Prefrontal cortex projections to the basilar pons in rhesus monkey: implications for the cerebellar contribution to higher function (2023)

Cited by (209)

  • The association of reproductive stage with lobular cerebellar network connectivity across female adulthood

    2022, Neurobiology of Aging

    Sex-specific differences in the aging cerebellum may be related to hormone changes with menopause. We evaluated the association between reproductive stage and lobular cerebellar network connectivity using data from the Cambridge Centre for Ageing and Neuroscience repository. We used raw structural and resting state neuroimaging data and information regarding age, sex, and menopause-related variables. Crus I and II and Lobules V and VI were our cerebellar seeds of interest. We characterized reproductive stage using the Stages of Reproductive Aging Workshop criteria. Results show that postmenopausal females have lower cerebello-striatal and cerebello-cortical connectivity, particularly in frontal regions, along with lower connectivity within the cerebellum, compared to reproductive females. Postmenopausal females also exhibit greater connectivity in some brain areas as well. Differences begin to emerge across transitional stages of menopause. Further, results reveal sex-specific differences in connectivity between female reproductive groups and age-matched male control groups. This suggests that menopause may be associated with cerebellar network connectivity in aging females, and sex differences in the aging brain may be related to this biological process.

  • Neuronal activation of cerebellum functional circuits in motor and non-motor functions in mice

    2021, Neuroscience Letters

    The cerebellum is involved in the control of balance, movement and the acquisition of motor skills. Scientific and technological advances have shown that the cerebellum also participates in non-motor functions, such as emotional control, memory and language. However, which cerebellar areas and functional circuits are predominantly activated in these different functions is not known. The current study analyzed the neuronal activation of cerebellar areas and other brain structures (e.g., hippocampus, amygdala, prelimbic cortex and infralimbic cortex) after exposure to rotarod and inhibitory avoidance behavioral models to establish possible neuronal circuits for motor and non-motor functions. Naïve male Swiss albino mice weighing 25 to 35g were used. The animals were subjected to three conditions for behavioral evaluation: inhibitory avoidance, which is a model used to infer emotional memory; rotarod, which assesses motor performance and motor learning; and housing box/control. The mice remained in their housing box in Condition 1. Mice in Condition 2 were exposed to the inhibitory avoidance box for 2days, and mice in Condition 3 were exposed to the rotarod for 3days. The animals were euthanized after the last exposure to the apparatus then perfused with paraformaldehyde. Brains were extracted and sectioned for immunofluorescence analysis of c-Fos protein in pre-established structures. Images of the brain structures were obtained, and neuronal activation was analyzed microscopically. One-way analysis of variance was used, followed by Tukey’s post-hoc test. There was no significant difference in c-Fos expression in lobe VI of the cerebellum between the different conditions. Differences in c-Fos expression were observed in the basolateral amygdala, infralimbic cortex and prelimbic cortex, which are relevant to emotional processes, after exposure to the evaluation apparatuses. Pearson’s r correlation coefficient test showed a positive correlation between the variables of structures related to emotional processes. We concluded that there was no significant difference in c-Fos expression in lobe VI of the cerebellum after exposure of the animals to the evaluation apparatus. However, there was a difference in c-Fos expression in other brain structures related to emotional processes after exposure of animals to the apparatus.

  • White matter integrity and functional connectivity in adolescents with a parental history of substance use disorder

    2021, Neuroimage: Reports

    A family history (FH+) of substance use disorder (SUD) increases an adolescent's risk for substance use initiation and progression. Greater impulsivity and reward seeking behavior is known to be associated with such risk. At the neurological level, dysfunction of cortico-striatal and cortico-limbic pathways have been proposed as contributors to the increased SUD risk in adolescents with FH+. In addition, disadvantaged environments have been associated with atypical brain connectivity and higher SUD risk. However, it remains unclear if this increased risk is manifested in structural and functional brain abnormalities prior to regular drug use. To examine this, we employed complementary imaging of structural and functional connectivity of 60 FH+ and 55 FH- minority adolescents, all from families with low socio-economic status. We acquired diffusion tensor-imaging (DTI) and resting state fMRI data across the whole brain. Structural connectivity was examined by measuring fractional anisotropy (FA) using DTI, to indicate integrity of the white matter tracts. Functional connectivity within and between resting state networks was assessed by the correlation of blood-oxygen-level-dependent (BOLD) signal between intra and inter-network nodes. Psychological measures of impulsivity and reward seeking were also obtained with standardized measures, the BIS-11 and the BIS/BAS, and their association with FA and functional connectivity was evaluated. We found no differences in white matter integrity between the groups. Compared to FH-, FH+adolescents showed significantly greater functional connectivity between posterior regions of the Default Mode Network (DMN) and the Fronto-Parietal Network (FPN). While psychological measures of reward seeking behavior did not differ between the FH+ and FH- groups, impulsivity, assessed by the BIS-11, was significantly higher for FH+. However, we did not find significant differences between the FH+ and FH- groups when comparing associations of BIS-11 scores and white matter integrity or functional connectivity measures. The stronger inter-network functional connectivity between the DMN and FPN in FH+adolescents suggests that transmitted risk for SUD may be related to large-scale brain dynamics. The lack of structural differences support the importance of early prevention efforts for FH+adolescents, before initiation of drug use, allowing for healthy brain development.

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  • Resistance, vulnerability and resilience: A review of the cognitive cerebellum in aging and neurodegenerative diseases

    2020, Neurobiology of Learning and Memory

    Citation Excerpt :

    Cerebellar circuits in the default mode network show reduced activity in AD, and cerebellar circuits in the salience network show reduced activity in frontotemporal dementia (Guo et al., 2016). Several observations at the circuit level support the idea that the cerebellum acts in this fashion in cognition, as cerebrocerebellar connections appear to be organized into long-range loops (Kelly & Strick, 2003; Middleton & Strick, 2001; Schmahmann & Pandya, 1989, 1991, 1992, 1993, 1995; Watson, Becker, Apps, & Jones, 2014; Watson, Jones, & Apps, 2009). The cerebellar nuclei have analogous subdivisions, and both cerebellar cortex and nuclei receive inputs from distinct cerebrocerebellar pathways (Cicirata et al., 2005).

    In the context of neurodegeneration and aging, the cerebellum is an enigma. Genetic markers of cellular aging in cerebellum accumulate more slowly than in the rest of the brain, and it generates unknown factors that may slow or even reverse neurodegenerative pathology in animal models of Alzheimer’s Disease (AD). Cerebellum shows increased activity in early AD and Parkinson’s disease (PD), suggesting a compensatory function that may mitigate early symptoms of neurodegenerative pathophysiology. Perhaps most notably, different parts of the brain accumulate neuropathological markers of AD in a recognized progression and generally, cerebellum is the last brain region to do so. Taken together, these data suggest that cerebellum may be resistant to certain neurodegenerative mechanisms.

    On the other hand, in some contexts of accelerated neurodegeneration, such as that seen in chronic traumatic encephalopathy (CTE) following repeated traumatic brain injury (TBI), the cerebellum appears to be one of the most susceptible brain regions to injury and one of the first to exhibit signs of pathology. Cerebellar pathology in neurodegenerative disorders is strongly associated with cognitive dysfunction. In neurodegenerative or neurological disorders associated with cerebellar pathology, such as spinocerebellar ataxia, cerebellar cortical atrophy, and essential tremor, rates of cognitive dysfunction, dementia and neuropsychiatric symptoms increase. When the cerebellum shows AD pathology, such as in familial AD, it is associated with earlier onset and greater severity of disease. These data suggest that when neurodegenerative processes are active in the cerebellum, it may contribute to pathological behavioral outcomes.

    The cerebellum is well known for comparing internal representations of information with observed outcomes and providing real-time feedback to cortical regions, a critical function that is disturbed in neuropsychiatric disorders such as intellectual disability, schizophrenia, dementia, and autism, and required for cognitive domains such as working memory. While cerebellum has reciprocal connections with non-motor brain regions and likely plays a role in complex, goal-directed behaviors, it has proven difficult to establish what it does mechanistically to modulate these behaviors. Due to this lack of understanding, it’s not surprising to see the cerebellum reflexively dismissed or even ignored in basic and translational neuropsychiatric literature.

    The overarching goals of this review are to answer the following questions from primary literature: When the cerebellum is affected by pathology, is it associated with decreased cognitive function? When it is intact, does it play a compensatory or protective role in maintaining cognitive function? Are there theoretical frameworks for understanding the role of cerebellum in cognition, and perhaps, illnesses characterized by cognitive dysfunction? Understanding the role of the cognitive cerebellum in neurodegenerative diseases has the potential to offer insight into origins of cognitive deficits in other neuropsychiatric disorders, which are often underappreciated, poorly understood, and not often treated.

  • Cerebellar contribution to vocal emotion decoding: Insights from stroke and neuroimaging

    2019, Neuropsychologia

    While the role of the cerebellum in emotion recognition has been explored with facial expressions, its involvement in the auditory modality (i.e., emotional prosody) remains to be demonstrated. The present study investigated the recognition of emotional prosody in 15 patients with chronic cerebellar ischaemic stroke and 15 matched healthy controls, using a validated task, as well as clinical, motor, neuropsychological, and psychiatric assessments. We explored the cerebellar lesion-behaviour relationship using voxel-based lesion-symptom mapping. Results showed a significant difference between the stroke and healthy control groups, with patients giving erroneous ratings on the Surprise scale when they listened to fearful stimuli. Moreover, voxel-based lesion-symptom mapping revealed that these emotional misattributions correlated with lesions in right Lobules VIIb, VIIIa,b and IX. Interestingly, the posterior cerebellum has previously been found to be involved in affective processing, and Lobule VIIb in rhythm discrimination. These results point to the cerebellum’s functional involvement in vocal emotion decoding.

    (Video) Josef Rauschecker
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    There is now considerable evidence that white matter abnormalities play a role in the neurobiology of autism. Little research has been directed, however, at understanding (a) typical white matter development in autism and how this relates to neurocognitive impairments observed in the disorder. In this study we used probabilistic tractography to identify the cingulum bundle in 21 adolescents and young adults with Autism Spectrum Disorder (ASD), and 21 age- and sex-matched healthy volunteers. We investigated group differences in the relationships between age and fractional anisotropy, a putative measure of white matter integrity, within the cingulum bundle. Moreover, in a preliminary investigation, we examined the relationship between cingulum fractional anisotropy and executive functioning using the Behavior Rating Inventory of Executive Function (BRIEF). The ASD participants demonstrated significantly lower fractional anisotropy within the cingulum bundle compared to the typically developing volunteers. There was a significant group-by-age interaction such that the ASD group did not show the typical age-associated increases in fractional anisotropy observed among healthy individuals. Moreover, lower fractional anisotropy within the cingulum bundle was associated with worse BRIEF behavioral regulation index scores in the ASD group. The current findings implicate a dysregulation in cingulum bundle white matter development occurring in late adolescence and early adulthood in ASD, and suggest that greater disturbances in this trajectory are associated with executive dysfunction in ASD.

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    Cerebellar vermis contributes to the extinction of conditioned fear

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    The cerebellum is known to contribute to the acquisition and retention of conditioned motor and emotional responses. Eyeblink conditioning and fear conditioning have been studied in greatest detail. Whereas a considerable number of studies have shown that the cerebellum is also involved in extinction of conditioned eyeblink responses, the likely contribution of the cerebellum to extinction of conditioned fear responses has largely been ignored. In the present study, we analyzed functional brain imaging data (fMRI) of previous work investigating extinction of conditioned fear in 32 young and healthy men, in which event-related fMRI analysis did not include the cerebellum. This dataset was analyzed using a spatial normalization method optimized for the cerebellum. During fear acquisition, an unpleasant electric shock (unconditioned stimulus; US) was paired with one of two pictures of geometrical figures (conditioned stimulus; CS+), while the other picture (CS−) was never paired with the US. During extinction, CS+ and CS− were presented without the US. During the acquisition phase, the fMRI signal related to the CS+ was significantly higher in hemispheric lobule VI in early compared to late acquisition (p<.05, permutation corrected). During the extinction phase, the fMRI signal related to the contrast CS+>CS− was significantly higher within the anterior vermis in early compared to late extinction (p<.05, permutation corrected). The present data show that the cerebellum is not only associated with the acquisition but also with the extinction of conditioned fear.

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    Modeling healthy male white matter and myelin development: 3 through 60months of age

    NeuroImage, Volume 84, 2014, pp. 742-752

    An emerging hypothesis in developmental and behavioral disorders is that they arise from disorganized brain messaging or reduced connectivity. Given the importance of myelin to efficient brain communication, characterization of myelin development in infancy and childhood may provide salient information related to early connectivity deficits. In this work, we investigate regional and whole brain growth trajectories of the myelin water fraction, a quantitative magnetic resonance imaging measure sensitive and specific to myelin content, in data acquired from 122 healthy male children from 3 to 60months of age. We examine common growth functions to find the most representative model of myelin maturation and subsequently use the best of these models to develop a continuous population-averaged, four-dimensional model of normative myelination. Through comparisons with an independent sample of 63 male children across the same age span, we show that the developed model is representative of this population. This work contributes to understanding the trajectory of myelination in healthy infants and toddlers, furthering our knowledge of early brain development, and provides a model that may be useful for identifying developmental abnormalities.

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    Cerebellar lesions disrupt spatial and temporal visual attention

    Cortex, Volume 139, 2021, pp. 27-42

    The current study represents the first comprehensive examination of spatial, temporal and sustained attention following cerebellar damage. Results indicated that, compared to controls, cerebellar damage resulted in a larger cueing effect at the longest SOA – possibly reflecting a slowed the onset of inhibition of return (IOR) during a reflexive covert attention task, and reduced the ability to detect successive targets during an attentional blink task. However, there was little evidence to support the notion that cerebellar damage disrupted voluntary covert attention or the sustained attention to response task (SART). Lesion overlay data and supplementary voxel-based lesion symptom mapping (VLSM) analyses indicated that impaired performance on the reflexive covert attention and attentional blink tasks were related to damage to Crus II of the left posterior cerebellum. In addition, subsequent analyses indicated our results are not due to either general motor impairments or to damage to the deep cerebellar nuclei. Collectively these data demonstrate, for the first time, that the same cerebellar regions may be involved in both spatial and temporal visual attention.

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    Diffusion MRI of white matter microstructure development in childhood and adolescence: Methods, challenges and progress

    Developmental Cognitive Neuroscience, Volume 33, 2018, pp. 161-175

    Diffusion magnetic resonance imaging (dMRI) continues to grow in popularity as a useful neuroimaging method to study brain development, and longitudinal studies that track the same individuals over time are emerging. Over the last decade, seminal work using dMRI has provided new insights into the development of brain white matter (WM) microstructure, connections and networks throughout childhood and adolescence. This review provides an introduction to dMRI, both diffusion tensor imaging (DTI) and other dMRI models, as well as common acquisition and analysis approaches. We highlight the difficulties associated with ascribing these imaging measurements and their changes over time to specific underlying cellular and molecular events. We also discuss selected methodological challenges that are of particular relevance for studies of development, including critical choices related to image acquisition, image analysis, quality control assessment, and the within-subject and longitudinal reliability of dMRI measurements. Next, we review the exciting progress in the characterization and understanding of brain development that has resulted from dMRI studies in childhood and adolescence, including brief overviews and discussions of studies focusing on sex and individual differences. Finally, we outline future directions that will be beneficial to the field.

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    Topography of the cerebellum in relation to social brain regions and emotions

    Handbook of Clinical Neurology, Volume 154, 2018, pp. 71-84

    In the last few decades, an increasing number of studies have focused on better characterizing the cerebellar functions beyond motor control, including emotional and social domains. Anatomic and functional evidence strongly contributes to delineating the cerebellar functional subdivisions and their integration with cerebral functional networks strictly related to emotional regulation and social functioning, thus suggesting a model of cerebellar organization that resembles that of the cerebral cortex. Overcoming the traditional segregation of cerebrocerebellar networks in sensorimotor/cognitive functional modules, during emotional/social processes, the cerebellar activity reflects a domain-specific mentalizing functionality that is strongly connected with corresponding mentalizing networks in the cerebrum. Additionally, the cerebrocerebellar organization has been shown to have a specific functional and maturational trajectory that is only in part dependent on a structural maturational process and that is protracted from an early stage of life through adolescence and adulthood, when the mature control networks involve both segregation and integration of the brain regions that comprise them. Altogether, these findings underscore the importance of regional functional differences within the cerebellum in relation to emotional and social processing and raise questions about the clinical implication of cerebellar injury on emotional/social behaviors, both in the developing and the adult brain.

Copyright © 1995 Published by Elsevier Ireland Ltd.

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