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

Human beings may have evolved the largest asymmetries of brain organization in the animal kingdom. Hemispheric left-vs-right specialization is especially pronounced in our species-unique capacities. Yet, brain asymmetry features appear to be strongly shaped by non-genetic influences. We hence charted the largest longitudinal brain-imaging adult resource, yielding evidence that brain asymmetry changes continuously in a manner suggestive of neural plasticity. In the UK Biobank population cohort, we demonstrate that asymmetry changes show robust associations across 959 distinct phenotypic variables spanning 11 categories. We also find that changes in brain asymmetry over years co-occur with changes among specific lifestyle markers. Finally, we reveal relevance of brain asymmetry changes to major disease categories across thousands of medical diagnoses. Our results challenge the tacit assumption that asymmetrical neural systems are highly conserved throughout adulthood., Competing Interests: Additional Declarations: There is NO Competing Interest.

The amygdala nuclei modulate distributed neural circuits that most likely evolved to respond to environmental threats and opportunities. So far, the specific role of unique amygdala nuclei in the context processing of salient environmental cues lacks adequate characterization across neural systems and over time. Here, we present amygdala nuclei morphometry and behavioral findings from longitudinal population data (>1400 subjects, age range 40-69 years, sampled 2-3 years apart): the UK Biobank offers exceptionally rich phenotyping along with brain morphology scans. This allows us to quantify how 18 microanatomical amygdala subregions undergo plastic changes in tandem with coupled neural systems and delineating their associated phenome-wide profiles. In the context of population change, the basal, lateral, accessory basal, and paralaminar nuclei change in lockstep with the prefrontal cortex, a region that subserves planning and decision-making. The central, medial and cortical nuclei are structurally coupled with the insular and anterior-cingulate nodes of the salience network, in addition to the MT/V5, basal ganglia, and putamen, areas proposed to represent internal bodily states and mediate attention to environmental cues. The central nucleus and anterior amygdaloid area are longitudinally tied with the inferior parietal lobule, known for a role in bodily awareness and social attention. These population-level amygdala-brain plasticity regimes in turn are linked with unique collections of phenotypes, ranging from social status and employment to sleep habits and risk taking. The obtained structural plasticity findings motivate hypotheses about the specific functions of distinct amygdala nuclei in humans., (© 2024. The Author(s).)

Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities., (© 2024. The Author(s).)

Copy number variations (CNVs) are rare genomic deletions and duplications that can affect brain and behaviour. Previous reports of CNV pleiotropy imply that they converge on shared mechanisms at some level of pathway cascades, from genes to large-scale neural circuits to the phenome. However, existing studies have primarily examined single CNV loci in small clinical cohorts. It remains unknown, for example, how distinct CNVs escalate vulnerability for the same developmental and psychiatric disorders. Here we quantitatively dissect the associations between brain organization and behavioural differentiation across 8 key CNVs. In 534 CNV carriers, we explored CNV-specific brain morphology patterns. CNVs were characteristic of disparate morphological changes involving multiple large-scale networks. We extensively annotated these CNV-associated patterns with ~1,000 lifestyle indicators through the UK Biobank resource. The resulting phenotypic profiles largely overlap and have body-wide implications, including the cardiovascular, endocrine, skeletal and nervous systems. Our population-level investigation established brain structural divergences and phenotypical convergences of CNVs, with direct relevance to major brain disorders., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Broca reported ~150 years ago that particular lesions of the left hemisphere impair speech. Since then, other brain regions have been reported to show lateralized structure and function. Yet, studies of brain asymmetry have limited their focus to pairwise comparisons between homologous regions. Here, we characterized separable whole-brain asymmetry patterns in grey and white matter structure from n = 37,441 UK Biobank participants. By pooling information on left-right shifts underlying whole-brain structure, we deconvolved signatures of brain asymmetry that are spatially distributed rather than locally constrained. Classically asymmetric regions turned out to belong to more than one asymmetry pattern. Instead of a single dominant signature, we discovered complementary asymmetry patterns that contributed similarly to whole-brain asymmetry at the population level. These asymmetry patterns were associated with unique collections of phenotypes, ranging from early lifestyle factors to demographic status to mental health indicators., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Alzheimer's disease is marked by intracellular tau aggregates in the medial temporal lobe (MTL) and extracellular amyloid aggregates in the default network (DN). Here, we examined codependent structural variations between the MTL's most vulnerable structure, the hippocampus (HC), and the DN at subregion resolution in individuals with Alzheimer's disease and related dementia (ADRD). By leveraging the power of the approximately 40,000 participants of the UK Biobank cohort, we assessed impacts from the protective APOE ɛ2 and the deleterious APOE ɛ4 Alzheimer's disease alleles on these structural relationships. We demonstrate ɛ2 and ɛ4 genotype effects on the inter-individual expression of HC-DN co-variation structural patterns at the population level. Across these HC-DN signatures, recurrent deviations in the CA1, CA2/3, molecular layer, fornix's fimbria, and their cortical partners related to ADRD risk. Analyses of the rich phenotypic profiles in the UK Biobank cohort further revealed male-specific HC-DN associations with air pollution and female-specific associations with cardiovascular traits. We also showed that APOE ɛ2/2 interacts preferentially with HC-DN co-variation patterns in estimating social lifestyle in males and physical activity in females. Our structural, genetic, and phenotypic analyses in this large epidemiological cohort reinvigorate the often-neglected interplay between APOE ɛ2 dosage and sex and link APOE alleles to inter-individual brain structural differences indicative of ADRD familial risk., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Savignac et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Congenital paraspinal arteriovenous fistulae are rare and usually diagnosed after neurologic or cardiovascular manifestations. They may be discovered unexpectedly in children during clinical examination, which reveals the presence of a vascular murmur. The association with multicystic kidney is exceptional. We report 1 case with thoracic localization of a congenital paraspinal arteriovenous fistula associated with a multicystic kidney in a 3-year-old boy who was treated by endovascular embolization.