Reduction In Cerebellar Volume Research Articles

Decreased gray matter volume in the anterior cerebellar of attention deficit/hyperactivity disorder comorbid oppositional defiant disorder children with associated cerebellar-cerebral hyperconnectivity: insights from a combined structural MRI and resting-state fMRI study.

Attention deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) are highly comorbid. Many prior investigations have found that ADHD relates to anatomical abnormalities in gray matter. The abnormal gray matter of ADHD comorbid ODD is still poorly understood. This study aimed to explore the effect of comorbid ODD on gray matter volume (GMV) and functional alterations in ADHD. All data were provided by the ADHD-200 Preprocessed Repository, including 27 ADHD-only children, 27 ADHD + ODD children, and 27 healthy controls aged 9-14 years. Voxel-based morphometry (VBM) and functional connectivity (FC) of resting-state functional magnetic resonance imaging (fMRI) were used to compare the difference in GMV and FC between ADHD + ODD, ADHD-only, and healthy children. The results showed that ADHD children with comorbid ODD had a more significant reduction in cerebellar volume, mainly in the anterior regions of the cerebellum (Cerebellum_4_5). The Cerebellum_4_5 showed increased functional connectivity with multiple cortical regions. These brain regions include numerous executive functioning (EF) and brain default mode network (DMN) nodes. The GMV abnormalities and excessive connectivity between brain regions may further exacerbate the emotional and cognitive deficits associated with ADHD.

Cerebellar Volume Reduction in Patients with Isolated REM Sleep Behavior Disorder: Evidence of a Potential Role of the Cerebellum

Introduction: In this study, we aimed to investigate changes in the total cerebellar volume, subdivisions of the cerebellar volume, and intrinsic cerebellar network in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD) compared to healthy controls. Methods: We enrolled patients with newly diagnosed iRBD and healthy controls who had no structural lesions according to their brain MRI. All participants underwent three-dimensional T1-weighted imaging. We obtained the total cerebellar volume and subdivisions of the cerebellar volume using the ACAPULCO program and calculated the intrinsic cerebellar network using a BRAPH program based on the subdivisions of the cerebellar volume by applying a graph theory. We compared the cerebellar volumes and intrinsic cerebellar network between the patients with iRBD and healthy controls. Results: In total, we enrolled 43 patients with iRBD and 47 healthy controls. Total cerebellar volume in patients with iRBD was lower than that in the healthy controls (8.4637 vs. 9.0863%, p = 0.0001). There were significant differences in the subdivisions of cerebellar volume between the groups. The volumes of the right and left lobule VIIB in the patients with iRBD were lower than those in the healthy controls (right, 0.3495 vs. 0.4025%, p = 0.0009; left, 0.3561 vs. 0.4293%, p < 0.0001). However, the other cerebellar volumes, such as the corpus meullare and vermis, were not different between the groups. The intrinsic cerebellar network was not different between the patients with iRBD and healthy controls. Conclusion: We found decreased total cerebellar volumes and subdivisions of the cerebellar volume, particularly in the right and left lobule VIIB, in patients with iRBD compared to healthy controls. The present results suggest that the cerebellum may play a potential role in the pathogenesis of iRBD.

Consensus Paper: Cerebellum and Ageing.

Given the key roles of the cerebellum in motor, cognitive, and affective operations and given the decline of brain functions with aging, cerebellar circuitry is attracting the attention of the scientific community. The cerebellum plays a key role in timing aspects of both motor and cognitive operations, including for complex tasks such as spatial navigation. Anatomically, the cerebellum is connected with the basal ganglia via disynaptic loops, and it receives inputs from nearly every region in the cerebral cortex. The current leading hypothesis is that the cerebellum builds internal models and facilitates automatic behaviors through multiple interactions with the cerebral cortex, basal ganglia and spinal cord. The cerebellum undergoes structural and functional changes with aging, being involved in mobility frailty and related cognitive impairment as observed in the physio-cognitive decline syndrome (PCDS) affecting older, functionally-preserved adults who show slowness and/or weakness. Reductions in cerebellar volume accompany aging and are at least correlated with cognitive decline. There is a strongly negative correlation between cerebellar volume and age in cross-sectional studies, often mirrored by a reduced performance in motor tasks. Still, predictive motor timing scores remain stable over various age groups despite marked cerebellar atrophy. The cerebello-frontal network could play a significant role in processing speed and impaired cerebellar function due to aging might be compensated by increasing frontal activity to optimize processing speed in the elderly. For cognitive operations, decreased functional connectivity of the default mode network (DMN) is correlated with lower performances. Neuroimaging studies highlight that the cerebellum might be involved in the cognitive decline occurring in Alzheimer's disease (AD), independently of contributions of the cerebral cortex. Grey matter volume loss in AD is distinct from that seen in normal aging, occurring initially in cerebellar posterior lobe regions, and is associated with neuronal, synaptic and beta-amyloid neuropathology. Regarding depression, structural imaging studies have identified a relationship between depressive symptoms and cerebellar gray matter volume. In particular, major depressive disorder (MDD) and higher depressive symptom burden are associated with smaller gray matter volumes in the total cerebellum as well as the posterior cerebellum, vermis, and posterior Crus I. From the genetic/epigenetic standpoint, prominent DNA methylation changes in the cerebellum with aging are both in the form of hypo- and hyper-methylation, and the presumably increased/decreased expression of certain genes might impact on motor coordination. Training influences motor skills and lifelong practice might contribute to structural maintenance of the cerebellum in old age, reducing loss of grey matter volume and therefore contributing to the maintenance of cerebellar reserve. Non-invasive cerebellar stimulation techniques are increasingly being applied to enhance cerebellar functions related to motor, cognitive, and affective operations. They might enhance cerebellar reserve in the elderly. In conclusion, macroscopic and microscopic changes occur in the cerebellum during the lifespan, with changes in structural and functional connectivity with both the cerebral cortex and basal ganglia. With the aging of the population and the impact of aging on quality of life, the panel of experts considers that there is a huge need to clarify how the effects of aging on the cerebellar circuitry modify specific motor, cognitive, and affective operations both in normal subjects and in brain disorders such as AD or MDD, with the goal of preventing symptoms or improving the motor, cognitive, and affective symptoms.

Reduction of Microvessel Number and Length in the Cerebellum of Purkinje Cell Degeneration Mice.

Degenerative effects of nerve tissues are often accompanied by changes in vascularization. In this regard, knowledge about hereditary cerebellar degeneration is limited. In this study, we compared the vascularity of the individual cerebellar components of 3-month-old wild-type mice (n = 8) and Purkinje cell degeneration (pcd) mutant mice, which represent a model of hereditary cerebellar degeneration (n = 8). Systematic random samples of tissue sections were processed, and laminin was immunostained to visualize microvessels. A computer-assisted stereology system was used to quantify microvessel parameters including total number, total length, and associated densities in cerebellar layers. Our results in pcd mice revealed a 45% (p < 0.01) reduction in the total volume of the cerebellum, a 28% (p < 0.05) reduction in the total number of vessels and a lower total length, approaching 50% (p < 0.001), compared to the control mice. In pcd mutants, cerebellar degeneration is accompanied by significant reduction in the microvascular network that is proportional to the cerebellar volume reduction therefore does not change density of in the cerebellar gray matter of pcd mice.

Disease progression and brain atrophy in NMDAR encephalitis: Associated factor &amp; clinical implication

ObjectiveWe investigated the longitudinal pattern, determining factors, and clinical implications of brain volume changes in N‐methyl d‐aspartate receptor‐antibody (NMDAR) encephalitis.MethodsBaseline clinical profiles, treatment profiles, and outcome measured using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) and modified Rankin scale (mRS) were obtained from a long‐term clinical database documenting an NMDAR encephalitis cohort. In serial MRI, the change in the normalized volume of different brain regions from the baseline evaluation was measured. At each MRI evaluation time point, the cumulative disease burden (CASE score × months) and the cumulative duration of status epilepticus were also evaluated.ResultsThirty‐six patients were followed‐up for 28.5 months (range 12–63 months). The volume ratio at last MRI to baseline was the lowest in the cerebellum (94.4 ± 5.7%, p < 0.001). Once developed, cerebellar volume reduction followed a progressive course until 2 years from disease onset. The degree of cerebellar volume reduction was positively correlated with mRS and total CASE scores (all, p < 0.001), and CASE scores in the domains of memory, language, and psychiatric problems, gait instability/ataxia, and weakness (all, p < 0.01). In linear mixed model analyses, the degree of cerebellar volume reduction was associated with cumulative disease burden up to 2 years (p < 0.001) and duration of status epilepticus (p < 0.001), and delayed removal of teratoma for ≥1 month (p = 0.006).InterpretationIn NMDAR encephalitis, cerebellar volume reduction was progressive once developed. Cerebellar volume reduction might reflect disease burden and extent of progression and be associated with poor outcomes in multiple functional domains.

Association between acute kidney injury and brain injury on term-equivalent age brain magnetic resonance imaging in very preterm infants.

This study aimed to investigate the relationship between acute kidney injury (AKI) in the first 2weeks of life and brain injury on term-equivalent age magnetic resonance imaging in very preterm infants. We included 116 infants with a birth weight of < 1500g who were born at the King Saud Medical City at ≤ 32 gestational weeks. They were admitted to the neonatal intensive care unit and underwent term-equivalent age and pre-discharge brain magnetic resonance imaging. A negative binomial with generalized linear models and a robust variance estimator (Huber-White) was applied for univariate relative risk analysis. The Kidokoro score was then used to determine the effect of AKI on brain morphology and growth at term-equivalent age. Sixty-eight (64.2%) infants had developed an AKI in the first 2weeks of life. AKI was significantly associated with cerebellum signal abnormalities, cerebellar volume reduction, and a high total cerebellum score (P = 0.04, P < 0.001, P < 0.001, respectively). AKI in the first 2weeks of life is associated with brain insult, especially in the cerebellum. More well-designed studies are required to investigate the association and impact of AKI on the central nervous system. A higher resolution version of the Graphical abstract is available as Supplementary information.

Structural brain abnormalities in epilepsy with myoclonic atonic seizures

ObjectiveEpilepsy with myoclonic atonic seizure (EMAS) occurs in young children with previously normal to subnormal development. The outcome ranges from seizure freedom with preserved cognitive abilities to refractory epilepsy with intellectual disability (ID). Routine brain imaging typically shows no abnormalities. We aimed to compare the brain morphometry of EMAS patients with healthy subjects several years after epilepsy onset, and to correlate it to epilepsy severity and cognitive findings. MethodsFourteen EMAS patients (4 females, 5–14 years) and 14 matched healthy controls were included. Patients were classified into three outcome groups (good, intermediate, poor) according to seizure control and cognitive and behavioral functioning. Individual anatomical data (T1-weighted sequence) were processed using the FreeSurfer pipeline. Cortical volume (CV), cortical thickness (CT), local gyrification index (LGI), and subcortical volumes were used for group-comparison and linear regression analyses. ResultsMorphometric comparison between EMAS patients and healthy controls revealed that patients have 1) reduced CV in frontal, temporal and parietal lobes (p = <.001; 0.009 and 0.024 respectively); 2) reduced CT and LGI in frontal lobes (p = 0.036 and 0.032 respectively); and 3) a neat cerebellar volume reduction (p = 0.011). Neither the number of anti-seizure medication nor the duration of epilepsy was related to cerebellar volume (both p > 0.62). Poor outcome group was associated with lower LGI. Patients in good and intermediate outcome groups had a comparable LGI to their matched healthy controls (p > 0.27 for all lobes). ConclusionsStructural brain differences were detectable in our sample of children with EMAS, mainly located in the frontal lobes and cerebellum. These findings are similar to those found in patients with genetic/idiopathic generalized epilepsies. Outcome groups correlated best with LGI. Whether these anatomical changes reflect genetically determined abnormal neuronal networks or a consequence of sustained epilepsy remains to be solved with prospective longitudinal studies.

Regional Cerebellar Volume Loss Predicts Future Disability in Multiple Sclerosis Patients

Cerebellar symptoms in multiple sclerosis (MS) are well described; however, the exact contribution of cerebellar damage to MS disability has not been fully explored. Longer-term observational periods are necessary to better understand the dynamics of pathological changes within the cerebellum and their clinical consequences. Cerebellar lobe and single lobule volumes were automatically segmented on 664 3D-T1-weighted MPRAGE scans (acquired at a single 1.5 T scanner) of 163 MS patients (111 women; mean age: 47.1 years; 125 relapsing–remitting (RR) and 38 secondary progressive (SP) MS, median EDSS: 3.0) imaged annually over 4 years. Clinical scores (EDSS, 9HPT, 25FWT, PASAT, SDMT) were determined per patient per year with a maximum clinical follow-up of 11 years. Linear mixed-effect models were applied to assess the association between cerebellar volumes and clinical scores and whether cerebellar atrophy measures may predict future disability progression. SPMS patients exhibited faster posterior superior lobe volume loss over time compared to RRMS, which was related to increase of EDSS over time. In RRMS, cerebellar volumes were significant predictors of motor scores (e.g. average EDSS, T25FWT and 9HPT) and SDMT. Atrophy of motor-associated lobules (IV-VI + VIII) was a significant predictor of future deterioration of the 9HPT of the non-dominant hand. In SPMS, the atrophy rate of the posterior superior lobe (VI + Crus I) was a significant predictor of future PASAT performance deterioration. Regional cerebellar volume reduction is associated with motor and cognitive disability in MS and may serve as a predictor for future disease progression, especially of dexterity and impaired processing speed.

Cortical volume reductions as a sign of secondary cerebral and cerebellar impairment in patients with degenerative cervical myelopathy

This study investigated supra- and infratentorial structural gray and white matter (GM, WM) alterations in patients with degenerative cervical myelopathy (DCM) as an indicator of secondary harm due to chronic cervical cord compression and micro trauma. With MRI-based anatomical assessment and subsequent voxel-based morphometry analyses, pre- and postoperative volume alterations in the primary motor cortex (MI), the primary somatosensory cortex (SI), the supplementary motor area (SMA), and the cerebellum were analyzed in 43 DCM patients and 20 controls. We assessed disease-related symptom severity by the modified Japanese Orthopaedic Association scale (mJOA). The study also explored symptom severity-based brain volume alterations as well as their association with clinical status. Patients had lower mJOA scores (p = .000) and lower GM volume than controls in SI (p = .016) and cerebellar regions (p = .001). Symptom severity-based subgroup analyses revealed volume reductions in almost all investigated GM ROIs (MI: p = .001; CB: p = .040; SMA: p = .007) in patients with severe clinical symptoms as well as atrophy already present in patients with moderate symptom severity. Clinical symptoms in DCM were associated with cortical and cerebellar volume reduction. GM volume alterations may serve as an indicator of both disease severity and ongoing disease progression in DCM, and should be considered in further patient care and treatment monitoring.

Postnatal alcohol exposure and adolescent exercise have opposite effects on cerebellar microglia in rat.

Developmental alcohol exposure results in altered neuroimmune function in both humans and rodents. Given the critical role for the principle neuroimmune cell, microglia, in maintaining synaptic form and function, microglial dysfunction in the cerebellum may be an important mechanism underlying the aberrant cerebellar connectivity observed in rodent models of fetal alcohol spectrum disorders. Using an established rodent model of alcohol exposure during human third-trimester fetal development, we examine the cerebellum of male and female Long Evans rats to determine the impact of early postnatal alcohol exposure on cerebellar microglia, and the potential therapeutic effects of an adolescent intervention consisting of voluntary exercise (running). All cerebelli were examined at postnatal day 42 (i.e., late adolescence), and microglia were labeled with Iba1, a microglia-specific protein. Early postnatal alcohol exposure caused an increase in microglial density throughout cerebellum and a reduction in cerebellar volume, and a reduction in the proportion of fully ramified (often called "resting state") microglia selective to lobules 1-4. In contrast, adolescent exercise decreased microglial density throughout cerebellum and increased cerebellar volume, while activating microglia (as indicated by increases in amoeboid microglia, and reductions in fully and partially ramified microglia) selectively in lobules 1-4. These results suggest that adolescent exercise may be a suitable intervention to ameliorate alcohol-induced neuroimmune dysfunction as it alters microglia density and cerebellar volume in opposite to the effects of developmental alcohol exposure. Importantly, exercise intervention can be flexibly implemented well after the time window of vulnerability to alcohol.

Clinical and MRI findings in two unrelated cats with globoid cell leucodystrophy

Two unrelated male cats, both five months old, were referred for progressive neurological signs characterised by intentional tremors, paraplegia with absence of nociception in the pelvic limbs, weakness, dysmetria with reduced flexor reflex in the thoracic limbs, and bilaterally reduced menace response. MRI, performed by a 0.25 T Esaote Vet Grande, showed diffuse and irregular intramedullary T2 weighted hyperintensity between T3 and L3; these lesions were isointense on T1 weighted images without contrast uptake. In one patient MRI of the brain was obtained and mild cerebellar volume reduction was found. Histological examination of the brain and spinal cord demonstrated myelin loss and perivascular accumulation of periodic acid-Schiff-positive big macrophages. These findings were consistent with globoid cell leucodystrophy, as previously described in cats. Although not specific, in young cats with progressive spinal neurological signs, especially when associated with cerebellar signs, and irregular but diffuse T2 intramedullary hyperintensity and T1 isointensity without contrast uptake, globoid cell leucodystrophy should be suspected.

Impaired Cerebellar Maturation, Growth Restriction, and Circulating Insulin-Like Growth Factor 1 in Preterm Rabbit Pups

Cerebellar growth is impeded following very preterm birth in human infants and the observed reduction in cerebellar volume is associated with neurodevelopmental impairment. Decreased levels of circulating insulin-like growth factor 1 (IGF-1) are associated with decreased cerebellar volume. The relationship between preterm birth, circulating IGF-1, and key cell populations supporting cerebellar proliferation is unknown. The aim of this study was to evaluate the effect of preterm birth on postnatal growth, circulating IGF-1, and cerebellar maturation in a preterm rabbit pup model. Preterm rabbit pups (PT) were delivered by cesarean section at day 29 of gestation, cared for in closed incubators with humidified air, and gavage fed with formula. Control term pups (T) delivered by spontaneous vaginal delivery at day 32 of gestation were housed and fed by their lactating doe. In vivo perfusion-fixation for immunohistochemical evaluation of cerebellar proliferation, cell maturation, and apoptosis was performed at repeated time points in PT and T pups. Results show that the mean weight of the pups and circulating IGF-1 protein levels were lower in the PT group at all time points (p < 0.05) than in the T group. Postnatal weight development correlated with circulating IGF-1 (r² = 0.89) independently of gestational age at birth and postnatal age. The proliferative (Ki-67-positive) portion of the external granular layer (EGL) was decreased in the PT group at postnatal day 2 (P2) compared to in the T group (p = 0.01). Purkinje cells exhibited decreased calbindin staining at P0 (p = 0.003), P2 (p = 0.004), and P5 (p = 0.04) in the PT group compared to in the T group. Staining for sonic hedgehog was positive in neuronal EGL progenitors and Purkinje cells at early time points but was restricted to a well-defined Purkinje cell monolayer at later time points. Preterm birth in rabbit pups is associated with lower circulating levels of IGF-1, decreased postnatal growth, and decreased cerebellar EGL proliferation and Purkinje cell maturation. The preterm rabbit pup model exhibits important characteristics of human preterm birth, and may thus be suitable for the evaluation of interventions aiming to modify growth and cerebellar development in the preterm population.

Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls.

Although cerebellar involvement across a wide range of cognitive and neuropsychiatric phenotypes is increasingly being recognized, previous large-scale studies in schizophrenia (SZ) have primarily focused on supratentorial structures. Hence, the across-sample reproducibility, regional distribution, associations with cerebrocortical morphology and effect sizes of cerebellar relative to cerebral morphological differences in SZ are unknown. We addressed these questions in 983 patients with SZ spectrum disorders and 1349 healthy controls (HCs) from 14 international samples, using state-of-the-art image analysis pipelines optimized for both the cerebellum and the cerebrum. Results showed that total cerebellar grey matter volume was robustly reduced in SZ relative to HCs (Cohens's d=-0.35), with the strongest effects in cerebellar regions showing functional connectivity with frontoparietal cortices (d=-0.40). Effect sizes for cerebellar volumes were similar to the most consistently reported cerebral structural changes in SZ (e.g., hippocampus volume and frontotemporal cortical thickness), and were highly consistent across samples. Within groups, we further observed positive correlations between cerebellar volume and cerebral cortical thickness in frontotemporal regions (i.e., overlapping with areas that also showed reductions in SZ). This cerebellocerebral structural covariance was strongest in SZ, suggesting common underlying disease processes jointly affecting the cerebellum and the cerebrum. Finally, cerebellar volume reduction in SZ was highly consistent across the included age span (16-66 years) and present already in the youngest patients, a finding that is more consistent with neurodevelopmental than neurodegenerative etiology. Taken together, these novel findings establish the cerebellum as a key node in the distributed brain networks underlying SZ.

Regional brain volume reduction and cognitive outcomes in preterm children at low risk at 9years of age.

More information is needed on "low-risk" preterm infants' neurological outcome so that they can be included in follow-up programs. A prospective study was performed to examine the regional brain volume changes compared to term children and to assess the relationship between the regional brain volumes to cognitive outcome of the low-risk preterm children at 9years of age. Subjects comprised 22 preterm children who were determined to be at low risk for neurodevelopmental deficits with a gestational age between 28 and 33weeks without a major neonatal morbidity in the neonatal period and 24 age-matched term control children term and matched for age, sex, and parental educational and occupational status. Regional volumetric analysis was performed for cerebellum, hippocampus, and corpus callosum area. Cognitive outcomes of both preterm and control subjects were assessed by Weschler Intelligence Scale for Children Revised (Turkish version), and attention and executive functions were assessed by Wisconsin Card Sorting Test and Stroop Test TBAG version. Low-risk preterm children showed regional brain volume reduction in cerebellum, hippocampus, and corpus callosum area and achieved statistical significance when compared with term control. When the groups were compared for all WISC-R subscale scores, preterm children at low risk had significantly lower scores on information, vocabulary, similarities, arithmetics, picture completion, block design, object assembly, and coding compared to children born at term. Preterm and term groups were compared on the Stroop Test for mistakes and corrections made on each card, the time spent for completing each card, and total mistakes and corrections. In the preterm group, we found a positive correlation between regional volumes with IQ, attention, and executive function scores. Additionally, a significant correlation was found between cerebellar volume and attention and executive function scores in the preterm group. Low-risk preterm children achieve lower scores in neurophysiological tests than children born at term. Preterm birth itself has a significant impact on regional brain volumes and cognitive outcome of children at 9years of age. It is a risk factor for regional brain volume reductions in preterm children with low risk for neurodevelopmental deficits. The significant interaction between cerebellar volume reduction and executive function and attention may suggest that even in preterm children at low risk can have different trajectories in the growth and development of overall brain structure.

Correlation among Magnetic Resonance Imaging Parameters of Brain in Preterm Neonates at Term Equivalent Age.

To assess the spectrum of Magnetic Resonance Imaging (MRI) abnormalities among preterm babies at term equivalent age using objective scoring and to study the association among MRI variables. Ninety-four preterm babies born at ≤32 wk of gestation and / or birth weight≤1500g at term equivalent age who underwent cranial MRI between April 2011 and August 2012 and the MRI interpreted by experienced radiologists were studied. In 2014, the MRI was retrospectively re-interpreted by the same radiologists using an objective scoring system described by Kidokoro. Spectrum of MRI abnormalities, their association with perinatal variables and correlation among white matter (WM), grey matter and cerebellar scores were analyzed. MRI abnormalities observed were WM signal abnormality (24%), lateral ventricular dilatation (16%), WM cystic abnormality (13%), deep grey matter signal abnormality (9%), cerebellar volume reduction (9%) and deep grey matter volume reduction (8%). Sepsis was significantly associated with occurrence of WM and cerebellar abnormalities (p<0.05). WM scores did not show significant correlation with cortical grey matter and deep grey matter scores while cerebellar scores showed a weak positive correlation with WM (r=0.33), cortical grey matter (r=0.27) and deep grey matter scores (r=0.22). MRI abnormalities are common in preterm infants, with 60% showing some abnormality at term equivalent age. Among perinatal characteristics, sepsis was identified as risk factor for WM and cerebellar injury. Grey matter abnormality occurs independent of WM abnormality. Cerebellar abnormalities appear to coexist with either WM or grey matter changes.

Impaired growth of the cerebellum in pediatric-onset acquired CNS demyelinating disease

Background: Acquired demyelinating syndromes (ADS) have the potential to negatively impact cerebellar growth, given the proclivity for infratentorial lesions in pediatric-onset multiple sclerosis (MS) and ADS. Objective: To investigate cerebellar growth longitudinally in pediatric ADS. Methods: Cerebellar volumes from 472 magnetic resonance imaging (MRI) scans of 98 patients with monophasic ADS (monoADS), monophasic acute disseminated encephalomyelitis (ADEM), and MS (49 girls; mean age: 11.4 years at first scan, mean follow-up: 3.1 years) imaged serially from onset and 897 MRI scans of 418 healthy children (223 girls, mean age: 11.3 years, mean follow-up: 2.9 years) were segmented automatically, analyzed with mixed-effect models, and compared with cerebral volume. Results: Cerebellar developmental trajectories followed a U-shaped curve, showing larger volumes in boys (p < 0.001). Cerebellar volumes in all three patient groups failed to reach age-expected trajectories, leading to significantly smaller volumes, notably in the posterior lobes. Cerebellar volume reductions were of a similar magnitude to cerebral volume reductions. Cerebellar white matter volume declined in MS and ADEM patients over time, while in monoADS patients it remained similar to controls. Cerebellar volumes did not correlate either with lesion volumes at onset or with physical disability. Conclusion: MonoADS, ADEM, and MS in childhood lead to impaired age-expected growth of the cerebellum.

The association of DNA methylation and brain volume in healthy individuals and schizophrenia patients

Both methylation and brain volume patterns hold important biological information for the development and prognosis of schizophrenia (SZ). A combined study to probe the association between them provides a new perspective to understanding SZ. Genomic methylation of peripheral blood and regional brain volumes derived from magnetic resonance imaging were analyzed using parallel independent component analyses in this study. Nine methylation components and five brain volumetric components were extracted for 94 SZ patients and 106 healthy controls. After controlling for age, sex, race, and substance use, a component comprised primarily of bilateral cerebellar volumes was significantly correlated to a methylation component from 14 CpG sites in 13 genes. Both patients and healthy controls demonstrated similar associations, but patients had significantly smaller cerebellar volumes and dysmethylation in the associated epigenetic component compared to controls. The 13 genes are enriched in cellular growth and proliferation with some genes involved in neuronal growth and cerebellum development (GATA4, ADRA1D, EPHA3, and KCNK10), and these genes are prominently associated with neurological and psychological disorders. Such findings suggest that the methylation pattern of the genes coding for cellular growth may influence the cerebellar development through regulating gene expression, and the alteration in the methylation of these genes in SZ patients may contribute to the cerebellar volume reduction observed in patients.

Milestones in Friedreich ataxia: more than a century and still learning.

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia worldwide. This review highlights the main clinical features, pathophysiological mechanisms, and therapeutic approaches for FRDA patients. The disease is characterized by a combination of neurological involvement (ataxia and neuropathy), cardiomyopathy, skeletal abnormalities, and glucose metabolism disturbances. FRDA is caused by expanded guanine-adenine-adenine (GAA) triplet repeats in the first intron of the frataxin gene (FXN), resulting in reduction of messenger RNA and protein levels of frataxin in different tissues. The molecular and metabolic disturbances, including iron accumulation, lead to pathological changes characterized by spinal cord and dorsal root ganglia atrophy, dentate nucleus atrophy without global cerebellar volume reduction, and hypertrophic cardiomyopathy. DNA analysis is the hallmark for the diagnosis of FRDA. There is no specific treatment to stop the disease progression in FRDA patients. However, a number of drugs are under investigation. Therapeutic approaches intend to improve mitochondrial functioning and to increase FXN expression.

Importance of genetics in fetal alcohol effects: Null mutation of the nNOS gene worsens alcohol-induced cerebellar neuronal losses and behavioral deficits

The cerebellum is a major target of alcohol-induced damage in the developing brain. However, the cerebella of some children are much more seriously affected than others by prenatal alcohol exposure. As a consequence of in utero alcohol exposure, some children have substantial reductions in cerebellar volume and corresponding neurodevelopmental problems, including microencephaly, ataxia, and balance deficits, while other children who were exposed to similar alcohol quantities are spared. One factor that likely plays a key role in determining the impact of alcohol on the fetal cerebellum is genetics. However, no specific gene variant has yet been identified that worsens cerebellar function as a consequence of developmental alcohol exposure. Previous studies have revealed that mice carrying a homozygous mutation of the gene for neuronal nitric oxide synthase (nNOS−/− mice) have more severe acute alcohol-induced neuronal losses from the cerebellum than wild type mice. Therefore, the goals of this study were to determine whether alcohol induces more severe cerebellum-based behavioral deficits in nNOS−/− mice than in wild type mice and to determine whether these worsened behavior deficits are associated with worsened cerebellar neuronal losses. nNOS−/− mice and their wild type controls received alcohol (0.0, 2.2, or 4.4mg/g) daily over postnatal days 4–9. In adulthood, the mice underwent behavioral testing, followed by neuronal quantification. Alcohol caused dose-related deficits in rotarod and balance beam performance in both nNOS−/− and wild type mice. However, the alcohol-induced behavioral deficits were substantially worse in the nNOS−/− mice than in wild type. Likewise, alcohol exposure led to losses of Purkinje cells and cerebellar granule cells in mice of both genotypes, but the cell losses were more severe in the nNOS−/− mice than in wild type. Behavioral performances were correlated with neuronal number in the nNOS−/− mice, but not in wild type. Thus, homozygous mutation of the nNOS gene increases vulnerability to alcohol-induced cerebellar dysfunction and neuronal loss. nNOS is the first gene identified whose mutation worsens alcohol-induced cerebellar behavioral deficits.

Toward Defining the Neural Substrates of ADHD

Objective: We assessed the neural correlates of adult ADHD in treatment-naïve participants, an approach necessary for identifying neural substrates unconfounded by medication effects. Method: The sample consisted of 24 medication-naïve adults with Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) diagnosed ADHD and 24 healthy controls, comparable on age, sex, handedness, reading achievement, IQ, and psychiatric comorbidity. All participants were assessed with structured diagnostic interviews. Magnetic resonance imaging (MRI)-based regional voxel-based morphometry (r-VBM) was used to assess volumetric differences in a priori defined brain regions of interest. Results: VBM analysis revealed group differences in the hypothesized cortical and subcortical areas; however, only cerebellar volume reductions in ADHD retained significance (p < .05) after corrections for multiple comparisons. Conclusion: These results support the notion that medication-naïve ADHD as expressed in adulthood, manifests subtle brain volume reductions from normal in the cerebellum, and possibly in other syndrome-congruent gray-matter structures. Larger samples are required to confirm these findings.