Cerebellar White Matter Volumes Research Articles

Cerebellar Volumes and Sensorimotor Behavior in Autism Spectrum Disorder.

BackgroundSensorimotor issues are common in autism spectrum disorder (ASD), though their neural bases are not well understood. The cerebellum is vital to sensorimotor control and reduced cerebellar volumes in ASD have been documented. Our study examined the extent to which cerebellar volumes are associated with multiple sensorimotor behaviors in ASD.Materials and MethodsFifty-eight participants with ASD and 34 typically developing (TD) controls (8–30 years) completed a structural MRI scan and precision grip testing, oculomotor testing, or both. Force variability during precision gripping as well as absolute error and trial-to-trial error variability of visually guided saccades were examined. Volumes of cerebellar lobules, vermis, and white matter were quantified. The relationships between each cerebellar region of interest (ROI) and force variability, saccade error, and saccade error variability were examined.ResultsRelative to TD controls, individuals with ASD showed increased force variability. Individuals with ASD showed a reduced volume of cerebellar vermis VI-VII relative to TD controls. Relative to TD females, females with ASD showed a reduced volume of bilateral cerebellar Crus II/lobule VIIB. Increased volume of Crus I was associated with increased force variability. Increased volume of vermal lobules VI-VII was associated with reduced saccade error for TD controls but not individuals with ASD. Increased right lobule VIII and cerebellar white matter volumes as well as reduced right lobule VI and right lobule X volumes were associated with greater ASD symptom severity. Reduced volumes of right Crus II/lobule VIIB were associated with greater ASD symptom severity in only males, while reduced volumes of right Crus I were associated with more severe restricted and repetitive behaviors only in females.ConclusionOur finding that increased force variability in ASD is associated with greater cerebellar Crus I volumes indicates that disruption of sensory feedback processing supported by Crus I may contribute to skeletomotor differences in ASD. Results showing that volumes of vermal lobules VI-VII are associated with saccade precision in TD but not ASD implicates atypical organization of the brain systems supporting oculomotor control in ASD. Associations between volumes of cerebellar subregions and ASD symptom severity suggest cerebellar pathological processes may contribute to multiple developmental challenges in ASD.

Post-Concussive Vestibular Dysfunction Is Related to Injury to the Inferior Vestibular Nerve.

Symptoms of vestibular dysfunction such as dizziness and vertigo are common after sports-related concussions (SRC) and associated with a worse outcome and a prolonged recovery. Vestibular dysfunction after SRC can be because of an impairment of the peripheral or central neural parts of the vestibular system. The aim of the present study was to establish the cause of vestibular impairment in athletes with SRC who have persisting post-concussive symptoms (PPCS). We recruited 42 participants—21 athletes with previous SRCs and PPCS ≥6 months and 21 healthy athletic age- and sex-matched controls—who underwent symptom rating, a detailed test battery of vestibular function and 7T magnetic resonance imaging with diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) of cerebellar white matter tracts, and T1-weighted imaging for cerebellar volumetrics. Vestibular dysfunction was observed in 13 SRC athletes and three controls (p = 0.001). Athletes with vestibular dysfunction reported more pronounced symptoms on the Dizziness Handicap Inventory (DHI; p < 0.001) and the Hospital Anxiety and Depression Scale (HADS; p < 0.001). No significant differences in DTI metrics were found, while in DKI two metrics were observed in the superior and/or inferior cerebellar tracts. Cerebellar gray and white matter volumes were similar in athletes with SRC and controls. Compared with controls, pathological video head impulse test results (vHIT; p < 0.001) and cervical vestibular evoked myogenic potentials (cVEMP; p = 0.002) were observed in athletes with SRC, indicating peripheral vestibular dysfunction and specifically suggesting injury to the inferior vestibular nerve. In athletes with persisting symptoms after SRC, vestibular dysfunction is associated with injury to the inferior vestibular nerve.

Neuropsychological correlates of cerebellar volumes in multiple sclerosis: an MRI volumetric analysis study.

The hallmark of Multiple Sclerosis (MS) pathophysiology is the damage to the myelin sheath around axons. The cerebellum is a predilection site for demyelination with a well-recognized role in motor and a rather understudied contribution to cognitive functions. The aim of this study is to investigate patterns of cerebellar grey and white matter pathology, expressed as reduced volume, as well as cortical thickness and their potential contribution to cognitive performance and disability status of patients with MS. 24 patients with MS underwent extensive neuropsychological assessment using paper and pencil tests and the Brain Health Assessment (BHA) tablet-based battery. Cerebellar lobular volumes and thickness were calculated using a volumetric analysis with automated segmentation of the cerebellum and its lobules. The main findings are a reduction of cerebellar grey matter (CGMV) and white matter volumes (CWMV) in lobule X and a widespread cerebellar cortical thinning in patients. Overall disease severity and neurological disability, assessed with the Expanded Disability Status Severity Scale, was correlated with fatigue and information processing speed tasks, but not with CGMV and CWMV. CWMV and CGMV of lobule I-II was negatively correlated with information processing speed, as well as visuospatial memory tests and, finally, inverse cortical thinning associations were noted between the whole cerebellum, lobule I-II, lobule III, lobule VI, Crus I, lobule VIIIA and information processing speed and verbal fluency tasks. The inverse associations observed may represent a compensatory mechanism activated in MS engaging additional high-level cortical areas functionally interconnected with the damaged cerebellum, in order to cope with the cognitive demands of a task.

Biallelic SEPSECS variants in two siblings with pontocerebellar hypoplasia type 2D underscore the relevance of splice-disrupting synonymous variants in disease.

Noncoding and synonymous coding variants that exert their effects via alternative splicing are increasingly recognized as an important category of disease-causing variants. In this report, we describe two siblings who presented with hypotonia, profound developmental delays, and seizures. Brain magnetic resonance imaging (MRI) in the proband at 5 yr showed diffuse cerebral and cerebellar white matter volume loss. Both siblings later developed ventilator-dependent respiratory insufficiency and scoliosis and are currently nonverbal and nonambulatory. Extensive molecular testing including oligo array and clinical exome sequencing was nondiagnostic. Research genome sequencing under an institutional review board (IRB)-approved study protocol revealed that both affected children were compound-heterozygous for variants in the SEPSECS gene. One variant was an initiator codon change (c.1A > T) that disrupted protein translation, consistent with the observation that most disease-causing variants are loss-of-function changes. The other variant was a coding change (c.846G > A) that was predicted to be synonymous but had been demonstrated to disrupt mRNA splicing in a minigene assay. The SEPSECS gene encodes O-phosphoseryl-tRNA(Sec) selenium transferase, an enzyme that participates in the biosynthesis and transport of selenoproteins in the body. Variations in SEPSECS cause autosomal recessive pontocerebellar hypoplasia type 2D (PCHT 2D; OMIM #613811), a neurodegenerative condition characterized by progressive cerebrocerebellar atrophy, microcephaly, and epileptic encephalopathy. The identification of biallelic pathogenic variants in this family—one of which was a synonymous change not identified by prior clinical testing—not only ended the diagnostic odyssey for this family but also highlights the contribution of occult pathogenic variants that may not be recognized by standard genetic testing methodologies.

Abstract 10137: Functional Brain Imaging Reveals Decreased Cerebellar Volume and Altered Brain Connectivity in Pulmonary Arterial Hypertension

Introduction: Psychiatric and cognitive deficiencies are increasingly appreciated in pulmonary arterial hypertension (PAH). Brain abnormalities potentially underlying these disease manifestations have been ill-defined. Hypothesis: Altered brain structure and functional connectivity correlate with neurocognitive changes in PAH patients. Methods: PAH patients at UPMC were enrolled from 2017 to 2018. Participants underwent T1/T2 structural and resting functional brain MRI (fMRI) in addition to cognitive testing. Case data were compared in a 1:4 ratio to that of age-, gender-, and education-matched non-PAH controls. Linear regression analysis with clustered sandwich estimator and adjustment for multiple hypothesis testing was used for comparisons. Most recent hemodynamic data for PAH patients were reviewed including pulmonary vascular resistance (PVR). Pearson correlations were computed between PVR and brain volumes. Results: 12 PAH patients (median age, 45 years [range 26-61]; 9 women) were enrolled. T1/T2 MRI analysis identified 18 regions with volumetric differences (q&lt;0.05), with notable involvement of limbic (6/18, 33%) and basal ganglia (4/18, 22%) structures. PAH patients showed decreased left cerebellar cortical (45178 ± 1417 vs 53295 ± 583 mm 3 ; q=0.01) and right cerebellar white matter volumes (16458 ± 727 vs 39675 ± 5846 mm 3 ; q=0.018). Structural changes concorded with results from fMRI analysis: PAH patients had decreased functional connectivity in the left cerebellum (q=0.003). Corresponding with modulation of executive functions by the cerebellum, a trend was seen toward decreased inhibitory control and attention (83 ± 3 vs 95 ± 1; q=0.07) and pattern comparison processing speed (93 ± 5 vs 106 ± 4; q=0.07) in PAH patients. A trend toward negative correlation of PVR with left cerebellar white matter volume (r = -0.82, q = 0.06) was also observed. Conclusion: Limbic, basal ganglia, and cerebellar regions were smaller and less functionally connected in PAH cases than in matched controls. Decreased cerebellar volume may correlate with more severe hemodynamic disease. Any links among brain changes, cognitive dysfunction, and PAH pathophysiology deserve further study and may lead to neurologic modalities to diagnose and treat disease.

Cerebellar White Matter Abnormalities in Charcot-Marie-Tooth Disease: A Combined Volumetry and Diffusion Tensor Imaging Analysis.

Charcot–Marie–Tooth disease (CMT) is a genetically heterogeneous hereditary peripheral neuropathy. Brain volumetry and diffusion tensor imaging (DTI) were performed in 47 controls and 47 CMT patients with PMP22 duplication (n = 10), MFN2 (n = 15), GJB1 (n = 11), or NEFL mutations (n = 11) to investigate for structural changes in the cerebellum. Volume of cerebellar white matter (WM) was significantly reduced in CMT patients with NEFL mutations. Abnormal DTI findings were observed in the superior, middle, and inferior cerebellar peduncles, predominantly in NEFL mutations and partly in GJB1 mutations. Cerebellar ataxia was more prevalent in the NEFL mutation group (72.7%) than the GJB1 mutation group (9.1%) but was not observed in other genotypic subtypes, which indicates that structural cerebellar abnormalities were associated with the presence of cerebellar ataxia. However, NEFL and GJB1 mutations did not affect cerebellar gray matter (GM), and neither cerebellar GM nor WM abnormalities were observed in the PMP22 duplication or MFN2 mutation groups. We found structural evidence of cerebellar WM abnormalities in CMT patients with NEFL and GJB1 mutations and an association between cerebellar WM involvement and cerebellar ataxia in these genetic subtypes, especially in the NEFL subgroup. Therefore, we suggest that neuroimaging, such as MRI volumetry or DTI, for CMT patients could play an important role in detecting abnormalities of cerebellar WM.

Cerebellar Cortex and Cerebellar White Matter Volume in Normal Cognition, Mild Cognitive Impairment, and Dementia.

The cerebellum is commonly viewed as a structure that is primarily responsible for the coordination of voluntary movement, gait, posture, and speech. Recent research has shown evidence that the cerebellum is also responsible for cognition. We analyzed 28 participants divided into three groups (9 with normal cognition, 9 with mild cognitive impairment, and 10 with moderate/severe cognitive impairment) based on the Montreal Cognitive Assessment. We analyzed the cerebellar cortex and white matter volume and assessed differences between groups. Participants with normal cognition had higher average values in total cerebellar volume, cerebellar white matter volume, and cerebellar cortex volume in both hemispheres, but by performing the Kruskal–Wallis test, we did not find these values to be statistically significant.

Design-based stereological study of the guinea-pig (Cavia porcellus) cerebellum.

Guinea pigs have proved useful as experimental animal models in studying cerebellar anatomical and structural alterations in human neurological disease; however, they are also currently acquiring increasing veterinary interest as companion animals. The morphometric features of the normal cerebellum in guinea pigs have not been previously investigated using stereology. The objective of the present work was to establish normal volumetric and quantitative stereological parameters for cerebellar tissues in guinea pigs, by means of unbiased design-based stereology. Cerebellar total volume, gray and white matter volume fractions, molecular and granular layers volume fractions, cerebellar surface area, Purkinje cellular and nuclear volumes, and the Purkinje cell total count were stereologically estimated. For this purpose, cerebellar hemispheres from six adult male guinea pigs were employed. Isotropic, uniform random sections were obtained by applying the orientator method, and subsequently processed for light microscopy. The cerebellar total volume, the white and grey matter volume fractions, and the molecular and granular layer volumes were estimated using the Cavalieri's principle and the point counting system. The cerebellar surface area was estimated through the use of test lines; Purkinje cellular and nuclear volumes were analysed using the nucleator technique, whereas the Purkinje cell total count was obtained by means of the optical disector technique. The mean±standard deviation total volume of a guinea-pig cerebellar hemisphere was 0.11±0.01cm3 . The mean volumetric proportions occupied by the gray and white matters were, respectively, 78.0±2.6% and 22.0±2.6%, whereas their mean absolute volumes were found to be 0.21±0.02cm3 and 0.059±0.006cm3 . The volumes of the molecular and granular layers were estimated at 112.4±20.6mm3 and 104.4±7.3mm3 , whereas their mean thicknesses were calculated to be 0.184±0.020mm and 0.17±0.02mm. The molecular and granular layers accounted for 40.7±3.9% and 37.4±1.8% of total cerebellar volume respectively. The surface area of the cerebellum measured 611.4±96.8mm2 . Purkinje cells with a cellular volume of 3210.1µm3 and with a nuclear volume of 470.9µm3 had a higher incidence of occurrence. The mean total number of Purkinje cells for a cerebellar hemisphere was calculated to be 253,090±34,754. The morphometric data emerging from the present study provide a set of reference data which might prove valuable as basic anatomical contribution for practical applications in veterinary neurology.

The effects of early-treated phenylketonuria on volumetric measures of the cerebellum

Past murine studies of phenylketonuria (PKU) have documented significant effects on cerebellum at both the gross and cellular levels. The profile of neurocognitive and motor difficulties associated with early-treated PKU (ETPKU) is also consistent with potential cerebellar involvement. Previous neuroanatomical studies of cerebellum in patients with PKU, however, have yielded mixed results. The objective of the present study was to further examine potential differences in cerebellar morphometry between individuals with and without ETPKU. To this end, we analyzed high resolution T1-weighted MR images from a sample of 20 individuals with ETPKU and an age-matched comparison group of 20 healthy individuals without PKU. Measurements of whole brain volume, whole cerebellum volume, cerebellar gray matter volume, and cerebellar white matter volume were collected by means of semiautomatic volumetric analysis. Data analysis revealed no significant group differences in whole brain volume, whole cerebellar volume, or cerebellar white matter volume. A significant reduction in cerebellar gray matter volume, however, was observed for the ETPKU group compared to the non-PKU comparison group. These findings expand on previous animal work suggesting that cerebellar gray matter is impacted by PKU. It is also consistent with the hypothesis that the cognitive difficulties experienced by individuals with ETPKU may be related to disruptions in gray matter. Additional studies are needed to fully elucidate the timing and extent of the impact of ETPKU on cerebellum and the associated neurocognitive consequences.

Resilience and Vulnerability: Neurodevelopment of Very Preterm Children at Four Years of Age.

Children born very preterm (VPT) are at high-risk for altered brain development and impaired neurodevelopmental outcomes but are not well-studied before school-age. We investigated 64 four-year-olds: 37 VPT children [<32 weeks gestational age [GA]; 22 males; mean GA: 28.8 weeks ± 1.6], 25 full-term (FT) children (12 males), plus two VPT cases with ventriculomegaly and exceptionally resilient outcomes. All children underwent high-resolution structural magnetic resonance imaging and developmental assessments. Measures of brain volume, cortical thickness, and surface area were obtained. Children born VPT demonstrated reduced cerebral and cerebellar white matter volumes yet increased cerebral gray matter, temporal lobe, occipital lobe and ventricle volumes after adjusting for total brain volume. Cortical thickness was greater in the VPT children compared to FT children across all lobes. On developmental assessments, the VPT children scored lower on average than FT children while the two cases had intact cognitive abilities. In addition to larger ventricle volumes, the two cases had white matter and gray matter volumes within the ranges of the FT children. The VPT children displayed distinct differences in structural brain volumes at 4 years of age, consistent with delayed maturation. The cases with persistent ventriculomegaly and good cognitive outcomes displayed typical gray matter and increased white matter volumes, indicating a potential protective developmental phenomenon contributing to their intact cognitive abilities.

Acoustic Speech Analytics Are Predictive of Cerebellar Dysfunction in Multiple Sclerosis.

Speech production relies on motor control and cognitive processing and is linked to cerebellar function. In diseases where the cerebellum is impaired, such as multiple sclerosis (MS), speech abnormalities are common and can be detected by instrumental assessments. However, the potential of speech assessments to be used to monitor cerebellar impairment in MS remains unexplored. The aim of this study is to build an objectively measured speech score that reflects cerebellar function, pathology and quality of life in MS. Eighty-five people with MS and 21 controls participated in the study. Speech was independently assessed through objective acoustic analysis and blind expert listener ratings. Cerebellar function and overall disease disability were measured through validated clinical scores; cerebellar pathology was assessed via magnetic resonance imaging, and validated questionnaires informed quality of life. Selected speech variables were entered in a regression model to predict cerebellar function. The resulting model was condensed into one composite speech score and tested for prediction of abnormal 9-hole peg test (9HPT), and for correlations with the remaining cerebellar scores, imaging measurements and self-assessed quality of life. Slow rate of syllable repetition and increased free speech pause percentage were the strongest predictors of cerebellar impairment, complemented by phonatory instability. Those variables formed the acoustic composite score that accounted for 54% of variation in cerebellar function, correlated with cerebellar white matter volume (r = 0.3, p =0.017), quality of life (r = 0.5, p < 0.001) and predicted an abnormal 9HPT with 85% accuracy. An objective multi-feature speech metric was highly representative of motor cerebellar impairment in MS.

Morphometrical study of the cat cerebellum using unbiased design-based stereology.

The objective of the present study was to investigate the morphometrical features of the cat cerebellum using design-based stereology. Cerebellar hemispheres from four male cats were examined. Isotropic, uniform random sections were obtained and processed for light microscopy. Cerebellar total volume (V), white (WM) and grey matter (GM) volume fractions, and the volumes of the molecular and granular layers were measured using the Cavalieri's estimator and the point counting system. Cerebellar surface area was estimated using test lines, and Purkinje cellular and nuclear volumes were analysed using the nucleator technique. The volume of the cat cerebellar hemispheres was 2.06±0.29cm3 . The relative volume fractions of the GM and WM were 70.6±2.6% and 29.3±2.6%, respectively. The surface area of the cerebellar hemisphere was 68.2±17.8cm2 . The volumes of the molecular and granular layers were estimated at 0.89±0.16cm3 and 0.56±0.1cm3 , respectively. The Purkinje cell volumes were found to be ranging from 1,717 to 28,489µm3 , of which cells with a perikaryon volume of 6,994µm3 had a higher incidence. The Purkinje nuclear volume was estimated at 440-3,561µm3 , and nuclei with a volume of 1,252µm3 were the most frequently occurring ones. Our data might contribute to the veterinary comparative neuroanatomy knowledge, help develop experimental studies in this field, and possibly lead to advancement in the diagnosis and treatment of nervous diseases in the cat.

Cerebellar volume loss in radiologically isolated syndrome

Radiologically isolated syndrome (RIS), in which asymptomatic demyelinating-appearing lesions are detected incidentally on MRI, can be a pre-clinical form of multiple sclerosis (MS). In this study, we measured cerebellar volumes on 3D T1-weighted 3T MR images in 21 individuals with RIS and 38 age- and sex-matched healthy controls (HC). Normalized cerebellar white matter volume and the anterior cerebellar gray matter volume were significantly decreased in RIS compared to HC (p = 0.003 and p = 0.005, respectively). Our findings support reports of regional brain atrophy in RIS prior to the development of a seminal attack related to inflammatory demyelination.

Neuroanatomical alterations in people with high and low cannabis dependence

We aimed to investigate whether severity of cannabis dependence is associated with the neuroanatomy of key brain regions of the stress and reward brain circuits. To examine dependence-specific regional brain alterations, we compared the volumes of regions relevant to reward and stress, between high-dependence cannabis users (CD+, n = 25), low-dependence cannabis users (CD-, n = 20) and controls (n = 37). Compared to CD- and/or controls, the CD+ group had lower cerebellar white matter and hippocampal volumes, and deflation of the right hippocampus head and tail. These findings provide initial support for neuroadaptations involving stress and reward circuits that are specific to high-dependence cannabis users.

Atrophy of cerebellar peduncles in essential tremor: a machine learning-based volumetric analysis.

Subtle cerebellar signs are frequently observed in essential tremor (ET) and may be associated with cerebellar dysfunction. This study aims to evaluate the macrostructural integrity of the superior, middle, and inferior cerebellar peduncles (SCP, MCP, ICP) and cerebellar gray and white matter (GM, WM) volumes in patients with ET, and compare these volumes between patients with and without cerebellar signs (ETc and ETnc). Forty patients with ET and 37 age- and gender-matched healthy controls were recruited. Atlas-based region-of-interest analysis of the SCP, MCP, and ICP and automated analysis of cerebellar GM and WM volumes were performed. Peduncular volumes were employed in a multi-variate classification framework to attempt discrimination of ET from controls. Significant atrophy of bilateral MCP and ICP and bilateral cerebellar GM was observed in ET. Cerebellar signs were present in 20% of subjects with ET. Comparison of peduncular and cerebellar volumes between ETnc and ETc revealed atrophy of right SCP, bilateral MCP and ICP, and left cerebellar WM in ETc. The multi-variate classifier could discriminate between ET and controls with a test accuracy of 86.66%. Patients with ET have significant atrophy of cerebellar peduncles, particularly the MCP and ICP. Additional atrophy of the SCP is observed in the ETc group. These abnormalities may contribute to the pathogenesis of cerebellar signs in ET. • Patients with ET have significant atrophy of bilateral middle and inferior cerebellar peduncles and cerebellar gray matter in comparison with healthy controls. • Patients of ET with cerebellar signs have significant atrophy of right superior cerebellar peduncle, bilateral middle and inferior cerebellar peduncle, and left cerebellar white matter in comparison with ET without cerebellar signs. • A multi-variate classifier employing peduncular volumes could discriminate between ET and controls with a test accuracy of 86.66%.

Genetic and environmental influences on structural brain measures in twins with autism spectrum disorder

Atypical growth patterns of the brain have been previously reported in autism spectrum disorder (ASD) but these alterations are heterogeneous across individuals, which may be associated with the variable effects of genetic and environmental influences on brain development. Monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD (aged 6–15 years) were recruited to participate in this study. T1-weighted MRIs (n = 164) were processed with FreeSurfer to evaluate structural brain measures. Intra-class correlations were examined within twin pairs and compared across diagnostic groups. ACE modeling was also completed. Structural brain measures, including cerebral and cerebellar gray matter (GM) and white matter (WM) volume, surface area, and cortical thickness, were primarily influenced by genetic factors in TD twins; however, mean curvature appeared to be primarily influenced by environmental factors. Similarly, genetic factors accounted for the majority of variation in brain size in twins with ASD, potentially to a larger extent regarding curvature and subcortical GM; however, there were also more environmental contributions in twins with ASD on some structural brain measures, such that cortical thickness and cerebellar WM volume were primarily influenced by environmental factors. These findings indicate potential neurobiological outcomes of the genetic and environmental risk factors that have been previously associated with ASD and, although preliminary, may help account for some of the previously outlined neurobiological heterogeneity across affected individuals. This is especially relevant regarding the role of genetic and environmental factors in the development of ASD, in which certain brain structures may be more sensitive to specific influences.

Brain morphometry of preschool age children affected by autism spectrum disorder: Correlation with clinical findings.

The aim of our study was to use a combined imaging and clinical approach to identify possible patterns of clinical and imaging findings in a cohort of preschool age autism spectrum disorder (ASD) patients. In order to identify imaging patterns that could be related to specific clinical features, a selected group of ASD patients (age range 3-6 years) without dysmorphic features, epilepsy or other major neurological signs, malformations or other lesions at MRI was subjected to brain volumetric analysis using semiautomatic brain segmentation. An age-matched group of typically developing children was subjected to the same analysis. Our results were consistent with previous literature: Total gray matter volume, total cortical gray matter volume and amygdalar volumes were significantly greater in the ASD group than the control group. When we divided the study group into subgroups on the basis of clinical findings such as high- or low-functioning, or verbal and nonverbal, the only significant difference between verbal and nonverbal subjects was in cerebellar hemispheric size. In conclusions, our results confirm that newer brain MRI techniques using semiautomatic brain segmentation can provide information useful for defining the differences between ASD patients and controls, particularly if they form part of an integrated approach between MRI and cognitive-behavioral and genetic data. Clin. Anat. 32:143-150, 2019. © 2018 Wiley Periodicals, Inc. HIGHLIGHTS: Combined imaging and clinical approach in autism spectrum disorders Semiautomatic brain segmentation in a selected preschool age ASD group Reduced total cerebellar white matter volume in non-verbal ASD patients.

Cerebellar development and its mediation role in cognitive planning in childhood.

Recent evidence suggests that the cerebellum contributes not only to the planning and execution of movement but also to the high-order cognitive planning. Childhood is a critical period for development of the cerebellum and cognitive planning. This study aimed (a) to examine the development of cerebellar morphology and microstructure and (b) to examine the cerebellar mediation roles in the relationship between age and cognitive planning in 6- to 10-year-old children (n = 126). We used an anatomical parcellation to quantify cerebellar regional gray matter (GM) and white matter (WM) volumes, and WM microstructure, including fractional anisotropy (FA) and mean diffusivity (MD). We assessed planning ability using the Stockings of Cambridge (SOC) task in all children. We revealed (a) a measure-specific anterior-to-posterior gradient of the cerebellar development in childhood, that is, smaller GM volumes and greater WM FA of the anterior segment of the cerebellum but larger GM volumes and lower WM FA in the posterior segment of the cerebellum in older children; (b) an age-related improvement of the SOC performance at the most demanding level of five-move problems; and (c) a mediation role of the lateral cerebellar WM volumes in age-related improvement in the SOC performance in childhood. These results highlight the differential development of the cerebellum during childhood and provide evidence that brain adaptation to the acquisition of planning ability during childhood could partially be achieved through the engagement of the lateral cerebellum.

Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study.

BackgroundGM1-gangliosidosis and GM2-gangliosidosis (Tay-Sachs disease and Sandhoff disease) are unrelenting heritable neurodegenerative conditions of lysosomal ganglioside accumulation. Although progressive brain atrophy is characteristic, longitudinal quantification of specific brain structures has not been systematically studied.ObjectivesThe goal of this longitudinal study has been to quantify and track brain MRI volume changes, including specific structure volume changes, at different times in disease progression of childhood gangliosidoses, and to explore quantitative brain MRI volumetry (qMRI) as a non-invasive marker of disease progression for future treatment trials.MethodsBrain qMRI studies were performed in 14 patients with gangliosidoses (9 infantile, 5 juvenile) yearly. Cerebellar cortex and white matter, caudate, putamen, corpus callosum, ventricles, total brain, and intracranial volumes were measured, as well as total brain volume. Age-matched controls were available for the patients with the juvenile phenotype.ResultsThe infantile phenotype of all gangliosidoses showed a consistent pattern of macrocephaly and rapidly increasing intracranial MRI volume with both (a) brain tissue volume (cerebral cortex and other smaller structures) and (b) ventricular volume (P < 0.01 for all). In contrast to apparent enlargement of the total brain volume, and chiefly the enlarged cerebral cortex, a subset of smaller brain substructures generally decreased in size: the corpus callosum, caudate and putamen became smaller with time. The volume of cerebellar cortex also decreased in patients with infantile GM1-gangliosidosis and juvenile GM1- and GM2-gangliosidosis; however, infantile GM2-gangliosidosis cerebellar cortex was the exception, increasing in size. Elevated intracranial pressure (estimated by lumbar spinal pressure) was a common finding in infantile disease and showed continued increases as the disease progressed, yet lacked MRI signs of hydrocephalus except for increasing ventricular size. Notably, in patients with juvenile gangliosidosis, macrocephaly and elevated intracranial pressure were absent and total brain volume decreased with time compared to controls (P = 0.004).ConclusionsThe disease course of infantile versus juvenile gangliosidoses is clearly distinguished by the rate of brain disease progression as characterized by qMRI. Assessments by qMRI represent a robust non-invasive method for monitoring CNS changes in the clinical course of gangliosidoses and is ideally suited to monitor effects of novel CNS-directed therapies in future clinical trials.

Neuroanatomical differences in FAST and SLOW rat strains with differential vulnerability to kindling and behavioral comorbidities.

The neurobiological factors underlying a predisposition towards developing epilepsy and its common behavioral comorbidities are poorly understood. FAST rats are a strain that has been selectively bred for enhanced vulnerability to kindling, while the SLOW strain has been bred to be resistant to kindling. FAST rats also exhibit behavioral traits reminiscent of those observed in neurodevelopmental disorders (autism spectrum disorder (ASD)/attention-deficit/hyperactivity disorder (ADHD)) commonly comorbid with epilepsy. In this study, we aimed to investigate neuroanatomical differences between these strains that may be associated with a differential vulnerability towards these interrelated disorders. Ex vivo high-resolution magnetic resonance imaging on adult male FAST and SLOW rat brains was performed to identify morphological differences in regions of interest between the two strains. Behavioral examination using open-field, water consumption, and restraint tests was also conducted on a subgroup of these rats to document their differential ASD/ADHD-like behavior phenotype. Using optical stereological methods, the volume of cerebellar granule, white matter, and molecular layer and number of Purkinje cells were compared in a separate cohort of adult FAST and SLOW rats. Behavioral testing demonstrated hyperactivity, impulsivity, and polydipsia in FAST versus SLOW rats, consistent with an ASD/ADHD-like phenotype. Magnetic resonance imaging analysis identified brain structural differences in FAST compared with SLOW rats, including increased volume of the cerebrum, corpus callosum, third ventricle, and posterior inferior cerebellum, while decreased volume of the anterior cerebellar vermis. Stereological measurements on histological slices indicated significantly larger white matter layer volume, reduced number of Purkinje cells, and smaller molecular layer volume in the cerebellum in FAST versus SLOW rats. These findings provide evidence of structural differences between the brains of FAST and SLOW rats that may be mechanistically related to their differential vulnerability to kindling and associated comorbid ASD/ADHD-like behaviors.