Fetal cerebellar development: 3D morphometric analysis of fetal postmortem MRI among Chinese fetuses.

The development of the cerebellum starts from early gestational period and extends postnatal. Because of its protracted development, the cerebellum is susceptible to developmental anomalies such as Dandy-Walker malformations, Blakes pouch cysts and vermin hypoplasia. Measurements of fetal cerebellar parameters of a normal growing fetus in each week of gestation is important for setting up morphometric standards and hence used as clinical reference data. Any deviation from the normal cerebellar parameters alerts the clinicians for the possibility of presence of cerebellar malformations. Study objective: The objective of this study was to assess the fetal cerebellar growth by quantifying the following parameters; fetal cerebellar volume, anterior-posterior diameter and superior-inferior diameter. Methods: We used 3T and 7T MRI to scan the postmortem fetal brains at different stages of development and subsequently analyze the images using ITK-SNAP software. Results: The mean superior-inferior cerebellar diameter was found to be 19.12+2. 70mm.The linear(y=bo+b1t) model was the best fit (r2=0.996, F=32022.961) to describe the relationship between the gestational age and the superior-inferior diameter(y=5.89+0.49t). There was significant correlation between the superior-inferior cerebellar diameter and the gestation age, Pearson correlation coefficient of 0.999, r=0.001. The median cerebellar volume was 8607.7mm, the mean rank high among males(78.12) as compared to female(68.25). There was no statistically significant difference of the cerebellar volume between males and females (u=2193.5,p=0.16). The quadratic(y=bo+b1t+b2t2) model was the best fit regression equation (r2=0.994,F=10791.157) describing the relationship between the cerebellar volume and the gestational age. The median anterior-posterior diameter was 12.45 mm. There was significant correlation between anterior-posterior diameter and the gestational age with Spearmans rho of (0.997, p=0.01). The linear model was the best fit the best fit model (y=bo+b1t) describing the relationship between anterior-posterior diameter and the gestational age(y=3.31+0.5t) r2=0.998, F=70646.838. Conclusion: Significant correlation between the superior-inferior cerebellar diameters, the anterior-posterior cerebellar diameter and the gestational age was found. These two linear parameters follow the first-degree polynomial in relation to the gestational age. The cerebellar volume follows the second-degree polynomial as it increases with the gestational age and correlate significantly with the gestational age. This study has provided new insight to the development of the cerebellum, and setup a benchmark data of which the deviation from it will alert the clinicians for the possibility of presence of cerebellar malformations. Key words: Cerebellar Development, Cranial Magnetic Resonance imaging, Cerebellar Malformations

Cerebral Abnormalities in Spina Bifida: A Neuropathological Study

Introduction Spina bifida (SB) is the most common neural tube defect in humans. Here, we analyzed systematically the neuropathological findings of the brain in SB cases. Methods 79 cases with SB aperta (SBA) and 6 cases with SB occulta (SBO) autopsied at the Charité Neuropathology from 1974 to 2000 were re-evaluated retrospectively. For this, case files and spinal cord as well as brain sections were studied. Results While no brain malformations were detected in SBO cases, 95% of SBA cases had brain malformations. Main brain anomalies identified were hydrocephalus (71%), Chiari II malformation (36%), heterotopia (34%), other cerebellar anomalies (36%), gyrification defects (33%), and ependymal denudation (29%). Hydrocephalus was observed as early as gestational week 17 and was highly associated to Chiari II and ependymal denudation. In 55% SBA was accompanied by further anomalies not primarily affecting the CNS. Conclusion We confirm using neuropathologic methods brain malformations in most SBA but none in SBO cases. In addition to our previous radiologic study, we now demonstrate the high prevalence of cerebellar malformations and cerebral heterotopias in SBA. The early detection of hydrocephalus and Chiari II malformation in fetuses raises the question whether these arise parallel rather than in strict temporal sequence.

Altered cerebellar response to somatosensory stimuli in the Cntnap2 mouse model of autism

Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied cerebellar integration of sensory information in a mouse model of autism, knockout for the Cntnap2 gene. Cntnap2 is widely expressed in Purkinje cells and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in this mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region upon electrical stimulation of the whisker pad in alert mice and found striking differences between WT and Cntnap2 KO mice. In addition, single-cell recordings identified alterations in both sensory-evoked and spontaneous firing patterns of Purkinje cells. These alterations were accompanied by altered intrinsic properties and morphological features of these neurons. Together, these results indicate that the Cntnap2 mouse model could provide novel insight into the pathophysiological mechanisms of ASD core sensory deficits.

Virtual Reality Social Prediction Improvement and Rehabilitation Intensive Training (VR-SPIRIT) for paediatric patients with congenital cerebellar diseases: study protocol of a randomized controlled trial.

Background: Patients with cerebellar malformations exhibit not only movement problems, but also important deficits in social cognition. Thus, rehabilitation approaches should not only involve the recovery of motor function but also of higher-order abilities, such as processing of social stimuli. In keeping with the general role of the cerebellum in anticipating and predicting events, we used a VR-based rehabilitation system to implement a social cognition intensive training specifically tailored to improve predictive abilities in social scenarios (VR-Spirit).Methods: The study is an interventional randomized controlled trial that aims to recruit 42 children, adolescents and young adults with congenital cerebellar malformations, randomly allocated to the experimental or active control group. The experimental group is administered the VR-Spirit, requiring the participants to compete with different avatars in the reaching of recreational equipment and implicitly prompting them to form expectations about their playing preference. The active control group participates to a VR-training with standard games currently adopted for motor rehabilitation. Both trainings are composed by 8 45-minute sessions and are administered in the GRAIL VR-Lab (Motekforce Link, NL), an integrated platform that allows patients to move in natural and attractive VR environments. An evaluation session in VR with the same paradigm used in the VR-Spirit but implemented in a different scenario is administered at the beginning (T0) of the two trainings (T1) and at the end (T2). Moreover, a battery of neurocognitive tests spanning different domains are administered to all participants at T0, T2 and in a follow-up session after two months from the end of the two trainings (T3).Discussion: This study offers a novel approach for rehabilitation based on specific neural mechanisms of the cerebellum. We aim to investigate the feasibility and efficacy of a new intensive social cognition training in a sample of Italian patients aged 7-25 years with congenital cerebellar malformations. We expect that VR-Spirit could enhance social prediction ability and indirectly improve cognitive performance in diverse domains. Moreover, through the comparison with a VR-active control training we aim to verify the specificity of VR-Spirit in improving social perception skills.Trial registration: ISRCTN, ISRCTN 22332873. Retrospectively registered on 12 March 2018. http://www.isrctn.com/ISRCTN22332873Keywords: Virtual reality; Social cognition training; Cerebellum; Paediatric patients; Rehabilitation; Grail.

Virtual Reality Social Prediction Improvement and Rehabilitation Intensive Training (VR-SPIRIT) for paediatric patients with congenital cerebellar diseases: study protocol of a randomized controlled trial.

Background: Patients with cerebellar malformations exhibit not only movement problems, but also important deficits in social cognition. Thus, rehabilitation approaches should not only involve the recovery of motor function but also of higher-order abilities, such as processing of social stimuli. In keeping with the general role of the cerebellum in anticipating and predicting events, we used a VR-based rehabilitation system to implement a social cognition intensive training specifically tailored to improve predictive abilities in social scenarios (VR-Spirit). Methods: The study is an interventional randomized controlled trial that aims to recruit 42 children, adolescents and young adults with congenital cerebellar malformations, randomly allocated to the experimental or active control group. The experimental group is administered the VR-Spirit, requiring the participants to compete with different avatars in the reaching of recreational equipment and implicitly prompting them to form expectations about their playing preference. The active control group participates to a VR-training with standard games currently adopted for motor rehabilitation. Both trainings are composed by 8 45-minute sessions and are administered in the GRAIL VR-Lab (Motekforce Link, NL), an integrated platform that allows patients to move in natural and attractive VR environments. An evaluation session in VR with the same paradigm used in the VR-Spirit but implemented in a different scenario is administered at the beginning (T0) and at the end (T1) of the two trainings. Moreover, a battery of neurocognitive tests spanning different domains are administered to all participants at T0, T1 and in a follow-up session after two months from the end of the two trainings (T2). Discussion: This study offers a novel approach for rehabilitation based on specific neural mechanisms of the cerebellum. We aim to investigate the feasibility and efficacy of a new intensive social cognition training in a sample of Italian patients aged 7-25 years with congenital cerebellar malformations. We expect that VR-Spirit could enhance social prediction ability and indirectly improve cognitive performance in diverse domains. Moreover, through the comparison with a VR-active control training we aim to verify the specificity of VR-Spirit in improving social perception skills.