ABSTRACT
Determining sex-bias in brain structure is of great societal interest to improve diagnostics and treatment of brain-related disorders. So far, studies on sex-bias in brain structure predominantly focus on macro-scale measures, and often ignore factors determining this bias. Here we study sex-bias in cortical and hippocampal microstructure in relation to sex hormones. Investigating quantitative intracortical profiling in-vivo using the T1w/T2w ratio in 1093 healthy females and males of the cross-sectional Human Connectome Project young adult sample, we find that regional cortical and hippocampal microstructure differs between males and females and that the effect size of this sex-bias varies depending on self-reported hormonal status in females. Microstructural sex-bias and expression of sex hormone genes, based on an independent post-mortem sample, are spatially coupled. Lastly, sex-bias is most pronounced in paralimbic areas, with low laminar complexity, which are predicted to be most plastic based on their cytoarchitectural properties. Albeit correlative, our study underscores the importance of incorporating sex hormone variables into the investigation of brain structure and plasticity.
Subject(s)
Cerebral Cortex , Connectome , Gonadal Steroid Hormones , Hippocampus , Humans , Female , Hippocampus/metabolism , Hippocampus/diagnostic imaging , Male , Young Adult , Adult , Gonadal Steroid Hormones/metabolism , Cerebral Cortex/metabolism , Cerebral Cortex/diagnostic imaging , Sex Characteristics , Magnetic Resonance Imaging/methods , Cross-Sectional StudiesABSTRACT
Adolescence is a period of dynamic brain remodeling and susceptibility to psychiatric risk factors, mediated by the protracted consolidation of association cortices. Here, we investigated whether longitudinal variation in adolescents' resilience to psychosocial stressors during this vulnerable period is associated with ongoing myeloarchitectural maturation and consolidation of functional networks. We used repeated myelin-sensitive Magnetic Transfer (MT) and resting-state functional neuroimaging (n = 141), and captured adversity exposure by adverse life events, dysfunctional family settings, and socio-economic status at two timepoints, one to two years apart. Development toward more resilient psychosocial functioning was associated with increasing myelination in the anterolateral prefrontal cortex, which showed stabilized functional connectivity. Studying depth-specific intracortical MT profiles and the cortex-wide synchronization of myeloarchitectural maturation, we further observed wide-spread myeloarchitectural reconfiguration of association cortices paralleled by attenuated functional reorganization with increasingly resilient outcomes. Together, resilient/susceptible psychosocial functioning showed considerable intra-individual change associated with multi-modal cortical refinement processes at the local and system-level.
Subject(s)
Magnetic Resonance Imaging , Myelin Sheath , Psychosocial Functioning , Resilience, Psychological , Humans , Adolescent , Male , Female , Myelin Sheath/metabolism , Longitudinal Studies , Prefrontal Cortex/physiology , Prefrontal Cortex/diagnostic imaging , Stress, Psychological/physiopathology , Cerebral Cortex/physiology , Cerebral Cortex/diagnostic imagingABSTRACT
The balance of excitation and inhibition is a key functional property of cortical microcircuits which changes through the lifespan. Adolescence is considered a crucial period for the maturation of excitation-inhibition balance. This has been primarily observed in animal studies, yet human in vivo evidence on adolescent maturation of the excitation-inhibition balance at the individual level is limited. Here, we developed an individualized in vivo marker of regional excitation-inhibition balance in human adolescents, estimated using large-scale simulations of biophysical network models fitted to resting-state functional magnetic resonance imaging data from two independent cross-sectional (N = 752) and longitudinal (N = 149) cohorts. We found a widespread relative increase of inhibition in association cortices paralleled by a relative age-related increase of excitation, or lack of change, in sensorimotor areas across both datasets. This developmental pattern co-aligned with multiscale markers of sensorimotor-association differentiation. The spatial pattern of excitation-inhibition development in adolescence was robust to inter-individual variability of structural connectomes and modeling configurations. Notably, we found that alternative simulation-based markers of excitation-inhibition balance show a variable sensitivity to maturational change. Taken together, our study highlights an increase of inhibition during adolescence in association areas using cross sectional and longitudinal data, and provides a robust computational framework to estimate microcircuit maturation in vivo at the individual level.
ABSTRACT
Growing evidence implicates systemic inflammation in the loss of structural brain integrity in natural ageing and disorder development. Chronic stress and glucocorticoid exposure can potentiate inflammatory processes and may also be linked to neuronal atrophy, particularly in the hippocampus and the human neocortex. To improve understanding of emerging maladaptive interactions between stress and inflammation, this study examined evidence for glucocorticoid- and inflammation-mediated neurodegeneration in healthy mid-aged adults. N = 169 healthy adults (mean age = 39.4, 64.5% female) were sampled from the general population in the context of the ReSource Project. Stress, inflammation and neuronal atrophy were quantified using physiological indices of chronic stress (hair cortisol (HCC) and cortisone (HEC) concentration), systemic inflammation (interleukin-6 (IL-6), high-sensitive C-reactive protein (hs-CRP)), the systemic inflammation index (SII), hippocampal volume (HCV) and cortical thickness (CT) in regions of interest. Structural equation models were used to examine evidence for pathways from stress and inflammation to neuronal atrophy. Model fit indices indicated good representation of stress, inflammation, and neurological data through the constructed models (CT model: robust RMSEA = 0.041, robust χ2 = 910.90; HCV model: robust RMSEA <0.001, robust χ2 = 40.95). Among inflammatory indices, only the SII was positively associated with hair cortisol as one indicator of chronic stress (ß = 0.18, p < 0.05). Direct and indirect pathways from chronic stress and systemic inflammation to cortical thickness or hippocampal volume were non-significant. In exploratory analysis, the SII was inversely related to mean cortical thickness. Our results emphasize the importance of considering the multidimensionality of systemic inflammation and chronic stress, with various indicators that may represent different aspects of the systemic reaction. We conclude that inflammation and glucocorticoid-mediated neurodegeneration indicated by IL-6 and hs-CRP and HCC and HEC may only emerge during advanced ageing and disorder processes, still the SII could be a promising candidate for detecting associations between inflammation and neurodegeneration in younger and healthy samples. Future work should examine these pathways in prospective longitudinal designs, for which the present investigation serves as a baseline.
ABSTRACT
Human neuroimaging studies consistently show multimodal patterns of variability along a key principle of macroscale cortical organization - the sensorimotor-association (S-A) axis. However, little is known about day-to-day fluctuations in functional activity along this axis within an individual, including sex-specific neuroendocrine factors contributing to such transient changes. We leveraged data from two densely sampled healthy young adults, one female and one male, to investigate intra-individual daily variability along the S-A axis, which we computed as our measure of functional cortical organization by reducing the dimensionality of functional connectivity matrices. Daily variability was greatest in temporal limbic and ventral prefrontal regions in both participants, and was more strongly pronounced in the male subject. Next, we probed local- and system-level effects of steroid hormones and self-reported perceived stress on functional organization. Our findings revealed modest effects that differed between participants, hinting at subtle -potentially sex-specific- associations between neuroendocrine fluctuations and intra-individual variability along the S-A axis. In sum, our study points to neuroendocrine factors as possible modulators of intra-individual variability in functional brain organization, highlighting the need for further research in larger samples.
ABSTRACT
Multimodal neuroimaging grants a powerful in vivo window into the structure and function of the human brain. Recent methodological and conceptual advances have enabled investigations of the interplay between large-scale spatial trends - or gradients - in brain structure and function, offering a framework to unify principles of brain organization across multiple scales. Strong community enthusiasm for these techniques has been instrumental in their widespread adoption and implementation to answer key questions in neuroscience. Following a brief review of current literature on this framework, this perspective paper will highlight how pragmatic steps aiming to make gradient methods more accessible to the community propelled these techniques to the forefront of neuroscientific inquiry. More specifically, we will emphasize how interest for gradient methods was catalyzed by data sharing, open-source software development, as well as the organization of dedicated workshops led by a diverse team of early career researchers. To this end, we argue that the growing excitement for brain gradients is the result of coordinated and consistent efforts to build an inclusive community and can serve as a case in point for future innovations and conceptual advances in neuroinformatics. We close this perspective paper by discussing challenges for the continuous refinement of neuroscientific theory, methodological innovation, and real-world translation to maintain our collective progress towards integrated models of brain organization.
ABSTRACT
Autism spectrum disorder is a common neurodevelopmental condition that manifests as a disruption in sensory and social skills. Although it has been shown that the brain morphology of individuals with autism is asymmetric, how this differentially affects the structural connectome organization of each hemisphere remains under-investigated. We studied whole-brain structural connectivity-based brain asymmetry in individuals with autism using diffusion magnetic resonance imaging obtained from the Autism Brain Imaging Data Exchange initiative. By leveraging dimensionality reduction techniques, we constructed low-dimensional representations of structural connectivity and calculated their asymmetry index. Comparing the asymmetry index between individuals with autism and neurotypical controls, we found atypical structural connectome asymmetry in the sensory and default-mode regions, particularly showing weaker asymmetry towards the right hemisphere in autism. Network communication provided topological underpinnings by demonstrating that the inferior temporal cortex and limbic and frontoparietal regions showed reduced global network communication efficiency and decreased send-receive network navigation in the inferior temporal and lateral visual cortices in individuals with autism. Finally, supervised machine learning revealed that structural connectome asymmetry could be used as a measure for predicting communication-related autistic symptoms and nonverbal intelligence. Our findings provide insights into macroscale structural connectome alterations in autism and their topological underpinnings.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Connectome , Humans , Autistic Disorder/diagnostic imaging , Autism Spectrum Disorder/diagnostic imaging , Autism Spectrum Disorder/pathology , Magnetic Resonance Imaging/methods , Brain/diagnostic imaging , Brain/pathologyABSTRACT
Autism spectrum disorder (ASD) is one of the most common neurodevelopmental diagnoses. Although incompletely understood, structural and functional network alterations are increasingly recognized to be at the core of the condition. We utilized multimodal imaging and connectivity modeling to study structure-function coupling in ASD and probed mono- and polysynaptic mechanisms on structurally-governed network function. We examined multimodal magnetic resonance imaging data in 80 ASD and 61 neurotypical controls from the Autism Brain Imaging Data Exchange (ABIDE) II initiative. We predicted intrinsic functional connectivity from structural connectivity data in each participant using a Riemannian optimization procedure that varies the times that simulated signals can unfold along tractography-derived personalized connectomes. In both ASD and neurotypical controls, we observed improved structure-function prediction at longer diffusion time scales, indicating better modeling of brain function when polysynaptic mechanisms are accounted for. Prediction accuracy differences (∆prediction accuracy) were marked in transmodal association systems, such as the default mode network, in both neurotypical controls and ASD. Differences were, however, lower in ASD in a polysynaptic regime at higher simulated diffusion times. We compared regional differences in ∆prediction accuracy between both groups to assess the impact of polysynaptic communication on structure-function coupling. This analysis revealed that between-group differences in ∆prediction accuracy followed a sensory-to-transmodal cortical hierarchy, with an increased gap between controls and ASD in transmodal compared to sensory/motor systems. Multivariate associative techniques revealed that structure-function differences reflected inter-individual differences in autistic symptoms and verbal as well as non-verbal intelligence. Our network modeling approach sheds light on atypical structure-function coupling in autism, and suggests that polysynaptic network mechanisms are implicated in the condition and that these can help explain its wide range of associated symptoms.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Connectome , Humans , Autistic Disorder/diagnostic imaging , Connectome/methods , Brain , Magnetic Resonance Imaging/methods , Brain Mapping/methodsABSTRACT
Brain size robustly differs between sexes. However, the consequences of this anatomical dimorphism on sex differences in intrinsic brain function remain unclear. We investigated the extent to which sex differences in intrinsic cortical functional organization may be explained by differences in cortical morphometry, namely brain size, microstructure, and the geodesic distances of connectivity profiles. For this, we computed a low dimensional representation of functional cortical organization, the sensory-association axis, and identified widespread sex differences. Contrary to our expectations, observed sex differences in functional organization were not fundamentally associated with differences in brain size, microstructural organization, or geodesic distances, despite these morphometric properties being per se associated with functional organization and differing between sexes. Instead, functional sex differences in the sensory-association axis were associated with differences in functional connectivity profiles and network topology. Collectively, our findings suggest that sex differences in functional cortical organization extend beyond sex differences in cortical morphometry.
ABSTRACT
Background: Neuroimaging studies have provided valuable insights into the macroscale impacts of antidepressants on brain functions in patients with major depressive disorder. However, the findings of individual studies are inconsistent. Here, we aimed to provide a quantitative synthesis of the literature to identify convergence of the reported findings at both regional and network levels and to examine their associations with neurotransmitter systems. Methods: Through a comprehensive search in PubMed and Scopus databases, we reviewed 5,258 abstracts and identified 37 eligible functional neuroimaging studies on antidepressant effects in major depressive disorder. Activation likelihood estimation was used to investigate regional convergence of the reported foci of consistent antidepressant effects, followed by functional decoding and connectivity mapping of the convergent clusters. Additionally, utilizing group-averaged data from the Human Connectome Project, we assessed convergent resting-state functional connectivity patterns of the reported foci. Next, we compared the convergent circuit with the circuits targeted by transcranial magnetic stimulation (TMS) therapy. Last, we studied the association of regional and network-level convergence maps with the selected neurotransmitter receptors/transporters maps. Results: We found regional convergence of the reported treatment-associated increases of functional measures in the left dorsolateral prefrontal cortex, which was associated with working memory and attention behavioral domains. No regional convergence was found across foci of alterations in functional imaging associated with antidepressants. Moreover, we found network-level convergence of functional alterations in a circuit that was prominent in the frontoparietal and salience networks. This circuit was co-aligned with a circuit targeted by anti-subgenual TMS therapy. We observed no significant correlations between our meta-analytic findings with the maps of neurotransmitter receptors/transporters. Conclusion: Our findings highlight the importance of the left dorsolateral prefrontal cortex, as well as frontoparietal network and the salience network in the therapeutic effects of anti-depressants, possibly associated with their role in improving executive functions and emotional processing.
ABSTRACT
Autism spectrum disorder is a common neurodevelopmental condition showing connectome disorganization in sensory and transmodal cortices. However, alterations in the inter-hemispheric asymmetry of structural connectome are remained to be investigated. Here, we studied structural connectome asymmetry in individuals with autism using dimensionality reduction techniques and assessed its topological underpinnings by associating with network communication measures. We found that the sensory and heteromodal association regions showed significant between-group differences in inter-hemispheric asymmetry between individuals with autism and neurotypical controls. In addition, the network communication ability was particularly altered between visual and limbic areas. Our findings provide insights for understanding structural connectome alteration in autism and its topological underpinnings.Clinical Relevance- This study provides insights into the understanding of atypical macroscale structural connectome organization in individuals with autism.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Connectome , Humans , Autism Spectrum Disorder/diagnostic imaging , Magnetic Resonance Imaging/methods , CommunicationABSTRACT
The reciprocal connections between the cerebellum and the cerebrum have been suggested to simultaneously play a role in brain size increase and to support a broad array of brain functions in primates. The cerebello-cerebral system has undergone marked functionally relevant reorganization. In particular, the lateral cerebellar lobules crura I-II (the ansiform) have been suggested to be expanded in hominoids. Here, we manually segmented 63 cerebella (34 primate species; 9 infraorders) and 30 ansiforms (13 species; 8 infraorders) to understand how their volumes have evolved over the primate lineage. Together, our analyses support proportional cerebellar-cerebral scaling, whereas ansiforms have expanded faster than the cerebellum and cerebrum. We did not find different scaling between strepsirrhines and haplorhines, nor between apes and non-apes. In sum, our study shows primate-general structural reorganization of the ansiform, relative to the cerebello-cerebral system, which is relevant for specialized brain functions in an evolutionary context.
Subject(s)
Cerebellum , Primates , Animals , Phylogeny , Biological Evolution , BrainABSTRACT
The human isocortex consists of tangentially organized layers with unique cytoarchitectural properties. These layers show spatial variations in thickness and cytoarchitecture across the neocortex, which is thought to support function through enabling targeted corticocortical connections. Here, leveraging maps of the 6 cortical layers based on 3D human brain histology, we aimed to quantitatively characterize the systematic covariation of laminar structure in the cortex and its functional consequences. After correcting for the effect of cortical curvature, we identified a spatial pattern of changes in laminar thickness covariance from lateral frontal to posterior occipital regions, which differentiated the dominance of infra- versus supragranular layer thickness. Corresponding to the laminar regularities of cortical connections along cortical hierarchy, the infragranular-dominant pattern of laminar thickness was associated with higher hierarchical positions of regions, mapped based on resting-state effective connectivity in humans and tract-tracing of structural connections in macaques. Moreover, we show that regions with similar laminar thickness patterns have a higher likelihood of structural connections and strength of functional connections. In sum, here we characterize the organization of laminar thickness in the human isocortex and its association with cortico-cortical connectivity, illustrating how laminar organization may provide a foundational principle of cortical function.
Subject(s)
Neocortex , Animals , Humans , Macaca , Cerebral CortexABSTRACT
Our understanding of the genetics of the human cerebral cortex is limited both in terms of the diversity and the anatomical granularity of brain structural phenotypes. Here we conducted a genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging-derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,663 individuals and identified 4,349 experiment-wide significant loci. These phenotypes include cortical thickness, surface area, gray matter volume, measures of folding, neurite density and water diffusion. We identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with cortical expansion are associated with cephalic disorders. Finally, we identified complex interphenotype and inter-regional genetic relationships among the 13 phenotypes, reflecting the developmental differences among them. Together, these analyses identify distinct genetic organizational principles of the cortex and their correlates with neurodevelopment.
Subject(s)
Cerebral Cortex , Genome-Wide Association Study , Humans , Cerebral Cortex/diagnostic imaging , Brain/diagnostic imaging , Neuroimaging , PhenotypeABSTRACT
Autism is a neurodevelopmental condition involving atypical sensory-perceptual functions together with language and socio-cognitive deficits. Previous work has reported subtle alterations in the asymmetry of brain structure and reduced laterality of functional activation in individuals with autism relative to non-autistic individuals (NAI). However, whether functional asymmetries show altered intrinsic systematic organization in autism remains unclear. Here, we examined inter- and intra-hemispheric asymmetry of intrinsic functional gradients capturing connectome organization along three axes, stretching between sensory-default, somatomotor-visual, and default-multiple demand networks, to study system-level hemispheric imbalances in autism. We observed decreased leftward functional asymmetry of language network organization in individuals with autism, relative to NAI. Whereas language network asymmetry varied across age groups in NAI, this was not the case in autism, suggesting atypical functional laterality in autism may result from altered developmental trajectories. Finally, we observed that intra- but not inter-hemispheric features were predictive of the severity of autistic traits. Our findings illustrate how regional and patterned functional lateralization is altered in autism at the system level. Such differences may be rooted in atypical developmental trajectories of functional organization asymmetry in autism.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Connectome , Humans , Magnetic Resonance Imaging , Brain , Functional Laterality/physiology , Brain MappingABSTRACT
BACKGROUND AND HYPOTHESIS: Schizophrenia is a polygenetic mental disorder with heterogeneous positive and negative symptom constellations, and is associated with abnormal cortical connectivity. The thalamus has a coordinative role in cortical function and is key to the development of the cerebral cortex. Conversely, altered functional organization of the thalamus might relate to overarching cortical disruptions in schizophrenia, anchored in development. STUDY DESIGN: Here, we contrasted resting-state fMRI in 86 antipsychotic-naive first-episode early-onset schizophrenia (EOS) patients and 91 typically developing controls to study whether macroscale thalamic organization is altered in EOS. Employing dimensional reduction techniques on thalamocortical functional connectome (FC), we derived lateral-medial and anterior-posterior thalamic functional axes. STUDY RESULTS: We observed increased segregation of macroscale thalamic functional organization in EOS patients, which was related to altered thalamocortical interactions both in unimodal and transmodal networks. Using an ex vivo approximation of core-matrix cell distribution, we found that core cells particularly underlie the macroscale abnormalities in EOS patients. Moreover, the disruptions were associated with schizophrenia-related gene expression maps. Behavioral and disorder decoding analyses indicated that the macroscale hierarchy disturbances might perturb both perceptual and abstract cognitive functions and contribute to negative syndromes in patients. CONCLUSIONS: These findings provide mechanistic evidence for disrupted thalamocortical system in schizophrenia, suggesting a unitary pathophysiological framework.
Subject(s)
Psychotic Disorders , Schizophrenia , Humans , Schizophrenia/diagnostic imaging , Cerebral Cortex/diagnostic imaging , Magnetic Resonance Imaging , Thalamus/diagnostic imaging , Neural PathwaysABSTRACT
Multiple studies have reported a link between mental health and high blood pressure with mixed or even contradictory findings. Here, we resolve those contradictions and further dissect the cross-sectional and longitudinal relationship between mental health, systolic blood pressure, and hypertension using extensive psychological, medical and neuroimaging data from the UK Biobank. We show that higher systolic blood pressure is associated with fewer depressive symptoms, greater well-being, and lower emotion-related brain activity. Interestingly, impending hypertension is associated with poorer mental health years before HTN is diagnosed. In addition, a stronger baseline association between systolic blood pressure and better mental health was observed in individuals who develop hypertension until follow-up. Overall, our findings offer insights on the complex relationship between mental health, blood pressure, and hypertension, suggesting that-via baroreceptor mechanisms and reinforcement learning-the association of higher blood pressure with better mental health may ultimately contribute to the development of hypertension.
Subject(s)
Hypertension , Mental Health , Humans , Blood Pressure/physiology , Cross-Sectional StudiesABSTRACT
Existing neuroimaging studies have reported divergent structural alterations in insomnia disorder (ID). In the present study, we performed a large-scale coordinated meta-analysis by pooling structural brain measures from 1085 subjects (mean [SD] age 50.5 [13.9] years, 50.2% female, 17.4% with insomnia) across three international Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA)-Sleep cohorts. Two sites recruited patients with ID/controls: Freiburg (University of Freiburg Medical Center, Freiburg, Germany) 42/43 and KUMS (Kermanshah University of Medical Sciences, Kermanshah, Iran) 42/49, while the Study of Health in Pomerania (SHIP-Trend, University Medicine Greifswald, Greifswald, Germany) recruited population-based individuals with/without insomnia symptoms 75/662. The influence of insomnia on magnetic resonance imaging-based brain morphometry using an insomnia brain score was then assessed. Within each cohort, we used an ordinary least-squares linear regression to investigate the link between the individual regional cortical and subcortical volumes and the presence of insomnia symptoms. Then, we performed a fixed-effects meta-analysis across cohorts based on the first-level results. For the insomnia brain score, weighted logistic ridge regression was performed on one sample (Freiburg), which separated patients with ID from controls to train a model based on the segmentation measurements. Afterward, the insomnia brain scores were validated using the other two samples. The model was used to predict the log-odds of the subjects with insomnia given individual insomnia-related brain atrophy. After adjusting for multiple comparisons, we did not detect any significant associations between insomnia symptoms and cortical or subcortical volumes, nor could we identify a global insomnia-related brain atrophy pattern. Thus, we observed inconsistent brain morphology differences between individuals with and without insomnia across three independent cohorts. Further large-scale cross-sectional/longitudinal studies using both structural and functional neuroimaging are warranted to decipher the neurobiology of insomnia.
Subject(s)
Sleep Initiation and Maintenance Disorders , Female , Humans , Male , Middle Aged , Brain/diagnostic imaging , Brain/pathology , Cross-Sectional Studies , Magnetic Resonance Imaging/methods , Neuroimaging/methods , Sleep , Sleep Initiation and Maintenance Disorders/complications , Sleep Initiation and Maintenance Disorders/diagnostic imaging , AdultABSTRACT
The longstanding idea that the cerebral cortex is the main neural correlate of human cognition can be elaborated by comparative analyses along the vertebrate phylogenetic tree that support the view that the cerebello-cerebral system is suited to support non-motor functions more generally. In humans, diverse accounts have illustrated cerebellar involvement in cognitive functions. Although the neocortex, and its transmodal association cortices such as the prefrontal cortex, have become disproportionately large over primate evolution specifically, human neocortical volume does not appear to be exceptional relative to the variability within primates. Rather, several lines of evidence indicate that the exceptional volumetric increase of the lateral cerebellum in conjunction with its connectivity with the cerebral cortical system may be linked to non-motor functions and mental operation in primates. This idea is supported by diverging cerebello-cerebral adaptations that potentially coevolve with cognitive abilities across other vertebrates such as dolphins, parrots, and elephants. Modular adaptations upon the vertebrate cerebello-cerebral system may thus help better understand the neuroevolutionary trajectory of the primate brain and its relation to cognition in humans. Lateral cerebellar lobules crura I-II and their reciprocal connections to the cerebral cortical association areas appear to have substantially expanded in great apes, and humans. This, along with the notable increase in the ventral portions of the dentate nucleus and a shift to increased relative prefrontal-cerebellar connectivity, suggests that modular cerebellar adaptations support cognitive functions in humans. In sum, we show how comparative neuroscience provides new avenues to broaden our understanding of cerebellar and cerebello-cerebral functions in the context of cognition.