Faculty Bibliography

There is considerable interest in the long-term brain health of retired contact and collision sport athletes; however, little is known about possible underlying changes in functional brain connectivity in this group. We evaluated whole-brain functional connectivity patterns using multi-voxel pattern analysis (MVPA) to determine whether alterations in functional connectivity distinguish retired professional athletes from a matched group of healthy community control subjects. Thirty-two retired athletes with a history of multiple self-reported sport-related concussions and 36 healthy community control subjects who were similar in age and education, completed functional magnetic resonance imaging. We identified brain regions with abnormal functional connectivity patterns using whole-brain MVPA as implemented in the Conn toolbox. First-level MVPA was performed using 64 principal component analysis (PCA) components. Second-level F test was performed using the first three MVPA components for retired athletes > controls group contrast. Post hoc seed-to-voxel analyses using the MVPA cluster results as seeds were performed to characterize functional connectivity abnormalities from brain regions identified by MVPA. MVPA revealed one cluster of abnormal functional connectivity located in cerebellar lobule V. This region of lobule V corresponded to the ventral attention network. Post hoc seed-to-voxel analysis using the cerebellar MVPA cluster as a seed revealed multiple areas of cerebral cortical hyper-connectivity and hypo-connectivity in retired athletes when compared with controls. This initial report suggests that cerebellar dysfunction might be present and clinically important in some retired athletes.

Our understanding of cerebellar involvement in brain disorders has evolved from motor processing to high-level cognitive and affective processing. Recent neuroscience progress has highlighted hierarchy as a fundamental principle for the brain organization. Despite substantial research on cerebellar dysfunction in schizophrenia, there is a need to establish a neurobiological framework to better understand the co-occurrence and interaction of low- and high-level functional abnormalities of cerebellum in schizophrenia. To help to establish such a framework, we investigated the abnormalities in the distribution of sensorimotor-supramodal hierarchical processing topography in the cerebellum and cerebellar-cerebral circuits in schizophrenia using a novel gradient-based resting-state functional connectivity (FC) analysis (96 patients with schizophrenia vs 120 healthy controls). We found schizophrenia patients showed a compression of the principal motor-to-supramodal gradient. Specifically, there were increased gradient values in sensorimotor regions and decreased gradient values in supramodal regions, resulting in a shorter distance (compression) between the sensorimotor and supramodal poles of this gradient. This pattern was observed in intra-cerebellar, cerebellar-cerebral, and cerebral-cerebellar FC. Further investigation revealed hyper-connectivity between sensorimotor and cognition areas within cerebellum, between cerebellar sensorimotor and cerebral cognition areas, and between cerebellar cognition and cerebral sensorimotor areas, possibly contributing to the observed compressed pattern. These findings present a novel mechanism that may underlie the co-occurrence and interaction of low- and high-level functional abnormalities of cerebellar and cerebro-cerebellar circuits in schizophrenia. Within this framework of abnormal motor-to-supramodal organization, a cascade of impairments stemming from disrupted low-level sensorimotor system may in part account for high-level cognitive cerebellar dysfunction in schizophrenia.

Cerebellar abnormalities are commonly reported in autism spectrum disorder (ASD). Dentate nuclei (DNs) are key structures in the anatomical circuits linking the cerebellum to the extracerebellum. Previous resting-state functional connectivity (RsFc) analyses reported DN abnormalities in high-functioning ASD (HF-ASD). This study examined the RsFc of the DN in young adults with HF-ASD compared with healthy controls (HCs) with the aim to expand upon previous findings of DNs in a dataset using advanced, imaging acquisition methods that optimize spatiotemporal resolution and statistical power. Additional seed-to-voxel analyses were carried out using motor and nonmotor DN coordinates reported in previous studies as seeds. We report abnormal dentato-cerebral and dentato-cerebellar functional connectivity in ASD. Our results expand and, in part, replicate previous descriptions of DN RsFc abnormalities in this disorder and reveal correlations between DN-cerebral RsFc and ASD symptom severity.

This study examines the resting-state functional-connectivity (RsFc) in young adults with high-functioning autism spectrum disorder (HF-ASD) using state-of-the-art fMRI data acquisition and analysis techniques. High temporal resolution fMRI using simultaneous multi-slice acquisition aided unbiased whole-brain connectome-wide multivariate pattern analysis (MVPA) techniques for assessing RsFc. MVPA revealed two clusters (Crus I/II and lobule IX) of abnormal connectivity in the cerebellum that are consistent with the notion of a triple representation of nonmotor processing in the cerebellum. Whole-brain seed-based RsFc analyses informed by these clusters showed significant under connectivity between the cerebellar and social, emotional, and language brain regions in the HF-ASD group compared to healthy controls. The results we report are coherent with existing structural, functional, and RsFc literature in autism, extend previous literature reporting cerebellar abnormalities in the neuropathology of autism, and highlight the cerebellum as a potential target for therapeutic, diagnostic, predictive, and prognostic developments in HF-ASD. The description of functional connectivity abnormalities reported in this study using whole-brain, data-driven analyses has the potential to crucially advance the development of ASD biomarkers, targets for therapeutic interventions, and neural predictors for measuring treatment response.

Gradient-based approaches to brain function have recently unmasked fundamental properties of brain organization. Diffusion map embedding analysis of resting-state fMRI data revealed a primary-to-transmodal axis of cerebral cortical macroscale functional organization. The same method was recently used to analyze resting-state data within the cerebellum, revealing for the first time a sensorimotor-fugal macroscale organization principle of cerebellar function. Cerebellar gradient 1 extended from motor to non-motor task-unfocused (default-mode network) areas, and cerebellar gradient 2 isolated task-focused processing regions. Here we present a freely available and easily accessible tool that applies this new knowledge to the topographical interpretation of cerebellar neuroimaging findings. LittleBrain illustrates the relationship between cerebellar data (e.g., volumetric patient study clusters, task activation maps, etc.) and cerebellar gradients 1 and 2. Specifically, LittleBrain plots all voxels of the cerebellum in a two-dimensional scatterplot, with each axis corresponding to one of the two principal functional gradients of the cerebellum, and indicates the position of cerebellar neuroimaging data within these two dimensions. This novel method of data mapping provides alternative, gradual visualizations that complement discrete parcellation maps of cerebellar functional neuroanatomy. We present application examples to show that LittleBrain can also capture subtle, progressive aspects of cerebellar functional neuroanatomy that would be difficult to visualize using conventional mapping techniques. Download and use instructions can be found at https://xaviergp.github.io/littlebrain.

Cerebellar neuroscience has undergone a paradigm shift. The theories of the universal cerebellar transform and dysmetria of thought and the principles of organization of cerebral cortical connections, together with neuroanatomical, brain imaging, and clinical observations, have recontextualized the cerebellum as a critical node in the distributed neural circuits subserving behavior. The framework for cerebellar cognition stems from the identification of three cognitive representations in the posterior lobe, which are interconnected with cerebral association areas and distinct from the primary and secondary cerebellar sensorimotor representations linked with the spinal cord and cerebral motor areas. Lesions of the anterior lobe primary sensorimotor representations produce dysmetria of movement, the cerebellar motor syndrome. Lesions of the posterior lobe cognitive-emotional cerebellum produce dysmetria of thought and emotion, the cerebellar cognitive affective/Schmahmann syndrome. The notion that the cerebellum modulates thought and emotion in the same way that it modulates motor control advances the understanding of the mechanisms of cognition and opens new therapeutic opportunities in behavioral neurology and neuropsychiatry.

Delineation of functional topography is critical to the evolving understanding of the cerebellum's role in a wide range of nervous system functions. We used data from the Human Connectome Project (n = 787) to analyze cerebellar fMRI task activation (motor, working memory, language, social and emotion processing) and resting-state functional connectivity calculated from cerebral cortical seeds corresponding to the peak Cohen's d of each task contrast. The combination of exceptional statistical power, activation from both motor and multiple non-motor tasks in the same participants, and convergent resting-state networks in the same participants revealed novel aspects of the functional topography of the human cerebellum. Consistent with prior studies there were two distinct representations of motor activation. Newly revealed were three distinct representations each for working memory, language, social, and emotional task processing that were largely separate for these four cognitive and affective domains. In most cases, the task-based activations and the corresponding resting-network correlations were congruent in identifying the two motor representations and the three non-motor representations that were unique to working memory, language, social cognition, and emotion. The definitive localization and characterization of distinct triple representations for cognition and emotion task processing in the cerebellum opens up new basic science questions as to why there are triple representations (what different functions are enabled by the different representations?) and new clinical questions (what are the differing consequences of lesions to the different representations?).

A central principle for understanding the cerebral cortex is that macroscale anatomy reflects a functional hierarchy from primary to transmodal processing. In contrast, the central axis of motor and nonmotor macroscale organization in the cerebellum remains unknown. Here we applied diffusion map embedding to resting-state data from the Human Connectome Project dataset (n = 1003), and show for the first time that cerebellar functional regions follow a gradual organization which progresses from primary (motor) to transmodal (DMN, task-unfocused) regions. A secondary axis extends from task-unfocused to task-focused processing. Further, these two principal gradients revealed novel functional properties of the well-established cerebellar double motor representation (lobules I-VI and VIII), and its relationship with the recently described triple nonmotor representation (lobules VI/Crus I, Crus II/VIIB, IX/X). Functional differences exist not only between the two motor but also between the three nonmotor representations, and second motor representation might share functional similarities with third nonmotor representation.

Cerebellar cognitive affective syndrome (CCAS; Schmahmann's syndrome) is characterized by deficits in executive function, linguistic processing, spatial cognition, and affect regulation. Diagnosis currently relies on detailed neuropsychological testing. The aim of this study was to develop an office or bedside cognitive screen to help identify CCAS in cerebellar patients. Secondary objectives were to evaluate whether available brief tests of mental function detect cognitive impairment in cerebellar patients, whether cognitive performance is different in patients with isolated cerebellar lesions versus complex cerebrocerebellar pathology, and whether there are cognitive deficits that should raise red flags about extra-cerebellar pathology. Comprehensive standard neuropsychological tests, experimental measures and clinical rating scales were administered to 77 patients with cerebellar disease-36 isolated cerebellar degeneration or injury, and 41 complex cerebrocerebellar pathology-and to healthy matched controls. Tests that differentiated patients from controls were used to develop a screening instrument that includes the cardinal elements of CCAS. We validated this new scale in a new cohort of 39 cerebellar patients and 55 healthy controls. We confirm the defining features of CCAS using neuropsychological measures. Deficits in executive function were most pronounced for working memory, mental flexibility, and abstract reasoning. Language deficits included verb for noun generation and phonemic > semantic fluency. Visual spatial function was degraded in performance and interpretation of visual stimuli. Neuropsychiatric features included impairments in attentional control, emotional control, psychosis spectrum disorders and social skill set. From these results, we derived a 10-item scale providing total raw score, cut-offs for each test, and pass/fail criteria that determined 'possible' (one test failed), 'probable' (two tests failed), and 'definite' CCAS (three tests failed). When applied to the exploratory cohort, and administered to the validation cohort, the CCAS/Schmahmann scale identified sensitivity and selectivity, respectively as possible exploratory cohort: 85%/74%, validation cohort: 95%/78%; probable exploratory cohort: 58%/94%, validation cohort: 82%/93%; and definite exploratory cohort: 48%/100%, validation cohort: 46%/100%. In patients in the exploratory cohort, Mini-Mental State Examination and Montreal Cognitive Assessment scores were within normal range. Complex cerebrocerebellar disease patients were impaired on similarities in comparison to isolated cerebellar disease. Inability to recall words from multiple choice occurred only in patients with extra-cerebellar disease. The CCAS/Schmahmann syndrome scale is useful for expedited clinical assessment of CCAS in patients with cerebellar disorders.awx317media15678692096001.

In this report, we analyze the relationship between embodied cognition and current theories of the cerebellum, particularly the Dysmetria of Thought theory and the concept of the Universal Cerebellar Transform (UCT). First, we describe the UCT and the Dysmetria of Thought theories, highlight evidence supporting these hypotheses and discuss their mechanisms, functions and relevance. We then propose the following relationships. (i) The UCT strengthens embodied cognition because it provides an example of embodiment where the nature and intensity of the dependence between cognitive, affective and sensorimotor processes are defined. (ii) Conversely, embodied cognition bolsters the UCT theory because it contextualizes a cerebellum-focused theory within a general neurological theory. (iii) Embodied cognition supports the extension to other brain regions of the principles of organization of cerebral cortical connections that underlie the UCT: The notion that cytoarchitectonically determined transforms manifest via connectivity as sensorimotor, cognitive and affective functions resonates with the embodiment thesis that cognitive, affective and sensorimotor systems are interdependent. (iv) Embodied cognition might shape future definitions of the UCT because embodiment redefines the relationship between the neurological systems modulated by the UCT. We conclude by analyzing the relationship between our hypotheses and the concept of syntax and action semantics deficits in motor diseases.