Targeting cortico-subcortico-cerebellar interactions in development, aging, and disease

Sheeba Anteraper, PhD Organizer
UT Southwestern Medical Center
Advanced Imaging Research Center
Dallas, TX 
United States
Boris Bernhardt Co Organizer
Montreal Neurological Institute and Hospital
Montreal, Quebec 
Wednesday, Jun 26: 9:00 AM - 10:15 AM
Room: ASEM Ballroom 202 
The field of human brain mapping has traditionally had a strong focus on cortical regions. In recent years, the “other part of the brain” i.e., the subcortical structures as well as the cerebellum are increasingly recognized to play pivotal roles in brain function and dysfunction. It is now widely accepted that the cerebellum is critical to human function beyond sensorimotor control. How and what this structure contributes to cognition is highly contested and many functional theories have been proposed. Studying the cerebellum in early development (including gestation), offers a new opportunity to identify unique cerebellar contributions to cognitive function. Taking a whole-brain approach and investigating cortico-subcortico-cerebellar networks would have long-ranging implications for understanding disease mechanisms. Furthermore, this knowledge is important for clinical translation considering the existence of critical periods of cerebellar development, which are associated with the onset of neuropsychiatric conditions.

Here, we will address these aspects (first two talks) and provide a framework of normal development of social cognitive abilities in the context of cortico-cerebellar connectivity, which can be used to further understand social cognitive deficits in neurodevelopmental disorders such as autism and schizophrenia. Several neurological disorders have links to alterations in subcortical regions. Understanding higher order interactions with methods such as edge time series and characterizing them in a healthy population will facilitate their applications in understanding disease relevant mechanisms of cortico-subcortico-cerebellar communication (third talk). The role of sleep in AD trajectory has been extensively studied, but exact mechanisms linking sleep and AD remain elusive. Subcortical structures are closely involved in maintaining normal sleep and wake homeostasis. Thus, clarifying cortico-subcortico-cerebellar interactions in AD will help unravel the relationship between sleep and AD (fourth talk).

The audience will learn about a diverse set of analytical approaches, including resting state functional connectivity analysis, MRI volumetry, task based effective connectivity modelling, as well as edge-based dynamic community detection approaches. Applied to the cerebellum and subcortical structures, these techniques allow for a targeted assessment of their grey matter integrity and their macroscale functional embedding.


1) Gain an in-depth understanding of subcortical and cerebellar anatomy.
2) Appreciate currently available analytical approaches to target cortico-subcortico-cerebellar networks.
3) Understand the role of subcortical and cerebellar networks in macrolevel brain function in health, aging, and disease.

Target Audience

The target audience are students and researchers interested in gaining an in-depth understanding of subcortical and cerebellar anatomy in development, aging, and disease. Those interested in targeting cortico-subcortico-cerebellar networks towards clinical translation will benefit from attending this symposium.  


1. Investigating cortico-cerebellar connectivity across the lifespan

Resting-state fMRI studies have illustrated patterns of connectivity between the human neocortex and cerebellum. However, what has not been established is the degree to which cortical inputs converge onto cerebellar regions. Does each cerebellar region receive input from a single cortical area or convergent inputs from multiple cortical areas? In a recently published study, we used task-based fMRI to build cortico-cerebellar connectivity models, allowing for different degrees of convergence, and we evaluated the models by their ability to predict novel cerebellar activity patterns. Models that allowed for convergence between the cortex and cerebellum provided the best prediction, and highest convergence was observed in regions of the cerebellum linked to language, working memory, and social cognition. These findings establish an important foundation for understanding how cortico-cerebellar circuits support motor and cognitive function in healthy adults. While much of the literature has focused on the “little brain” in its mature, adult form, we are starting to appreciate that the developing cerebellum offers a unique window into understanding how and what this structure contributes to cognition. In this lecture, I will review recent work that links the co-occurrence of neurodevelopmental disorders to atypical cerebellar development. Building on these observations, I will highlight the differences in cerebellar architecture through the lens of injury and will elaborate on how cerebellar function should be interpreted from infancy to adulthood. 


Maedbh King, PhD, Massachusetts Institute of Technology Cambridge, MA 
United States

2. Cortico-cerebellar connectivity changes underlie the emergence of Theory of Mind in early childhood

The neurobiological basis of social cognition is well-established in the cerebral cortex, but recent work in adult populations has shown that the cerebellum is also heavily involved in social cognitive processing. However, the role of the cerebellum in the early-life development of social cognition remains elusive, despite clinical evidence linking early-life cerebellar disruptions with social cognitive deficits in autism and schizophrenia. In the current study, we investigated the functional contribution of the cerebellum to Theory of Mind (ToM) in young children (N = 41, age range: 3-12 years) and compared it to its role in adult ToM (N = 78). We found evidence of functional reorganisation of cerebro-cerebellar connectivity as a function of ToM, with growing connections between the posterior cerebellum and ToM regions of the cerebral cortex as children developed ToM abilities. Further, dynamic causal modelling (DCM) during a movie-watching task revealed forward connections from the posterior cerebellum to the cerebral ToM network in children with emerging ToM abilities, whereas adults showed inverse connections from the cerebral ToM network to the posterior cerebellum. This suggests a developmental gradient from forward to inverse cerebro-cerebellar connectivity for ToM: forward connections from the cerebellum may support the construction of social schemas early in life and be gradually replaced by inverse cerebro-cerebellar connections, which may support automatic use of these schemas later in life. 


Katerina Manoli, Max Planck Institute for Human Cognitive and Brain Sciences Leipzig

3. Investigating cortico-subcortical interactions in functional connectivity with edge community structure

The structural interconnectivity between cortical and subcortical regions is well established, and both can be organized within functional networks. However, the predominant emphasis has been on region (node)-centric analysis of connectivity. Edge time-series, a framework that temporally unravels functional connectivity, allows us to study functional dynamics among edges of a network. Applying this framework to 92 participants from the Human Connectome Project (HCP), edge time-series were clustered into communities, where each edge was assigned into a community, allowing nodes to have multiple/overlapping community affiliations. Focusing on the subnetwork comprised only of the interaction edges between cortex and subcortex, we find that cortical and subcortical regions are functionally coupled via multiple edge communities, with hippocampus and amygdala showing a distinct patten from striatum and thalamus. Additionally, cortical functional organization could be estimated solely from the cortico-subcortical interaction edges. Finally, we applied a motif analysis, where edge community triads between any two cortical nodes and a subcortical node can be classified based on number of unique communities in the triad. In the HCP sample, 2-community triads where a single community coupled a subcortical to two cortical nodes, were found to be overrepresented relative to a null model. These findings are aligned with our current understanding of the role the subcortex plays in integrating and distributing information from/to cortical regions and highlight the potential for use of edge community motifs to study network interactions. 


Evgeny Chumin, PhD, Indiana University School of Medicine Indianapolis, IN 
United States

4. Subcortical and cerebellar neural correlates of prodromal Alzheimer's Disease with prolonged sleep latency

Despite the critical association among sleep, Alzheimer's disease (AD), subcortical structures and the cerebellum, few studies have been published about structural and functional magnetic resonance imaging results demonstrating this relationship. This study aimed to assess the effects of prolonged sleep latency on the structural and functional alterations in the subcortical and cerebellar neural correlates in prodromal AD patients. There was a statistically significant group by regional amyloid beta deposition interactions discovered in cerebro-cerebellar networks. Prolonged sleep latency may be a detrimental factor in compromising structural and functional correlates of subcortical structures and of the cerebellum, which may exacerbate AD pathophysiology.  


Yoo Hyun Um, MD, PhD, Catholic University of Korea Seoul, Seoul 
Korea, Republic of