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Background: Schizophrenia (SZ) is characterized by disconnected cerebral networks. Recent studies have shown that functional connectivity between the cerebellar dorsal dentate nucleus (dDN) and cerebrum is correlated with psychotic symptoms, and processing speed in SZ patients. Dynamic effective connectivity (dEC) is a reliable indicator of brain functional status. However, the dEC between the dDN and cerebrum in patients with SZ remains largely unknown., Methods: Resting-state functional MRI data, symptom severity, and cognitive performance were collected from 74 SZ patients and 53 healthy controls (HC). Granger causality analysis and sliding time window methods were used to calculate dDN-based dEC maps for all subjects, and k-means clustering was performed to obtain several dEC states. Finally, between-group differences in dynamic effective connectivity variability (dECV) and clinical correlations were obtained using two-sample t-tests and correlation analysis., Results: We detected four dEC states from the cerebrum to the right dDN (IN states) and three dEC states from the right dDN to the cerebrum (OUT states), with SZ group having fewer transitions in the OUT states. SZ group had increased dECV from the right dDN to the right middle frontal gyrus (MFG) and left lingual gyrus (LG). Correlations were found between the dECV from the right dDN to the right MFG and symptom severity and between the dECV from the right dDN to the left LG and working memory performance., Conclusions: This study reveals a dynamic causal relationship between cerebellar dDN and the cerebrum in SZ and provides new evidence for the involvement of cerebellar neural circuits in neurocognitive functions in SZ., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in conducting this study or preparing the manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Magnetic resonance spectroscopy (MRS) studies have indicated that the imbalance between gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels was the potential cause of migraine development. However, the changes in the GABA and Glx levels in patients with New daily persistent headache (NDPH) remain unclear. This study aimed to investigate the changes in GABA and Glx levels in the periaqueductal gray (PAG) and dentate nucleus (DN) in patients with NDPH using the MEGA-PRESS sequence., Methods: Twenty-one NDPH patients and 22 age- and sex-matched healthy controls (HCs) were included and underwent a 3.0T MRI examination, using the MEGA-PRESS sequence to analyze GABA and Glx levels of PAG and DN. The correlations between these neurotransmitter levels and clinical characteristics were also analyzed., Results: There were no significant differences in the GABA+/Water, GABA+/Cr, Glx/Water, and Glx/Cr levels in both PAG and DN between the two groups (all p > 0.05). Moderate-severe NDPH patients had lower levels of Glx/Water (p = 0.034) and Glx/Cr (p = 0.012) in DN than minimal-mild NDPH patients. In patients with NDPH, higher Glx/Water levels in the PAG (r=-0.471, p = 0.031, n = 21) and DN (r=-0.501, p = 0.021, n = 21) and higher Glx/Cr levels in DN (r=-0.483, p = 0.026, n = 21) were found to be correlated with lower Visual Analogue Scale scores. Additionally, a positive correlation was observed between the GABA+/Cr levels in the DN and the Generalized Anxiety Disorder-7 scores (r = 0.519, p = 0.039, n = 16)., Conclusions: The results of this study indicated that the GABA and Glx levels in the PAG and DN may not be the primary contributor to the development of NDPH. The correlations between certain clinical scales and the neurotransmitter levels may be derived from the NDPH related symptoms., (© 2024. The Author(s).)

Background: The dentate nuclei of the cerebellum are key sites of neuropathology in Friedreich ataxia (FRDA). Reduced dentate nucleus volume and increased mean magnetic susceptibility, a proxy of iron concentration, have been reported by magnetic resonance imaging studies in people with FRDA. Here, we investigate whether these changes are regionally heterogeneous., Methods: Quantitative susceptibility mapping data were acquired from 49 people with FRDA and 46 healthy controls. The dentate nuclei were manually segmented and analyzed using three dimensional vertex-based shape modeling and voxel-based assessments to identify regional changes in morphometry and susceptibility, respectively., Results: Individuals with FRDA, relative to healthy controls, showed significant bilateral surface contraction most strongly at the rostral and caudal boundaries of the dentate nuclei. The magnitude of this surface contraction correlated with disease duration, and to a lesser extent, ataxia severity. Significantly greater susceptibility was also evident in the FRDA cohort relative to controls, but was instead localized to bilateral dorsomedial areas, and also correlated with disease duration and ataxia severity., Conclusions: Changes in the structure of the dentate nuclei in FRDA are not spatially uniform. Atrophy is greatest in areas with high gray matter density, whereas increases in susceptibility-reflecting iron concentration, demyelination, and/or gliosis-predominate in the medial white matter. These findings converge with established histological reports and indicate that regional measures of dentate nucleus substructure are more sensitive measures of disease expression than full-structure averages. Biomarker development and therapeutic strategies that directly target the dentate nuclei, such as gene therapies, may be optimized by targeting these areas of maximal pathology. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: The dentato-thalamo-cortical tract (DTT) is the main cerebellar efferent pathway. Degeneration of the DTT is a core feature of Friedreich ataxia (FRDA). However, it remains unclear whether DTT disruption is spatially specific, with some segments being more impacted than others. This study aimed to investigate microstructural integrity along the DTT in FRDA using a profilometry diffusion MRI (dMRI) approach., Methods: MRI data from 45 individuals with FRDA (mean age: 33.2 ± 13.2, Male/Female: 26/19) and 37 healthy controls (mean age: 36.5 ± 12.7, Male/Female:18/19) were included in this cross-sectional multicenter study. A profilometry analysis was performed on dMRI data by first using tractography to define the DTT as the white matter pathway connecting the dentate nucleus to the contralateral motor cortex. The tract was then divided into 100 segments, and dMRI metrics of microstructural integrity (fractional anisotropy, mean diffusivity and radial diffusivity) at each segment were compared between groups. The process was replicated on the arcuate fasciculus for comparison., Results: Across all diffusion metrics, the region of the DTT connecting the dentate nucleus and thalamus was more impacted in FRDA than downstream cerebral sections from the thalamus to the cortex. The arcuate fasciculus was minimally impacted., Interpretation: Our study further expands the current knowledge about brain involvement in FRDA, showing that microstructural abnormalities within the DTT are weighted to early segments of the tract (i.e., the superior cerebellar peduncle). These findings are consistent with the hypothesis of DTT undergoing anterograde degeneration arising from the dentate nuclei and progressing to the primary motor cortex., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: Gadolinium deposition has been reported in several normal anatomical structures in the brain after repeated administration of intravenous gadolinium-based contrast agents (GBCAs) used in magnetic resonance imaging (MRI). This study presents preliminary results to see if there is any gadolinium deposition in the dentate nucleus and globus pallidus after using intrathecal GBCAs., Methods: Between November 2018 and November 2020, 29 patients who underwent intrathecal contrast-enhanced MR cisternography with the suspicion of rhinorrhea were included in this prospective study. In contrast-enhanced MR cisternography, gadoterate meglumine was administered by intrathecal injection at a dose of 1 ml. One month later, patients had a control MRI with 3D T1 SPACE fat-saturated (FS) and susceptibility weighted images (SWI) sequences. The ratio of dentate nucleus signal intensity to middle cerebellar peduncle signal intensity (DN/MCP ratio) and the ratio of globus pallidus signal intensity to thalamus signal intensity (GP/T ratio) were calculated using region of interest (ROI) on pre-contrast and control MRI sequences., Results: There was no significant difference for DN/MCP ratio and GP/T ratio on 3D T1 SPACE FS and SWI sequences after intrathecal GBCAs administration compared to baseline MRI., Conclusion: Administration of intrathecal GBCAs did not cause a measurable change in the signal intensity of the dentate nucleus and globus pallidus after a single injection., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The cerebellum is a key player in many brain functions and a major topic of neuroscience research. However, the cerebellar nuclei (CN), the main output structures of the cerebellum, are often overlooked. This neglect is because research on the cerebellum typically focuses on the cortex and tends to treat the CN as relatively simple output nuclei conveying an inverted signal from the cerebellar cortex to the rest of the brain. In this review, by adopting a nucleocentric perspective we aim to rectify this impression. First, we describe CN anatomy and modularity and comprehensively integrate CN architecture with its highly organized but complex afferent and efferent connectivity. This is followed by a novel classification of the specific neuronal classes the CN comprise and speculate on the implications of CN structure and physiology for our understanding of adult cerebellar function. Based on this thorough review of the adult literature we provide a comprehensive overview of CN embryonic development and, by comparing cerebellar structures in various chordate clades, propose an interpretation of CN evolution. Despite their critical importance in cerebellar function, from a clinical perspective intriguingly few, if any, neurological disorders appear to primarily affect the CN. To highlight this curious anomaly, and encourage future nucleocentric interpretations, we build on our review to provide a brief overview of the various syndromes in which the CN are currently implicated. Finally, we summarize the specific perspectives that a nucleocentric view of the cerebellum brings, move major outstanding issues in CN biology to the limelight, and provide a roadmap to the key questions that need to be answered in order to create a comprehensive integrated model of CN structure, function, development, and evolution., (© 2023. The Author(s).)

For years, the cerebellum was left out of functional magnetic resonance imaging (fMRI) studies due to technological limitations. The advent of novel data acquisition and reconstruction strategies (e.g., whole-brain simultaneous multi-slice imaging) employing multi-channel array coils has overcome such limitations, ushering unprecedented improvements in temporal signal-to-noise ratio and spatiotemporal resolution. Here, we aim to provide a brief report on the deep cerebellar nuclei, specifically focusing on the dentate nuclei, the primary output nuclei, situated within both cognitive and motor cerebello-cerebral circuits. We highlight the importance of functional parcellation in refining our understanding of broad resting-state functional connectivity (RSFC) in both health and disease. First, we review work relevant to the functional topography of the dentate nuclei, including recent advances in functional parcellation. Next, we review RSFC studies using the dentate nuclei as seed regions of interest in neurological and psychiatric populations and discuss the potential benefits of applying functionally defined subdivisions. Finally, we discuss recent technological advances and underscore ultrahigh-field neuroimaging as a tool to potentiate functionally parcellated RSFC analyses in clinical populations., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: As previous studies reported, gadolinium deposits in globus pallidus (GP) and dentate nucleus (DN) after repeated administrations of gadolinium-based contrast agents (GBCAs) and a signal intensity (SI) increase on T1-weighted images were related to linear GBCAs, not macrocyclic GBCAs., Purpose: To identify whether quantitative susceptibility mapping (QSM) could measure a subtle increase in magnetic susceptibility in DN and GP in patients after repeated administrations of gadoteric acid meglumine (Gd-DOTA)., Material and Methods: In this study, 50 patients with cerebral tumors who had received at least three injections of Gd-DOTA (GBCA group) and 50 individuals without a history of GBCA injections (non-GBCA group) were included. The image data for QSM and T1-weighted images were reviewed. Spearman rank correlation was used to estimate the associations between the values (magnetic susceptibility of QSM and SI ratios of T1-weighted images) and the number of Gd-DOTA injections., Results: The mean magnetic susceptibility of GP in GBCA group was 0.136 ±   0.031 ppm, which was significantly higher than that in control group (0.114 ±   0.030 ppm) ( P  = 0.001). In the GBCA group (n = 50), we found a substantial positive correlation between magnetic susceptibility of GP and the number of Gd-DOTA injections according to Spearman rank correlation coefficient (ρ = 0.673, P  = 0.0001). There was a modest but significant correlation between magnetic susceptibility of DN and the number of Gd-DOTA injections (ρ = 0.311, P  = 0.028)., Conclusion: In comparison to the control group, the magnetic susceptibility of GP in the GBCA group was significantly higher and had a substantial positive association with the number of Gd-DOTA injections.

Understanding cerebellar alterations due to healthy aging provides a reference point against which pathological findings in late-onset disease, for example spinocerebellar ataxia type 6 (SCA6), can be contrasted. In the present study, we investigated the impact of aging on the cerebellar nuclei and cerebellar cortex in 109 healthy controls (age range: 16 - 78 years) using 3 Tesla magnetic resonance imaging (MRI). Findings were compared with 25 SCA6 patients (age range: 38 - 78 years). A subset of 16 SCA6 (included: 14) patients and 50 controls (included: 45) received an additional MRI scan at 7 Tesla and were re-scanned after one year. MRI included T1-weighted, T2-weighted FLAIR, and multi-echo T2*-weighted imaging. The T2*-weighted phase images were converted to quantitative susceptibility maps (QSM). Since the cerebellar nuclei are characterized by elevated iron content with respect to their surroundings, two independent raters manually outlined them on the susceptibility maps. T1-weighted images acquired at 3T were utilized to automatically identify the cerebellar gray matter (GM) volume. Linear correlations revealed significant atrophy of the cerebellum due to tissue loss of cerebellar cortical GM in healthy controls with increasing age. Reduction of the cerebellar GM was substantially stronger in SCA6 patients. The volume of the dentate nuclei did not exhibit a significant relationship with age, at least in the age range between 18 and 78 years, whereas mean susceptibilities of the dentate nuclei increased with age. As previously shown, the dentate nuclei volumes were smaller and magnetic susceptibilities were lower in SCA6 patients compared to age- and sex-matched controls. The significant dentate volume loss in SCA6 patients could also be confirmed with 7T MRI. Linear mixed effects models and individual paired t-tests accounting for multiple comparisons revealed no statistical significant change in volume and susceptibility of the dentate nuclei after one year in neither patients nor controls. Importantly, dentate volumes were more sensitive to differentiate between SCA6 (Cohen's d = 3.02) and matched controls than the cerebellar cortex volume (d = 2.04). In addition to age-related decline of the cerebellar cortex and atrophy in SCA6 patients, age-related increase of susceptibility of the dentate nuclei was found in controls, whereas dentate volume and susceptibility was significantly decreased in SCA6 patients. Because no significant changes of any of these parameters was found at follow-up, these measures do not allow to monitor disease progression at short intervals., Competing Interests: Declaration of Competing Interest The authors report no applicable competing interests pertaining to this publication. There are no products used or discussed within our study., (Copyright © 2023. Published by Elsevier Inc.)

Objective: The aim of this study was to assess the presence of detectable changes of skin thickness on clinical brain magnetic resonance imaging (MRI) scans in patients with MS, history of multiple gadolinium-based contrast agents (GBCAs) administrations, and evidence of gadolinium deposition in the brain., Materials and Methods: In this observational cross-sectional study, 71 patients with MS who underwent conventional brain MRI with an imaging protocol including enhanced 3D volumetric interpolated breath-hold examination (VIBE) T1-weighted with fat saturation were assessed. Patients with bilateral isointense dentate nucleus on unenhanced T1-weighted images were assigned to group A (controls without MRI evidence of gadolinium deposition), and patients with visually hyperintense dentate nuclei were assigned to group B. Qualitative and quantitative assessment of the skin thickness were performed., Results: Group A included 27 patients (median age, 33 years [IQR, 27-46]; 20 women), and group B included 44 patients (median age, 42 years [IQR, 35-53]; 29 women). Qualitative and quantitative assessment of the skin revealed significant differences between group A and group B. The average skin-to-scalp thickness ratios was significantly higher in group B than in group A (mean ± standard deviation = 0.52 ± 0.02 in group B vs 0.41 ± 0.02 in group A, P < 0.0001) and showed a positive correlation with the total number of enhanced MRI scans ( r = 0.39; 95% confidence interval, 0.17-0.57, P < 0.01)., Conclusions: Brain MRI detects increased skin thickness of the scalp in patients with MS and dentate nucleus high signal intensity on unenhanced T1-weighted images and shows positive association with previous exposures to linear GBCAs rather than macrocyclic GBCAs., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The visualization and identification of the deep cerebellar nuclei (DCN) (dentate [DN], interposed [IN] and fastigial nuclei [FN]) are particularly challenging. We aimed to visualize the DCN using quantitative susceptibility mapping (QSM), predict the contrast differences between QSM and T2* weighted imaging, and compare the DCN volume and susceptibility in movement disorder populations and healthy controls (HCs). Seventy-one Parkinson's disease (PD) patients, 39 essential tremor patients, and 80 HCs were enrolled. The PD patients were subdivided into tremor dominant (TD) and postural instability/gait difficulty (PIGD) groups. A 3D strategically acquired gradient echo MR imaging protocol was used for each subject to obtain the QSM data. Regions of interest were drawn manually on the QSM data to calculate the volume and susceptibility. Correlation analysis between the susceptibility and either age or volume was performed and the intergroup differences of the volume and magnetic susceptibility in all the DCN structures were evaluated. For the most part, all the DCN structures were clearly visualized on the QSM data. The susceptibility increased as a function of volume for both the HC group and disease groups in the DN and IN (p < .001) but not the FN (p = .74). Only the volume of the FN in the TD-PD group was higher than that in the HCs (p = .012), otherwise, the volume and susceptibility among these four groups did not differ significantly. In conclusion, QSM provides clear visualization of the DCN structures. The results for the volume and susceptibility of the DCN can be used as baseline references in future studies of movement disorders., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: The role of the cerebellum in motor function is well recognized. However, its role in higher nervous system activities such as cognition, emotion, endocrine, and autonomic activities is less known. The present study aims to show direct dento-amygdala projections using a biotinylated dextran amine (BDA) tracer in rats and 3-tesla (T) high-resolution diffusion tensor imaging (DTI)-based tractography in humans. Materials and Methods: The BDA tracer was pressure injected into the dentate nucleus of the cerebellum of Wistar albino rats. Labeled cells and axons were documented. High-resolution 3-T tractography data were obtained from the Human Connectome Project database. Dento-amygdala tracts were analyzed using diffusion spectrum imaging (DSI) Studio software. Results: The experimental study showed bilateral projections between the dentate nucleus and the central and basal nuclei and ipsilateral projections between lateral nuclei of the amygdala. The fibers from the dentate nucleus reached the amygdala through the superior cerebellar peduncle (SCP), and the contralateral fibers crossed in the decussation of SCP at the midbrain. The dento-amygdala results of the experimental study corresponded with the 3-T tractography findings on humans. Additionally, DTI findings showed that most of the dentate fibers passed through the hypothalamus before reaching the amygdala, and the amygdalae of the two sides are connected through the anterior commissure. Discussion: The 3-T DTI data of adult humans showed both direct dento-amygdala and indirect dento-hypothalamo-amygdala projections. Thus, this may indicate cerebellar contribution in modulation of emotional and autonomic functions. Furthermore, this can explain the emotional and cognitive deficits that occur in patients with cerebellar or SCP damage. Impact statement The present study showed direct dento-amygdala connections in the rat brain and human brain, which may provide evidence for cerebellar contribution in modulation of emotional and autonomic functions.

Cerebellar symptoms remain orphan of treatment options despite being prevalent and incapacitating. Investigate whether dentate nucleus deep brain stimulation (DN DBS) is safe and leads to improvements in cerebellar symptoms when compared to sham stimulation. This randomized double-blind crossover pilot trial enrolled five patients with spinocerebellar ataxia type 3 or post-lesion ataxia. Active or sham phases were randomly performed three months apart. The primary outcome was ataxia improvement as measured by the Scale for the Assessment and Rating of Ataxia (SARA) after the active compared to the sham period. Secondary outcome measures included safety and tolerability, the Fahn-Tolosa-Marin Tremor Rating Scale (FTMRS), quality of life measurements, and patients' global impression of change. The effects on ataxia were numerically better in four out of five patients after active versus sham stimulation. The composite SARA score did not change after comparing active to sham stimulation (8.6 ± 3.6 versus 10.1 ± 4.1; p = 0.223). The FTMRS showed significant improvement after active stimulation versus sham (18.0 ± 17.2 versus 22.2 ± 19.5; p = 0.039) as did patients' global impression of change (p = 0.038). The quality of life was not modified by stimulation (p = 0.337). DN DBS was well tolerated without serious adverse events. One patient had the electrode repositioned. DN DBS is a safe and well tolerated procedure that is effective in alleviating cerebellar tremor. In this small cohort of ataxic patients, DN DBS did not achieve statistical significance for ataxia improvement., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: Repeat contrast-enhanced MR imaging exposes patients with relapsing-remitting MS to frequent administration of gadolinium-based contrast agents. We aimed to investigate the potential metabolite and neurochemical alterations of visible gadolinium deposition on unenhanced T1WI in the dentate nucleus using MRS., Materials and Methods: This prospective study was conducted in a referral university hospital from January 2020 to July 2021. The inclusion criteria for case and control groups were as follows: 1) case: patients with relapsing-remitting MS, visible gadolinium deposition in the dentate nucleus (ribbon sign), >5 contrast-enhanced MR images obtained; 2) control 1: patients with relapsing-remitting MS without visible gadolinium deposition in the dentate nucleus, >5 contrast-enhanced MR images obtained; 3) control 2: patients with relapsing-remitting MS without visible gadolinium deposition in the dentate nucleus, <5 contrast-enhanced-MR images obtained; and 4) control 3: adult healthy individuals, with no contrast-enhanced MR imaging. Dentate nucleus and pontine single-voxel 12 × 12 × 12 MRS were analyzed using short TEs., Results: Forty participants (10 per group; 27 [67.5%] female; mean age, 35.6 [SD, 9.6] years) were enrolled. We did not detect any significant alteration in the levels of NAA and choline between the studied groups. The mean concentrations of mIns were 2.7 (SD, 0.73) (case), 1.5 (SD, 0.8) (control 1), 2.4 (SD, 1.2) (control 2), and 1.7 (SD, 1.2) (control 3) ( P = .04). The mean concentration of Cr and mIns ( P = .04) and the relative metabolic concentration (dentate nucleus/pons) of lipid 1.3/Cr ( P = .04) were significantly higher in the case-group than in healthy individuals (controls 1-3). Further analyses compared the case group with cumulative control 1 and 2 groups and showed a significant increase in lactate ( P = .02), lactate/Cr ( P = .04), and Cr (dentate nucleus/pons) ( P = .03) in the case group., Conclusions: Although elevated concentrations of Cr, lactate, mIns, and lipid in the dentate nucleus of the case group indicate a metabolic disturbance, NAA and choline levels were normal, implying no definite neuronal damage., (© 2022 by American Journal of Neuroradiology.)

Introduction and Aims: Contradictory results have been reported about hyperintensity of the globus pallidus and/or dentate nucleus on unenhanced T1-weighted magnetic resonance (MR) images after exposure to various gadolinium-based contrast agents. This change in signal intensity varies with different gadolinium-based contrast agents. We aimed to determine whether signal intensity in the dentate nucleus is increased in unenhanced T1-weighted images in patients who have undergone multiple studies with the macrocyclic gadolinium-based contrast agent gadoterate meglumine. We thoroughly reviewed the literature to corroborate our results., Materials and Methods: We included patients who had undergone more than 10 MR studies with gadoterate meglumine. We quantitatively analyzed the signal intensity in unenhanced T1-weighted MR images measured in regions of interest placed in the dentate nucleus and the pons, and we calculated the dentate nucleus-to-pons signal intensity ratios and the differences between the ratio in the first MR study and the last MR study. We used t-tests to evaluate whether the differences between the signal intensity ratios were different from 0. We also analyzed the subgroups of patients who had been administered <15 and ≥15 doses of gadoterate meglumine. We used Pearson correlation to determine the relationships between the differences in the signal intensity ratios and the number of doses of gadoterate meglumine administered., Results: The 54 patients (26 men) had received a mean of 13.8±3.47 doses (range, 10-23 doses). The difference in the dentate nucleus-pons signal intensity ratio between the first and last MR study was -0.0275±0.1917 (not significantly different from 0; p=0.2968) in the entire group, -0.0357±0.2204 (not significantly different from 0; p = 0.351 in the patients who had received <15 doses (n=34), and -0.0135±0.1332 (not significantly different from 0; p = 0.655) in those who had received ≥15 doses (n=20). Differences in signal intensity ratios did not correlate significantly with the accumulated dose of gadoterate meglumine (P = 0.9064; ρ = -0.0164 [95%])., Conclusions: Receiving more than 10 doses of gadoterate meglumine was not associated with increased signal intensity in the dentate nucleus., (Copyright © 2020 SERAM. Published by Elsevier España, S.L.U. All rights reserved.)

This study aimed to investigate possible signal changes in the dentate nucleus (DN) on diffusion tensor imaging (DTI) after administration of gadobutrol in a pediatric cohort. Total of 50 pediatric patients (mean age: 6.2 ± 4.3 years) with normal renal function exposed exclusively to the macrocyclic GBCA (mcGBCA) gadobutrol and 50 age- and sex-matched control patients with nonpathological neuroimaging findings (and no GBCA administration). Mean diffusivity (MD) and fractional anisotropy (FA) values were determined in the DN. A paired t test was performed to compare FA, MD values, and DN-to-middle cerebral peduncle (MCP) T1WI SI ratios between children exposed to gadobutrol and controls. Pearson correlation analysis was conducted to determine any correlation between FA and MD values as well as T1WI SI ratios and confounding parameters. The mean FA values of DN was significantly lower in children with mcGBCA than in the control group (p < 0.001; non-GBCA group, 0.299 ± 0.03; mcGBCA group, 0.254 ± 0.05), but no significant difference of the T1WI SI ratio was noted between the mcGBCA group (0.946 ± 0.06) and the control group (0.963 ± 0.05; p = 0.336). There was also a significant MD value difference between mcGBCA group and control group (p < 0.001; non-GBCA group, 0.152 ± 0.02 × 10 -3 mm 2 /s; mcGBCA group, 0.173 ± 0.03 × 10 -3 mm 2 /s). A significant correlation was identified between FA/MD values and the number of mcGBCA administration (FA; correlation coefficient =  - 0.355, p = 0.011 and MD; correlation coefficient = 0.334, p = 0.018). The administration of the gadobutrol was associated with higher MD and lower FA values in DN suggesting a difference in cerebellar tissue integrity between children exposed to mcGBCAs and control group., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: The aim of the study was to investigate the possible influence of changes in the brain caused by age on relaxometric and relaxation time-weighted magnetic resonance imaging (MRI) parameters in the deep cerebellar nuclei (DCN) and the globus pallidus (GP) of Gd-exposed and control rats over the course of 1 year., Materials and Methods: Twenty-five Wistar-Han rats were equally subdivided into 5 groups and initially received 8 injections on 4 consecutive days per week of either 3.6 mL/kg body weight saline (group I-III) or 1.8 mmol Gd/kg body weight gadobutrol (group IV) or gadodiamide (group V). T1- and T2-weighted scans, as well as relaxation maps, were acquired at 1 week (all groups); 5, 12, 20, and 26 weeks (saline II, gadobutrol, gadodiamide); and at 35, 44, and 52 weeks (saline III, gadobutrol, gadodiamide) after the last administration. Saline I was euthanized after 1 week, saline II after 26 weeks, and the remaining groups after 52 weeks. Signal intensities (SIs) were evaluated for the DCN/pons (P) and the GP/piriform cortex (PC) ratios, and relaxation times for the DCN and the GP. Brain tissue was extracted, and the gadolinium, iron, and manganese contents were quantified with inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation-ICP-MS imaging., Results: T1-weighted SI ratios did not show any significant trend with age in any region. The between-group analysis at 52 weeks resulted in a significant difference for the DCN/P and GP/PC region ratio between gadodiamide and its comparators. T1 relaxation times dropped with increasing age in the GP with a 10% to 20% difference between first and last measurement for all groups, and in the DCN <10% with a significant decrease for the gadodiamide group only (DCN: P = 0.0158). Group-related differences were observed at the last measurement time point for T1 values between gadodiamide and saline III in the DCN (P = 0.0153) and gadodiamide and gadobutrol in the GP (P = 0.0287). Analysis of the SI ratios of the T2-weighted images revealed a significant increase for the DCN/P and a decrease for the GP/PC with increasing age for all groups and no differences at 52 weeks after the last injection between groups. T2 values of the GP showed a significant linear decrease over time for all groups (saline I-III: P = 0.0101; gadobutrol: P = 0.0001; gadodiamide: P = 0.0142) in the aging rat brain. Quantitative imaging of manganese and iron by laser ablation-ICP-MS showed a linear increase for the saline groups in the GP for both metals (Fe: P < 0.0001; Mn: P = 0.0306) and in the DCN for manganese only (P = 0.0187), but no differences between groups at 52 weeks., Conclusions: Extensive MRI evaluation did not reveal an indication of SI or relaxation time changes associated with multiple exposure to the macrocyclic-chelated GBCA gadobutrol in the DCN and the GP. With increasing age, a T1 and T2 shortening in the GP and an increase in T2-weighted SI ratio in the DCN/P, as well as a decrease in the GP/PC, were observed for all groups. Such age-related changes can potentially bias MRI results as an indicator for gadolinium presence in the brain., Competing Interests: Conflicts of interest and sources of funding: C.G., G.J., T.F., J.B., and H.P. are employees of Bayer AG. C.S. is a consultant to Bayer AG on an honorary basis., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: An association between consecutive administrations of macrocyclic gadolinium-based contrast agent (mcGBCA) gadobutrol and linear (L)-GBCA gadopentetate dimeglumine and gadolinium retention in the pediatric brain remains incompletely understood., Purpose: To compare signal intensity (SI) changes in the dentate nucleus (DN) on unenhanced T1-weighted imaging (T1WI) in children who obtained mcGBCA gadobutrol with those who had previously received L-GBCA gadopentetate dimeglumine., Material and Methods: This retrospective study included 27 children who received L-GBCA gadopentetate dimeglumine followed by mcGBCA gadobutrol and two different control groups matched for age and sex for both periods, each involving 27 individuals with no GBCA administration from January 2010 to January 2020. DN-to-middle cerebellar peduncle (MCP) SI ratios on T1WI were determined. A repeated-measures ANOVA was performed to compare the T1WI SI ratio between children exposed to GBCA in each of the two periods and controls. Pearson correlation analysis was conducted to determine any correlation between SI ratios and confounding parameters., Results: T1WI SI ratio was significantly higher in those who had only L-GBCA (1.005±0.087) or subsequent mcGBCA gadobutrol (1.002±0.104) than in control groups 1 (0.927±0.041; P <0.001) and 2 (0.930±0.041; P =0.002), respectively, but no significant difference of the T1WI SI ratio was noted between L-GBCA period and subsequent mcGBCA gadobutrol period ( P =0.917). T1WI SI ratios and the L-GBCA administration number revealed a modest but significant correlation (correlation coefficient=0.034; P =0.016)., Conclusion: Previous administration of gadopentetate dimeglumine is associated with increased T1WI SI in the DN, while subsequent administration of gadobutrol does not demonstrate any additional SI increase in the pediatric brain.

Purpose: Several preclinical studies have reported the presence of gadolinium (Gd) in different chemical forms in the brain, depending on the class (macrocyclic versus linear) of Gd-based contrast agent (GBCA) administered. The aim of this study was to identify, with a special focus on insoluble species, the speciation of Gd retained in the deep cerebellar nuclei (DCN) of rats administered repeatedly with gadoterate or gadodiamide 4 months after the last injection., Methods: Three groups (N = 6/group) of healthy female Sprague-Dawley rats (SPF/OFA rats; Charles River, L'Arbresle, France) received a cumulated dose of 50 mmol/kg (4 daily intravenous administrations of 2.5 mmol/kg, for 5 weeks, corresponding to 80-fold the usual clinical dose if adjusted for man) of gadoterate meglumine (macrocyclic) or gadodiamide (linear) or isotonic saline for the control group (4 daily intravenous administrations of 5 mL/kg, for 5 weeks). The animals were sacrificed 4 months after the last injection. Deep cerebellar nuclei were dissected and stored at -80°C before sample preparation. To provide enough tissue for sample preparation and further analysis using multiple techniques, DCN from each group of 6 rats were pooled. Gadolinium species were extracted in 2 consecutive steps with water and urea solution. The total Gd concentrations were determined by inductively coupled plasma mass spectrometry (ICP-MS). Soluble Gd species were analyzed by size-exclusion chromatography coupled to ICP-MS. The insoluble Gd species were analyzed by single-particle (SP) ICP-MS, nanoscale secondary ion mass spectroscopy (NanoSIMS), and scanning transmission electron microscopy with energy-dispersive X-ray spectroscopy (STEM-EDX) for elemental detection., Results: The Gd concentrations in pooled DCN from animals treated with gadoterate or gadodiamide were 0.25 and 24.3 nmol/g, respectively. For gadoterate, the highest amount of Gd was found in the water-soluble fractions. It was present exclusively as low-molecular-weight compounds, most likely as the intact GBCA form. In the case of gadodiamide, the water-soluble fraction of DCN was composed of high-molecular-weight Gd species of approximately 440 kDa and contained only a tiny amount (less than 1%) of intact gadodiamide. Furthermore, the column recovery calculated for this fraction was incomplete, which suggested presence of labile complexes of dissociated Gd3+ with endogenous molecules. The highest amount of Gd was detected in the insoluble residue, which was demonstrated, by SP-ICP-MS, to be a particulate form of Gd. Two imaging techniques (NanoSIMS and STEM-EDX) allowed further characterization of these insoluble Gd species. Amorphous, spheroid structures of approximately 100-200 nm of sea urchin-like shape were detected. Furthermore, Gd was consistently colocalized with calcium, oxygen, and phosphorous, strongly suggesting the presence of structures composed of mixed Gd/Ca phosphates. No or occasional colocalization with iron and sulfur was observed., Conclusion: A dedicated analytical workflow produced original data on the speciation of Gd in DCN of rats repeatedly injected with GBCAs. The addition, in comparison with previous studies of Gd speciation in brain, of SP element detection and imaging techniques allowed a comprehensive speciation analysis approach. Whereas for gadoterate the main fraction of retained Gd was present as intact GBCA form in the soluble fractions, for linear gadodiamide, less than 10% of Gd could be solubilized and characterized using size-exclusion chromatography coupled to ICP-MS. The main Gd species detected in the soluble fractions were macromolecules of 440 kDa. One of them was speculated to be a Gd complex with iron-binding protein (ferritin). However, the major fraction of residual Gd was present as insoluble particulate species, very likely composed of mixed Gd/Ca phosphates. This comprehensive Gd speciation study provided important evidence for the dechelation of linear GBCAs and offered a deeper insight into the mechanisms of Gd deposition in the brain., Competing Interests: Conflicts of interest and sources of funding: I.S., C.F., P.R., and C.C. are (or were) Guerbet employees at the time of the study. J.S., R.L., J.J.L., M.A.S., and D.S. (Institute of Analytical and Physical Chemistry for the Environment and Materials): activities related to the present article: the institution (IPREM) received funding from Guerbet within a common research project. Other relationships: R.L. was an academic tutor of the PhD thesis of I.S., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

We aimed to explore the altered functional connectivity patterns within cerebello-cerebral circuits in temporal lobe epilepsy (TLE) patients with and without focal to bilateral tonic-clonic seizures (FBTCS). Forty-two patients with unilateral TLE (21 with and 21 without FBTCS) and 22 healthy controls were recruited. We chose deep cerebellar nuclei as seed regions, calculated static and dynamic functional connectivity (sFC and dFC) in the patients with and without FBTCS and healthy controls, and compared sFC and dFC among the three groups. Correlation analyses were used to assess relationships between the significantly altered imaging features and patient clinical parameters. Compared to the group without FBTCS, the FBTCS group showed decreased sFC between the right dentate nuclei and left hemisphere regions including the middle frontal gyrus, superior temporal gyrus, superior medial frontal gyrus and posterior cingulate gyrus, and significantly increased dFC between the right interposed nuclei and contralateral precuneus. Relative to HCs, the FBTCS group demonstrated prominently decreased sFC between the right dentate nuclei and left middle frontal gyrus. No significant correlations between the altered imaging features and patient clinical parameters were observed. Our results suggest that the disrupted cerebello-cerebral FC might be related to cognitive impairment, epileptogenesis, and propagation of epileptic activities in patients with FBTCS., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The objective of this study is to find out whether gadolinium accumulation in the dentate nucleus (DN) after repeated gadolinium-based contrast agent (GBCA) administration in multiple sclerosis (MS) patients is related to tissue alteration detectable on transcranial ultrasound., Methods: In this case-control study, 34 patients (17 with, and 17 age-, sex-, MS severity-, and duration-matched participants without visually rated DN T1-hyperintensity) who had received 2-28 (mean, 11 ± 7) consecutive 1.5-Tesla MRI examinations with application of linear GBCA were included. Real-time MRI-ultrasound fusion imaging was applied, exactly superimposing the DN identified on MRI to calculate its corresponding echo-intensity on digitized ultrasound image analysis. In addition, cerebellar ataxia and cognitive performance were assessed. Correlation analyses were adjusted for age, MS duration, MS severity, and time between MRI scans., Results: DN-to-pons T1-signal intensity-ratios (DPSIR) were larger in patients with visually rated DN T1-hyperintensity compared to those without (1.16 ± 0.10 vs 1.09 ± 0.06; p = 0.01). In the combined group, DPSIR correlated with the cumulative linear-GBCA dose (r = 0.49, p = 0.003), as did the DPSIR change on last versus first MRI (r = 0.59, p = 0.003). Neither DPSIR nor globus pallidus internus-to-thalamus T1-signal intensity-ratios were related to echo-intensity of corresponding ROI's. DPSIR correlated with the dysarthria (r = 0.57, p = 0.001), but no other, subscore of the International Cooperative Ataxia Rating Scale, and no other clinical score., Conclusions: DN gadolinium accumulation is not associated with trace metal accumulation, calcification, or other tissue alteration detectable on ultrasound. A possible mild effect of DN gadolinium accumulation on cerebellar speech function in MS patients, suggested by present data, needs to be validated in larger study samples., (© 2021. The Author(s).)

The advent of susceptibility-sensitive MRI techniques, such as susceptibility weighted imaging (SWI), has enabled accurate in vivo visualization and quantification of iron deposition within the human brain. Although previous approaches have been introduced to segment iron-rich brain regions, such as the substantia nigra, subthalamic nucleus, red nucleus, and dentate nucleus, these methods are largely unavailable and manual annotation remains the most used approach to label these regions. Furthermore, given their recent success in outperforming other segmentation approaches, convolutional neural networks (CNN) promise better performances. The aim of this study was thus to evaluate state-of-the-art CNN architectures for the labeling of deep brain nuclei from SW images. We implemented five CNN architectures and considered ensembles of these models. Furthermore, a multi-atlas segmentation model was included to provide a comparison not based on CNN. We evaluated two prediction strategies: individual prediction, where a model is trained independently for each region, and combined prediction, which simultaneously predicts multiple closely located regions. In the training dataset, all models performed with high accuracy with Dice coefficients ranging from 0.80 to 0.95. The regional SWI intensities and volumes from the models' labels were strongly correlated with those obtained from manual labels. Performances were reduced on the external dataset, but were higher or comparable to the intrarater reliability and most models achieved significantly better results compared to multi-atlas segmentation. CNNs can accurately capture the individual variability of deep brain nuclei and represent a highly useful tool for their segmentation from SW images., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Stabilizing the eyes in space when looking at a target is provided by a brainstem/cerebellar gaze-holding network, including the flocculus/paraflocculus complex (non-human primate studies) and the caudal vermis, biventer, and inferior semilunar lobule (human studies). Previous research suggests that acute lateralized cerebellar lesions preferentially lead to gaze-evoked nystagmus (GEN) on ipsilesional gaze. Here, we further characterize the effect of unilateral cerebellar lesions on gaze-holding and hypothesize that the side-specific magnitude of gaze-holding impairment depends on the lesion location. Nine patients (age range = 31-62 years) with acute/subacute (≤ 10 days old) MRI-confirmed unilateral cerebellar stroke were included. Horizontal gaze holding was quantified while looking at a slowly moving (0.5°/s) flashing target (gaze angle = ±40°). Asymmetry in eye-drift velocity was calculated and compared with the different MRI patterns of cerebellar lesions. Individual peak eye-drift velocities (range = 1.7-8.8°/s) occurred at the most eccentric eye positions (gaze angle = 28-38°). We found significantly asymmetric eye-drift velocity (EDV) in eight out of nine patients. The four patients with MRI-confirmed involvement of the caudal vermis and the dentate nucleus all presented with ipsilesionally-predominant EDV, while in the five patients with lesions restricted to the cerebellar hemisphere, EDV was stronger on contralesional gaze in three out of four found with an asymmetric EDV. Involvement of the caudal vermis and the dentate nucleus is critical for determining the directional GEN asymmetry in unilateral cerebellar lesions. Thus, our findings support the occurrence of GEN without floccular/parafloccular lesions and suggest that the EDV asymmetry in relation to the side of the lesion provides information about the involvement of specific structures., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Purpose: Gadolinium complexes have paramagnetic properties; thus, we aimed to determine the susceptibility changes in the globus pallidus and dentate nucleus following administration of linear or macrocyclic gadolinium-based contrast agents in children., Materials and Methods: Thirty-three patients with linear gadolinium-based contrast agent gadopentetate dimeglumine administration, 33 age- and sex-matched patients with macrocyclic gadolinium-based contrast agent gadobutrol administration, and 33 age- and sex-matched control subjects without gadolinium exposure were enrolled in this retrospective study. The signal intensity on SWI and T1WI was determined in the dentate nucleus, middle cerebellar peduncle, globus pallidus, and pulvinar of the thalamus in an ROI-based analysis to calculate dentate nucleus-to-middle cerebellar peduncle and globus pallidus-to-thalamus ratios. A repeated measures ANOVA was performed to compare SWI minimum , SWI mean , and T1WI signal intensity ratios between gadolinium-based contrast agent groups and control subjects. Pearson correlation analysis was performed to determine any correlation between signal intensity ratios and variables., Results: Dentate nucleus-to-middle cerebellar peduncle and globus pallidus-to-thalamus ratios for both SWI mean and SWI minimum were lower for the linear gadolinium-based contrast agent group compared with macrocyclic gadolinium-based contrast agent and control groups ( P < .05). No significant difference of the SWI mean and SWI minimum ratios were noted between the macrocyclic gadolinium-based contrast agent group and the control group ( P > .05). Both dentate nucleus-to-middle cerebellar peduncle and globus pallidus-to-thalamus ratios on T1WI in the linear gadolinium-based contrast agent group were higher than in the control group and the macrocyclic gadolinium-based contrast agent group ( P < .05). A negative correlation was identified between SWI mean and SWI minimum ratios and the number of linear gadolinium-based contrast agent administrations (dentate nucleus-to-middle cerebellar peduncle ratio: SWI mean , r = -0.43, P = .005; SWI minimum , r = -0.38, P = .011; globus pallidus-to-thalamus ratio: SWI mean , r = -0.39, P = .009; SWI minimum , r = -0.33, P = .017)., Conclusions: SWI analysis of the pediatric brain demonstrated a statistically significant decrease in SWI minimum and SWI mean values for the dentate nucleus and globus pallidus after administration of linear gadolinium-based contrast agents but not macrocyclic gadolinium-based contrast agents., (© 2021 by American Journal of Neuroradiology.)

Cognitive impairments are the hallmark of schizophrenia and prominent in the early episode stage. However, the underlying pathological mechanisms of cognitive impairments are not fully understood. This study aimed to investigate the abnormal functional connectivity (FC) of the cerebellar dentate nucleus (DN) and its correlation with cognitive impairments in patients with drug-naive and first-episode schizophrenia. Resting-state functional magnetic resonance imaging data were acquired in 47 patients and 43 healthy controls. Cognitive functions were assessed by number sequence span, verbal category fluency, digit-symbol coding tests. The results showed that the patients had deficits in all three cognitive tests compared to the controls. Furthermore, the increased FC of DN with the bilateral postcentral gyrus and decreased FC of DN with the right inferior temporal gyrus and regional cerebellum (e.g., Vermis 4-5 and Crus I) were observed in the patient group compared to the control group. Importantly, these abnormal DN FC significantly correlated with cognitive tests (e.g., number sequence span and digit-symbol coding) and clinical symptoms (e.g., negative symptom) in the patient group. The results suggested that abnormal FC of DN with cortical and subcortical regions was associated with cognitive impairments and symptom severity and might be an underlying neural mechanism in schizophrenia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: To determine whether cerebral adrenoleukodystrophy (cALD) or brain irradiation in patients with primary brain tumor affects T1-weighted imaging (T1WI) signal intensity (SI) of the dentate nucleus (DN) in a pediatric cohort who had received consecutive macrocyclic gadolinium-based contrast agent (mcGBCA) gadobutrol., Methods: This study included 97 pediatric patients who underwent mcGBCA-enhanced MRI from 2010 to 2020 (29 children with primary brain tumors without brain radiation therapy [mcGBCA group-1], 33 children with primary brain tumors and radiation treatment [mcGBCA group-2], 35 children with cALD [mcGBCA group-3], and 97 sex-/age-matched control subjects [subgroups matched to each of the three subject groups] without GBCA administration). The DN-to-middle cerebellar peduncle (MCP) SI ratios on T1WI were then determined. A paired t-test was performed to compare SI ratios between children exposed to mcGBCA in each group and control subjects. The relationships between SI ratios and confounding variables were analyzed utilizing the Pearson correlation analysis., Results: The DN-to-MCP SI ratio was significantly higher of mcGBCA group-2 (1.046±.071) or mcGBCA group-3 (.972±.038) than in the control group-2 (.983±.041, P<.001) and control group-3 (.937±.051, P = .002), respectively, but no significant difference of the SI ratio was noted between mcGBCA group-1 (.984±.032) and control-group-1 (.982±.035, P = .860). No significant correlation was noted between SI ratio values and the cumulative dose or number of mcGBCA administrations, age, or the elapsed time between the MRI examinations (all P>.05)., Conclusions: Hyperintense T1WI signal in the DN may be seen in children with brain tumors undergoing brain irradiation, as well as in children with cALD., (© 2021 American Society of Neuroimaging.)

Neurodegeneration of the cerebellum progresses over years and primarily affects cerebellar cortex. It leads to a progressive loss of control and coordination of gait, posture, speech, fine motor, and oculomotor function. Yet, little is known how the cerebro-cerebellar network compensates for the loss in cerebellar cortical neurons. To address this knowledge gap, we examined 30 people with cerebellar cortical degeneration and a group of 30 healthy controls. We assessed visuomotor performance during a forearm-pointing task to 10°, 25°, and 50° targets. In addition, using MRI imaging, we determined neurodegenerative-induced changes in gray matter volume (GMV) in the cerebro-cerebellar network and correlated them to markers of motor performance. The main results are as follows: first, the relative joint position error (RJPE) during pointing was significantly greater in the ataxia group for all targets confirming the expected motor control deficit. Second, in the ataxia group, GMV was significantly reduced in cerebellar cortex but increased in the deep cerebellar nuclei. Motor error (RJPE) correlated negatively with decreased cerebellar GMV but positively with increased GMV in supplementary motor area (SMA) and premotor cortex. GMV of the deep cerebellar nuclei did not correlate significantly with markers of motor performance. We discuss whether the GMV changes in the cerebellar output nuclei and the extracerebellar efferent targets in secondary motor cortex can be understood as a central compensatory response to the neurodegeneration of the cerebellar cortex. NEW & NOTEWORTHY Neurodegeneration of the cerebellum progresses over years and primarily affects cerebellar cortex. It leads to a progressive loss of control and coordination of movement. We here show that the neurodegenerative process not only leads to cells loss in cerebellar cortex but also induces neurostructural changes in the form of increased gray matter in the efferent targets of the cerebellar cortex, namely, the cerebellar output nuclei, the SMA, and premotor cortex.

Objective: Approximately 50% of patients with tuberous sclerosis complex develop infantile spasms, a sudden onset epilepsy syndrome associated with poor neurological outcomes. An increased burden of tubers confers an elevated risk of infantile spasms, but it remains unknown whether some tuber locations confer higher risk than others. Here, we test whether tuber location and connectivity are associated with infantile spasms., Methods: We segmented tubers from 123 children with (n = 74) and without (n = 49) infantile spasms from a prospective observational cohort. We used voxelwise lesion symptom mapping to test for an association between spasms and tuber location. We then used lesion network mapping to test for an association between spasms and connectivity with tuber locations. Finally, we tested the discriminability of identified associations with logistic regression and cross-validation as well as statistical mediation., Results: Tuber locations associated with infantile spasms were heterogenous, and no single location was significantly associated with spasms. However, >95% of tuber locations associated with spasms were functionally connected to the globi pallidi and cerebellar vermis. These connections were specific compared to tubers in patients without spasms. Logistic regression found that globus pallidus connectivity was a stronger predictor of spasms (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.10-3.50, p = 0.02) than tuber burden (OR = 1.65, 95% CI = 0.90-3.04, p = 0.11), with a mean receiver operating characteristic area under the curve of 0.73 (±0.1) during repeated cross-validation., Interpretation: Connectivity between tuber locations and the bilateral globi pallidi is associated with infantile spasms. Our findings lend insight into spasm pathophysiology and may identify patients at risk. ANN NEUROL 2021;89:726-739., (© 2021 American Neurological Association.)

The dentato-rubro-thalamo-cortical tract (DRTC) is the main outflow pathway of the cerebellum, contributing to a finely balanced corticocerebellar loop involved in cognitive and sensorimotor functions. Damage to the DRTC has been implicated in cerebellar mutism syndrome seen in up to 25% of children after cerebellar tumor resection. Multi-shell diffusion MRI (dMRI) combined with quantitative constrained spherical deconvolution tractography and multi-compartment spherical mean technique modeling was used to explore the frontocerebellar connections and microstructural signature of the DRTC in 30 healthy children. The highest density of DRTC connections were to the precentral (M1) and superior frontal gyri (F1), and from cerebellar lobules I-IV and IX. The first evidence of a topographic organization of anterograde projections to the frontal cortex at the level of the superior cerebellar peduncle (SCP) is demonstrated, with streamlines terminating in F1 lying dorsomedially in the SCP compared to those terminating in M1. The orientation dispersion entropy of DRTC regions appears to exhibit greater contrast than that shown by fractional anisotropy. Analysis of a separate reproducibility cohort demonstrates good consistency in the dMRI metrics described. These novel anatomical insights into this well-studied pathway may prove to be of clinical relevance in the surgical resection of cerebellar tumors., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background and Purpose: Concern has grown about the finding of gadolinium deposits in the brain after administering gadolinium-based contrast agents (GBCAs). The mechanism is unclear, and related questions remain unanswered, including the stability over time. Therefore, we conducted a three-time-point study to explore T1-weighted (W) signal changes in the dentate nucleus (DN) and globus pallidus (GP), after the first, fifth, and tenth injections of either a macrocyclic agent (gadoterate meglumine) or a linear agent (gadobenate dimeglumine)., Materials and Methods: For this retrospective, multicenter, longitudinal study, two groups of 18 (gadoterate meglumine) and 19 (gadobenate dimeglumine) patients were identified. The evolution of the signal over time was analyzed using DN/pons (DN/P) and GP/thalamus (GP/T) ratios., Results: DN/P and GP/T ratios tended to increase after the fifth administration of gadobenate dimeglumine, following by a downward trend. A trend in a decrease in DN/P and GP/T ratios were found after the fifth and tenth administrations of gadoterate meglumine., Conclusion: After exposure to gadobenate dimeglumine, the signal intensity (SI) tended to increase after the fifth injection owing to gadolinium accumulation, however, a SI increase was not found after the tenth administration supporting the hypothesis of a slow elimination of the previously retained gadolinium (wash-out effect) from the brain or of a change in form (by dechelation), causing the signal to fade. No increasing SI was found in the DN and GP after exclusive exposure to gadoterate meglumine, thus confirming its stability. We found, instead, a trend for a significative gadolinium elimination over time., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A 73-year-old man who presented with fever and abdominal discomfort was diagnosed to have a liver abscess. He was treated with antimicrobials which included metronidazole. One month into treatment, he developed neurological symptoms and signs that were suggestive of cerebellar pathology. MRI of the brain showed T2/fluid attenuated inversion recovery hyperintensities involving bilateral dentate, fastigial and interpositus nuclei. After excluding common aetiologies, the possibility of metronidazole-induced neurotoxicity was considered. After stopping metronidazole, his symptoms and signs resolved. A subsequent MRI scan of the brain showed reversal of changes. Neurotoxicity caused by metronidazole is an uncommon adverse effect of a commonly used antimicrobial drug and should be considered in the appropriate clinical scenario., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Gadolinium based contrast agents (GBCAs) are widely used in clinical MRI since the mid-1980s. Recently, concerns have been raised that trace amounts of Gadolinium (Gd), detected in brains even long time after GBCA application, may cause yet unrecognized clinical consequences. We therefore assessed the behavioral phenotype, neuro-histopathology, and Gd localization after repeated administration of linear (gadodiamide) or macrocyclic (gadobutrol) GBCA in rats. While most behavioral tests revealed no difference between treatment groups, we observed a transient and reversible decrease of the startle reflex after gadodiamide application. Residual Gd in the lateral cerebellar nucleus was neither associated with a general gene expression pathway deregulation nor with neuronal cell loss, but in gadodiamide-treated rats Gd was associated with the perineuronal net protein aggrecan and segregated to high molecular weight fractions. Our behavioral finding together with Gd distribution and speciation support a substance class difference for Gd presence in the brain after GBCA application.

Background and Purpose: We aimed to determine whether lobar cerebellar microbleeds or concomitant lobar cerebellar and deep microbleeds, in the presence of lobar cerebral microbleeds, attribute to underlying advanced cerebral amyloid angiopathy pathology or hypertensive arteriopathy., Methods: We categorized 71 patients with suspected cerebral amyloid angiopathy markers (regardless of the presence of deep and cerebellar microbleeds) into 4 groups according to microbleed distribution: L (strictly lobar cerebral, n=33), L/LCbll (strictly lobar cerebral and strictly lobar cerebellar microbleeds, n=13), L/Cbll/D (lobar, cerebellar, and deep microbleeds, n=17), and L/D (lobar and deep, n=8). We additionally categorized patients with cerebellar microbleeds into 2 groups according to dentate nucleus involvement: strictly lobar cerebellar (n=16) and dentate (n=14). We then compared clinical characteristics, Aβ (amyloid-β) positivity on PET (positron emission tomography), magnetic resonance imaging cerebral amyloid angiopathy markers, and cerebral small vessel disease burden among groups., Results: The frequency of Aβ positivity was higher in the L and L/LCbll groups (81.8% and 84.6%) than in the L/Cbll/D and L/D groups (37.5% and 29.4%; P <0.001), while lacune numbers were lower in the L and L/LCbll groups (1.7±3.3 and 1.7±2.6) than in the L/Cbll/D and L/D groups (8.0±10.3 and 13.4±17.7, P =0.001). The L/LCbll group had more lobar cerebral microbleeds than the L group (93.2±121.8 versus 38.0±40.8, P =0.047). The lobar cerebellar group had a higher Aβ positivity (75% versus 28.6%, P =0.011) and lower lacune number (2.3±3.7 versus 8.6±1.2, P =0.041) than the dentate group., Conclusions: Strictly lobar cerebral and cerebellar microbleeds are related to cerebral amyloid angiopathy, whereas any combination of concurrent lobar and deep microbleeds suggest hypertensive angiopathy regardless of cerebral or cerebellar compartments.

Background: Brain irradiation is considered a cofactor influencing the dentate nucleus (DN) signal intensity (SI) on unenhanced T 1 -weighted images in patients exposed to gadolinium-based contrast agents (GBCAs)., Purpose: To assess the effect of gadodiamide and whole-brain radiation therapy (WBRT) on T 1 -weighted images and on apparent diffusion coefficient (ADC) maps of DN., Study Type: Single-center retrospective., Population: In all, 125 patients who underwent brain MRIs were classified into four groups: 1) patients who did neither receive intravenous GBCAs injections nor irradiation (controls); 2) patients having ≥3 GBCAs-enhanced scans and no WBRT; 3) patients having WBRT and < 3 GBCAs-enhanced scans; and 4) patients having WBRT and ≥ 3 GBCAs-enhanced scans., Field Strength/sequence: 1.5T magnet, echo-planar diffusion weighted imaging (DWI) and unenhanced T 1 -weighted sequences., Assessment: The DN-to-pons SI ratio on unenhanced T 1 -weighted images and ADC values of the DN were calculated. Values were compared between groups and relative to the cumulative gadolinium dose and to the time delay after WBRT., Statistical Tests: Statistical analysis included the Mann-Whitney U-test and Spearman's rank-order correlation., Results: DN ADC values were not significantly different (P = 0.34) between patients exposed to gadodiamide (0.81 ± 0.06) and controls (0.83 ± 0.07). There were no differences in DN ADC values (P = 0.28) and DN-to-pons SI ratios (P = 0.42) between patients exposed to WBRT (ADC values: 0.85 ± 0.09; SI ratio: 1.11 ± 0.10) and controls (ADC values: 0.83 ± 0.06; SI ratio: 1.09 ± 0.06). There was a significant negative correlation between DN ADC values and the time (days) since the end of WBRT (r = - 0.33; 95% confidence interval [CI]: -0.55, -0.06; P < 0.05)., Data Conclusion: We did not find changes suggestive of gadolinium-related tissue microstructural damage of the DN. The ADC values of the DN are associated with the time from WBRT., Level of Evidence: 3 TECHNICAL EFFICACY STAGE: 5., (© 2020 International Society for Magnetic Resonance in Medicine.)

Background: Palatal tremor is involuntary, rhythmic and oscillatory movement of the soft palate. Palatal tremor can be classified into three subtypes; essential, symptomatic and palatal tremor associated with progressive ataxia., Methods: A thorough Pubmed search was conducted to look for the original articles, reviews, letters to editor, case reports, and teaching neuroimages, with the keywords "essential", "symptomatic palatal tremor", "myoclonus", "ataxia", "hypertrophic", "olivary" and "degeneration"., Results: Essential palatal tremor is due to contraction of the tensor veli palatini muscle, supplied by the 5 th cranial nerve. Symptomatic palatal tremor occurs due to the contraction of the levator veli palatini muscle, supplied by the 9% th and 10% th cranial nerves. Essential palatal tremor is idiopathic, while symptomatic palatal tremor occurs due to infarction, bleed or tumor within the Guillain-Mollaret triangle. Progressive ataxia and palatal tremor can be familial or idiopathic. Symptomatic palatal tremor and sporadic progressive ataxia with palatal tremor show signal changes in inferior olive of medulla in magnetic resonance imaging. The treatment options available for essential palatal tremor are clonazepam, lamotrigine, sodium valproate, flunarizine and botulinum toxin. The treatment of symptomatic palatal tremor involves the treatment of the underlying cause., Discussion: Further studies are required to understand the cause and pathophysiology of Essential palatal tremor and progressive ataxia and palatal tremor. Similarly, the link between tauopathy and palatal tremor associated progressive ataxia needs to be explored further. Oscillopsia and progressive ataxia are more debilitating than palatal tremor and needs new treatment approaches., Competing Interests: The author has no competing interests to declare., (Copyright: © 2020 The Author(s).)

Objectives: Gadolinium deposition is widely believed to occur, but questions regarding accumulation pattern and permanence remain. We conducted a retrospective study of intracranial signal changes on monthly triple-dose contrast-enhanced magnetic resonance imaging (MRI) examinations from the previously published Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial (N = 67) to characterize the dynamics of gadolinium deposition in several deep brain nuclei and track persistence versus washout of gadolinium deposition on long-term follow-up (LTFU) examinations (N = 28) obtained approximately 10 years after enrollment in the Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial., Materials and Methods: Using T2 and proton density images and using image analysis software (ITK-SNAP), manual regions of interest were created ascribing boundaries of the caudate nucleus, dentate nucleus, globus pallidus, pulvinar, putamen, white matter, and air. Intensity analysis was conducted on T1-weighted fat-saturated (fat-sat) images using the FSL package. A linear rigid-body transform was calculated from the fat-sat image at each target time point to the region of interest segmentation reference time point fat-sat image. Serial MRI signal was analyzed using linear mixed regression modeling with random intercept. Annual MRI signal changes including LTFU scans were assessed with t test., Results: During monthly scanning, all gray matter structures demonstrated a significant (P < 0.0001) increase in contrast-to-noise ratio. Yearly changes in deposition showed distinctive patterns for the specific nucleus: globus pallidus showed complete retention, pulvinar showed partial washout, while dentate, caudate, and putamen returned to baseline (ie, complete washout)., Conclusions: Monthly increased contrast-to-noise ratio in gray matter nuclei is consistent with gadolinium deposition over time. The study also suggests that some deep gray matter nuclei permanently retain gadolinium, whereas others demonstrate washout of soluble gadolinium.

Background The relationship between administration of macrocyclic gadolinium-based contrast agents and T1-weighted signal intensity (SI) change of the globus pallidus (GP) and dentate nucleus (DN) is, to the knowledge of the authors, not known. Purpose To determine if quantitative susceptibility mapping (QSM) can detect changes in magnetic susceptibility of the GP and DN after serial administration of macrocyclic gadobutrol in patients with primary brain tumors. Materials and Methods Patients diagnosed with primary brain tumors from August 2014 to February 2019 were eligible for this single-center retrospective study. Among 501 consecutive adult patients who were given at least one administration of gadobutrol, those who were previously administered an unknown or linear gadolinium-based contrast agent were excluded. Brain MRI scans with three-dimensional gradient-recalled-echo image phase data for QSM processing were reviewed. Regions of interest were drawn on the GP and DN on the basis of semiautomatic thresholding. Univariable generalized estimation equations were used to determine the associations between MRI measures (SI on T1-weighted images and magnetic susceptibility on QSM) and number of gadobutrol doses. Potential confounding factors were adjusted for in multivariable generalized estimating equation. Results Ninety patients (mean age, 51 years ± 17 [standard deviation]; 51 men) with 199 MRI scans were analyzed. In models adjusted for repeated observations between injections, the number of injections of gadobutrol was associated with the magnetic susceptibility of the GP (1.4 × 10 -3 ppm/number of gadobutrol injections; P = .01) and DN (8.1 × 10 -4 ppm/number of gadobutrol injections; P = .03). After adjustment for confounders, the number of gadobutrol injections remained an independent predictor of increased magnetic susceptibility in the GP (1.3 × 10 -3 ppm/number of gadobutrol injections; 95% confidence interval: 0.39 × 10 -3 , -2.4 × 10 -3 ; P = .006). There were no associations between number of gadobutrol injections and SI or magnetic susceptibility in the DN. Conclusion The magnetic susceptibility of the globus pallidus increased after serial administration of gadobutrol. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Wang and Prince in this issue.

Niemann-Pick Type C (NPC) is a rare genetic disorder characterized by progressive cell death in various tissues, particularly in the cerebellar Purkinje cells, with no known cure. Mouse models for human NPC have been generated and characterized histologically, behaviorally, and using longitudinal magnetic resonance imaging (MRI). Previous imaging studies revealed significant brain volume differences between mutant and wild-type animals, but stopped short of making volumetric comparisons of the cerebellar sub-regions. In this study, we present longitudinal manganese-enhanced MRI (MEMRI) data from cohorts of wild-type, heterozygote carrier, and homozygote mutant NPC mice, as well as deformation-based morphometry (DBM) driven brain volume comparisons across genotypes, including the cerebellar cortex, white matter, and nuclei. We also present the first comparisons of MEMRI signal intensities, reflecting brain and cerebellum sub-regional Mn 2+ -uptake over time and across genotypes., Competing Interests: Declaration of competing interest The authors have no conflicts to declare., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)