems that are accessible, ethically justified, and replicate human context. Human pluripotent stem cell (hPSC)-derived brain organoids offer such a system, which recapitulates features of early human neurodevelopment in vitro, including the generation, proliferation, and differentiation of neural progenitors into neurons and glial cells and the complex interactions among the diverse, emergent cell types of the developing brain in three-dimensions (3-D). In recent years, numerous brain organoid protocols and related techniques have been developed to recapitulate aspects of embryonic and fetal brain development in a reproducible and predictable manner. Altogether, these different organoid technologies provide distinct bioassays to unravel novel, disease-associated phenotypes and mechanisms. In this review, we summarize how the diverse brain organoid methods can be utilized to enhance our understanding of brain disorders. FACTS: Brain organoids offer an in vitro approach to study aspects of human brain development and disease. Diverse brain organoid techniques offer bioassays to investigate new phenotypes associated with human brain disorders that are difficult to study in monolayer cultures. Brain organoids have been particularly useful to study phenomena and diseases associated with neural progenitor morphology, survival, proliferation, and differentiation. OPEN QUESTION: Future brain organoid research needs to aim at later stages of neurodevelopment, linked with neuronal activity and connections, to unravel further disease-associated phenotypes. Continued improvement of existing organoid protocols is required to generate standardized methods that recapitulate in vivo-like spatial diversity and complexity.

Recent work demonstrating low test-retest reliability of neural activation during fMRI tasks raises questions about the utility of task-based fMRI for the study of individual variation in brain function. Two possible sources of the instability in task-based BOLD signal over time are noise or measurement error in the instrument, and meaningful variation across time within-individuals in the construct itself—brain activation elicited during fMRI tasks. Examining the contribution of these two sources of test-retest unreliability in task-evoked brain activity has far-reaching implications for cognitive neuroscience. If test-retest reliability largely reflects measurement error, it suggests that task-based fMRI has little utility in the study of either inter- or intra-individual differences. On the other hand, if task-evoked BOLD signal varies meaningfully over time, it would suggest that this tool may yet be well suited to studying intraindividual variation. We parse these sources of variance in BOLD signal in response to emotional cues over time and within-individuals in a longitudinal sample with 10 monthly fMRI scans. Test-retest reliability was low, reflecting a lack of stability in between-person differences across scans. In contrast, within-person, within-session internal consistency of the BOLD signal was higher, and within-person fluctuations across sessions explained almost half the variance in voxel-level neural responses. Additionally, monthly fluctuations in neural response to emotional cues were associated with intraindividual variation in mood, sleep, and exposure to stressors. Rather than reflecting trait-like differences across people, neural responses to emotional cues may be more reflective of intraindividual variation over time. These patterns suggest that task-based fMRI may be able to contribute to the study of individual variation in brain function if more attention is given to within-individual variation approaches, psychometrics—beginning with improving reliability beyond the modest estimates observed here, and the validity of task fMRI beyond the suggestive associations reported here.

Along with emergence of the organoids, their application in biomedical research has been currently one of the most fascinating themes. For the past few years, scientists have made significant contributions to deriving organoids representing the whole brain and specific brain regions. Coupled with somatic cell reprogramming and CRISPR/Cas9 editing, the organoid technologies were applied for disease modeling and drug screening. The methods to develop organoids further improved for rapid and efficient generation of cerebral organoids. Additionally, refining the methods to develop the regionally specified brain organoids enabled the investigation of development and interaction of the specific brain regions. Recent studies started resolving the issue in the lack of non-neuroectodermal cells in brain organoids, including vascular endothelial cells and microglia, which play fundamental roles in neurodevelopment and are involved in the pathophysiology of acute and chronic neural disorders. In this review, we highlight recent advances of neuronal organoid technologies, focusing on the region-specific brain organoids and complementation with endothelial cells and microglia, and discuss their potential applications to neuronal diseases.