Faculty Bibliography

Anatomical studies in animals and imaging studies in humans show that cerebral sensorimotor areas map onto corresponding cerebellar sensorimotor areas and that cerebral association areas map onto cerebellar posterior lobe regions designated as the representation of the association (cognitive and limbic) cerebellum. We report a patient with unilateral left hemispheric status epilepticus, whose brain MRI revealed diffuse unihemispheric cerebral cortical FLAIR and diffusion signal hyperintensity but spared primary motor, somatosensory, visual, and to lesser extent auditory cerebral cortices. Crossed cerebellar diaschisis (dysfunction at a site remote from, but connected to, the location of the primary lesion) showed signal hyperintensity in the right cerebellar posterior lobe and lobule IX, with sparing of the anterior lobe, and lobule VIII. This unique topographic pattern of involvement and sparing of cerebral and cerebellar cortical areas matches the anatomical and functional connectivity specialization in the cerebrocerebellar circuit. This first demonstration of within-hemispheric specificity in the areas affected and spared by cerebrocerebellar diaschisis provides further confirmation in the human brain for topographic organization of connections between the cerebral hemispheres and the cerebellum.

Neuroimaging studies have demonstrated aberrant structure and function of the "cognitive-affective cerebellum" in major depressive disorder (MDD), although the specific role of the cerebello-cerebral circuitry in this population remains largely uninvestigated. The objective of this study was to delineate the role of cerebellar functional networks in depression. A total of 308 unmedicated participants completed resting-state functional magnetic resonance imaging scans, of which 247 (148 MDD; 99 healthy controls, HC) were suitable for this study. Seed-based resting-state functional connectivity (RsFc) analysis was performed using three cerebellar regions of interest (ROIs): ROI₁ corresponded to default mode network (DMN)/inattentive processing; ROI₂ corresponded to attentional networks, including frontoparietal, dorsal attention, and ventral attention; ROI₃ corresponded to motor processing. These ROIs were delineated based on prior functional gradient analyses of the cerebellum. A general linear model was used to perform within-group and between-group comparisons. In comparison to HC, participants with MDD displayed increased RsFc within the cerebello-cerebral DMN (ROI₁) and significantly elevated RsFc between the cerebellar ROI₁ and bilateral angular gyrus at a voxel threshold (p < 0.001, two-tailed) and at a cluster level (p < 0.05, FDR-corrected). Group differences were non-significant for ROI₂ and ROI₃. These results contribute to the development of a systems neuroscience approach to the diagnosis and treatment of MDD. Specifically, our findings confirm previously reported associations between MDD, DMN, and cerebellum, and highlight the promising role of these functional and anatomical locations for the development of novel imaging-based biomarkers and targets for neuromodulation therapies. ClinicalTrials.gov TRN: NCT01655706; Date of Registration: August 2nd, 2012.

Gradient-based analyses have contributed to the description of cerebellar functional neuroanatomy. More recently, functional gradients of the cerebellum have been used as a multi-purpose tool for neuroimaging research. Here, we provide an overview of the many practical applications of cerebellar functional gradient analyses. These practical applications include examination of intra-cerebellar and cerebellar-extracerebellar organization; transformation of functional gradients into parcellations with discrete borders; projection of functional gradients calculated within cerebellar structures to other extracerebellar structures; interpretation of cerebellar neuroimaging findings using qualitative and quantitative methods; detection of differences in patient populations; and other more complex practical applications of cerebellar gradient-based analyses. This review may serve as an introduction and catalog of options for neuroscientists who wish to design and analyze imaging studies using functional gradients of the cerebellum.

The interaction of the cerebellum with cerebral cortical dynamics is still poorly understood. In this paper, dynamical causal modeling is used to examine the interaction between cerebellum and cerebral cortex as indexed by MRI resting-state functional connectivity in three large-scale networks on healthy young adults (N = 200; Human Connectome Project dataset). These networks correspond roughly to default mode, task positive, and motor as determined by prior cerebellar functional gradient analyses. We find uniform interactions within all considered networks from cerebellum to cerebral cortex, providing support for the notion of a universal cerebellar transform. Our results provide a foundation for future analyses to quantify and further investigate whether this is a property that is unique to the interactions from cerebellum to cerebral cortex.

Our previous work using 3T functional Magnetic Resonance Imaging (fMRI) parcellated the human dentate nuclei (DN), the primary output of the cerebellum, to three distinct functional zones each contributing uniquely to default-mode, salience-motor, and visual brain networks. In this perspective piece, we highlight the possibility to target specific functional territories within the cerebellum using non-invasive brain stimulation, potentially leading to the refinement of cerebellar-based therapeutics for precision psychiatry. Significant knowledge gap exists in our functional understanding of cerebellar systems. Intervening early, gauging severity of illness, developing intervention strategies and assessing treatment response, are all dependent on our understanding of the cerebello-cerebral networks underlying the pathology of psychotic disorders. A promising yet under-examined avenue for biomarker discovery is disruptions in cerebellar output circuitry. This is primarily because most 3T MRI studies in the past had to exclude cerebellum from the field of view due to limitations in spatiotemporal resolutions. Using recent technological advances in 7T MRI (e.g., parallel transmit head coils) to identify functional territories of the DN, with a focus on dentato-cerebello-thalamo-cortical (CTC) circuitry can lead to better characterization of brain-behavioral correlations and assessments of co-morbidities. Such an improved mechanistic understanding of psychiatric illnesses can reveal aspects of CTC circuitry that can aid in neuroprognosis, identification of subtypes, and generate testable hypothesis for future studies.

High co-morbidity and substantial overlap across psychiatric disorders encourage a transition in psychiatry research from categorical to dimensional approaches that integrate neuroscience and psychopathology. Converging evidence suggests that the cerebellum is involved in a wide range of cognitive functions and mental disorders. An important question thus centers on the extent to which cerebellar function can be linked to transdiagnostic dimensions of psychopathology. To address this question, we used a multivariate data-driven statistical technique (partial least squares) to identify latent dimensions linking human cerebellar connectome as assessed by functional MRI to a large set of clinical, cognitive, and trait measures across 198 participants, including healthy controls (n = 92) as well as patients diagnosed with attention-deficit/hyperactivity disorder (n = 35), bipolar disorder (n = 36), and schizophrenia (n = 35). Macroscale spatial gradients of connectivity at voxel level were used to characterize cerebellar connectome properties, which provide a low-dimensional representation of cerebellar connectivity, i.e., a sensorimotor-supramodal hierarchical organization. This multivariate analysis revealed significant correlated patterns of cerebellar connectivity gradients and behavioral measures that could be represented into four latent dimensions: general psychopathology, impulsivity and mood, internalizing symptoms and executive dysfunction. Each dimension was associated with a unique spatial pattern of cerebellar connectivity gradients across all participants. Multiple control analyses and 10-fold cross-validation confirmed the robustness and generalizability of the yielded four dimensions. These findings highlight the relevance of cerebellar connectivity as a necessity for the study and classification of transdiagnostic dimensions of psychopathology and call on researcher to pay more attention to the role of cerebellum in the dimensions of psychopathology, not just within the cerebral cortex.

Mapping the structural and functional connectivity of the central nervous system has become a key area within neuroimaging research. While detailed network structures across the entire brain have been probed using animal models, non-invasive neuroimaging in humans has thus far been dominated by cortical investigations. Beyond the cortex, subcortical nuclei have traditionally been less accessible due to their smaller size and greater distance from radio frequency coils. However, major neuroimaging developments now provide improved signal and the resolution required to study these structures. Here, we present an overview of the connectivity between the amygdala, brainstem, cerebellum, spinal cord and the rest of the brain. While limitations to their imaging and analyses remain, we also provide some recommendations and considerations for mapping brain connectivity beyond the cortex.

OBJECTIVE:The cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions. We recently developed a new parcellation of the dentate nuclei (DN), the major output nuclei of the cerebellum, which optimally divides the structure into 3 functional territories that contribute uniquely to default-mode, motor-salience, and visual processing networks as indexed by resting-state functional connectivity (RsFc). Here we test for the first time whether RsFc differences in the DN, precede the onset of psychosis in individuals at risk of developing schizophrenia. METHODS:We used the magnetic resonance imaging (MRI) dataset from the Shanghai At Risk for Psychosis study that included subjects at high risk to develop schizophrenia (N = 144), with longitudinal follow-up to determine which subjects developed a psychotic episode within 1 year of their functional magnetic resonance imaging (fMRI) scan (converters N = 23). Analysis used the 3 functional parcels (default-mode, salience-motor, and visual territory) from the DN as seed regions of interest for whole-brain RsFc analysis. RESULTS:RsFc analysis revealed abnormalities at baseline in high-risk individuals who developed psychosis, compared to high-risk individuals who did not develop psychosis. The nature of the observed abnormalities was found to be anatomically specific such that abnormal RsFc was localized predominantly in cerebral cortical networks that matched the 3 functional territories of the DN that were evaluated. CONCLUSIONS:We show for the first time that abnormal RsFc of the DN may precede the onset of psychosis. This new evidence highlights the role of the cerebellum as a potential target for psychosis prediction and prevention.

Adolescents with anxiety disorders exhibit excessive emotional and somatic arousal. Neuroimaging studies have shown abnormal cerebral cortical activation and connectivity in this patient population. The specific role of cerebellar output circuitry, specifically the dentate nuclei (DN), in adolescent anxiety disorders remains largely unexplored. Resting-state functional connectivity analyses have parcellated the DN, the major output nuclei of the cerebellum, into three functional territories (FTs) that include default-mode, salience-motor, and visual networks. The objective of this study was to understand whether FTs of the DN are implicated in adolescent anxiety disorders. Forty-one adolescents (mean age 15.19 ± 0.82, 26 females) with one or more anxiety disorders and 55 age- and gender-matched healthy controls completed resting-state fMRI scans and a self-report survey on anxiety symptoms. Seed-to-voxel functional connectivity analyses were performed using the FTs from DN parcellation. Brain connectivity metrics were then correlated with State-Trait Anxiety Inventory (STAI) measures within each group. Adolescents with an anxiety disorder showed significant hyperconnectivity between salience-motor DN FT and cerebral cortical salience-motor regions compared to controls. Salience-motor FT connectivity with cerebral cortical sensorimotor regions was significantly correlated with STAI-trait scores in HC (R² = 0.41). Here, we report DN functional connectivity differences in adolescents diagnosed with anxiety, as well as in HC with variable degrees of anxiety traits. These observations highlight the relevance of DN as a potential clinical and sub-clinical marker of anxiety.

Negative symptoms in the motivational domain are strongly correlated with deficits in social and occupational functioning in schizophrenia. However, the neural substrates underlying these symptoms remain largely unknown. Twenty-eight adults with schizophrenia and twenty healthy volunteers underwent functional magnetic resonance while completing a lottery game designed to capture reward-related cognitive processes. Each trial demanded an initial investment of effort in form of key presses to increase the odds of winning. Brain activity in response to different reward cues (1 euro versus 1 cent) was compared between groups. Whereas controls invested more effort in improving their chances to win 1 euro compared to 1 cent in the lottery game, patients invested similarly high amounts of effort in both reward conditions. The neuroimaging analysis revealed lower neural activity in the bilateral caudate and cingulo-opercular circuits and decreased effective connectivity between reward-associated areas and neural nodes in the frontoparietal and salience network in response to high- versus low-reward conditions in schizophrenia patients compared to controls. Effective connectivity differences across conditions were associated with amotivation symptoms in patients. Overall, our data provide the evidence of alterations in neural activity in the caudate and cingulo-opercular "task maintenance" circuits and frontoparietal effective connectivity with reward-associated nodes as possible underlying mechanisms of reward value discrimination deficits affecting effort computation in schizophrenia.