Cerebellar functions from a translational perspective: from neuronal to neurocognitive dysfunctions

This PhD project aimed to investigate cerebellar contribution to cognition from a translational perspective by integrating neuropsychological assessment and neuroimaging, incorporating neurocognitive and motor tests with 7T Magnetic resonance imaging (MRI). The results are clinically significant as they identify nonverbal cognitive deficits that often may go unnoticed in clinical practice, particularly visuospatial and visuoperceptual deficits associated with cerebellar dysfunction.Firstly, the focus was placed on adult patients with neuropsychiatric disorders, including Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD), given reported cerebellar morphological differences. Neurocognitive and motor functions were investigated across all relevant clinical subgroups, considering DSM-5 disorder severity. Sensorimotor functions dependent on cerebellar processing, as well as visuospatial perception and abilities, were assessed. Neuropsychiatric clinical subgroups performed significantly worse than controls, with notable associations between these functions. These results reveal deficits even in patients with mild disorder severity, supporting a link between these disorders and cerebellar dysfunction. Objective assessments of these functions could also enhance the accuracy and effectiveness of clinical evaluations. Subsequently, the same neurocognitive functions were examined in neurological diseases, including Spinocerebellar Ataxias (SCA) and other neurological conditions with marked cerebellar atrophy. Ataxia severity was moderately to strongly associated with impairments in sensorimotor functions, visuoconstructive abilities, and visuospatial perception, indicating deficits in both motor and higher cognitive processes. While cerebellar pathology is likely the main contributor, the potential influence of non-cerebellar factors cannot be excluded.Lastly, from a translational perspective, 7T MRI was used to examine the relationship between neurocognition and cerebellar cortical thickness, linking structural changes to functional and cognitive outcomes. Patients with Spinocerebellar Ataxia type 34 (SCA 34) show cerebellar degeneration with cognitive, motor, and socio-affective impairments consistent with Cerebellar Cognitive Affective Syndrome. Atrophy of the vermis, multiple lobules, and cerebellar peduncles highlights the cerebellum’s key role in cognition, advancing our understanding of its contribution to neurocognitive and psychiatric symptoms in genetic ataxias.