Reduced volume of the cerebellar vermis in neuroleptic-naive schizophrenia.

BACKGROUND: Neuroimaging studies have suggested the possible role of the cerebellum in the pathophysiology of schizophrenia. However, no study has investigated the detailed structures of the cerebellum in patients without a history of neuroleptic medication. The objective of this study is to examine the volume of detailed structures of the cerebellum in neuroleptic-naive schizophrenic patients and to examine the relationship between cerebellar morphology and clinical symptoms. METHODS: Magnetic resonance imaging scans were acquired from 20 male neuroleptic-naive schizophrenic patients and 20 healthy control subjects. We measured the volumes of the cerebrum, cerebellar hemisphere, cerebellar gray and white matter, and vermis. Symptoms were assessed with the Brief Psychiatric Rating Scale. Total Brief Psychiatric Rating Scale scores and subscale scores were used for analysis. RESULTS: The volume of the vermis was significantly reduced in the schizophrenic group relative to the control group, whereas no significant differences were found in the volumes of other cerebellar structures and the cerebrum. Reduction in the vermal volume correlated with the total Brief Psychiatric Rating Scale Depression subscore and Paranoia subscore. CONCLUSIONS: This study indicates that the volume of the vermis is reduced in patients with schizophrenia, and reduction in vermal volume is suggested to be related to the pathophysiology of the disease.     

Differences in cerebellar blood volume in schizophrenia and bipolar disorder

Brain morphometry has been studied extensively in schizophrenic patients, and among the cortical differences identified two consistent findings are decreased cerebellar vermal volume and increased volume of the fourth ventricle; although contradictory findings are reported as well. Recent cognitive activation studies utilizing PET, SPECT and fMRI have identified both decreased and increased activation in the cerebellum of schizophrenic patients compared with healthy controls. This study used DSC fMRI to map cerebellar blood volume in patients with schizophrenia or bipolar disorder and healthy controls. For all cerebellar regions analyzed, schizophrenic patients had the highest cerebellar blood volume, while bipolars had the lowest blood volume. Morphometric measurements were completed and indicated that the ratio of vermis to whole CBL tissue volume was 24% less for the schizophrenic population than controls, whereas the subjects with bipolar disorder had a ratio that was non-significantly smaller than controls by 19%. Comparison of morphometric data with blood volume data did not reveal any statistically significant correlations among the study groups.     

Cerebellar vermis area in schizophrenic patients - a post-mortem study

Neuroimaging studies of cerebellar atrophy in schizophrenia have yielded contradictory results. In computer-tomography (CT) studies, cerebellar atrophy was found in up to 40% of schizophrenic patients. However, several recent magnetic resonance imaging (MRI) studies could not replicate these early findings; in addition, contradictory observations of enlargement of vermal structures were reported. In contrast to the number of CT and MRI studies, there are only a few neuropathological reports on this subject. In a post-mortem study we analyzed the midsagittal vermal area of formaldehyde-fixed cerebella of 12 deceased schizophrenic patients and 12 age- and gender-matched control subjects by using morphometrical methods. Statistical analysis using ANOVA revealed no significant group effects, but there were interactions with gender and cerebellar brain weight. In view of the present results, the common concept of cerebellar atrophy in schizophrenic patients appears premature. Gender effects and secondary processes (e.g., relevant alcohol or drug abuse) cannot be excluded as possible factors causing decrease of vermal areas in schizophrenic patients.     

Morphometry of individual cerebellar lobules in schizophrenia

OBJECTIVE: Previous imaging studies have described focal cortical changes in schizophrenia, with predominant findings of abnormalities in the temporal and frontal regions. The current study hypothesized that cerebellar regions involved in feedback and feed-forward loops with cortical regions affected in schizophrenia would also demonstrate structural changes. METHOD: Using magnetic resonance imaging, the authors measured the volume of individual cerebellar lobules in 19 patients with schizophrenia and 19 healthy comparison subjects. RESULTS: The inferior vermis was significantly smaller in the schizophrenic group than in the comparison group. Patients with schizophrenia also demonstrated a significantly smaller cerebellar asymmetry than the comparison subjects. CONCLUSIONS: The authors hypothesize that these morphometric changes may be developmental in origin and possibly related to cortical abnormalities.     

MRI study of the cerebellum in young bipolar patients

Prior studies demonstrate structural abnormalities of cerebellar vermis in adult bipolar patients. Cerebella of 16 young bipolar patients (mean age+/-S.D.=15.5+/-3.4) and 21 healthy controls (mean age+/-S.D.=16.9+/-3.8) were examined using magnetic resonance imaging. The volumes of right, left and total cerebellum, vermis, and areas of vermal regions V1 (lobules I-V), V2 (lobules VI-VII), and V3 (lobules VIII-X) were measured. Analysis of covariance, with age, gender, and intra-cranial brain volume as covariates, revealed no significant differences in cerebellum or vermis measures between patients and controls; however, there was a trend to smaller vermis V2 areas in patients (p=0.06). The number of previous affective episodes and vermis area V2 were inversely correlated (partial correlation coefficient=-0.97, P=0.001) in the male bipolar patient group. Our results are preliminary, but consistent with the findings from studies in adult bipolar patients suggesting the involvement of structural changes in cerebellar vermis in the pathophysiology of bipolar disorder.     

Postnatal development of unipolar brush cells in the cerebellar cortex of cat

The postnatal developmental distribution pattern of metabotropic glutamate receptor (mGluR1a) immunoreactive unipolar brush cells (UBCs) was studied in the cerebellar cortex of kittens. On the day of birth (P0) UBCs are already present in the white matter in lobule X of the vermis, but only a few of these cell seemed to migrate to the deeper region of the internal granular layer. By the end of the first week (P8) UBCs were seen to invade the white matter + internal granular layer of lobules IX, VIII, I, and II of the vermis, and they spread further in the transitory area medio-laterally from the vermis toward the cerebellar hemispheres. By P15, UBCs appeared in lobules III and VII of the vermis, as well as in corresponding lobules of the neocerebellum, with especially high numbers in lobule VII. By P22, UBCs migrated further after their medio-lateral course in the neocerebellum, and began to invade lobules V and VI. At P62 the amount of UBCs in midsagittal planes of early developing vermal lobules (I, II, VII-X) resembled the P132 or adult pattern. The medio-lateral migration and incorporation of UBCs into the late-developing cerebellar lobules V and VI was completed only by P132, when the spatial distribution of UBCs in both the vermal and neocerebellar lobules was comparable to that seen in the 1 year old young adult cat. Although by P132 the postnatal migration of the vast majority of UBCs seemed to be completed, in the cerebellum of adult cats a few migrating UBCs could still be observed in the white matter of the cerebellar lobules, and beneath the ependyma of the fourth ventricle. It is concluded that during ontogenesis the migration course of UBCs follows essentially the developmental sequence of cerebellar lobules, although the incorporation of UBCs into the internal granular layer continues until 4 months postnatally, i.e., much beyond the apparent completion (about two months postnatally) of cytoarchitectonic built up of the cerebellar cortex of kittens.     

Clinical correlates of brain morphometric features of subjects with low-functioning autistic disorder

Numerous neuropathologic and imaging studies have reported different structural abnormalities in the brains of autistic subjects. However, whether or not the degree of brain abnormality is correlated with the severity of developmental impairment in autistic disorder is still unknown. The midsagittal area of the cerebrum, corpus callosum, midbrain, cerebellar vermis, and vermal lobules VI and VII was measured by means of magnetic resonance imaging in 22 boys with low-functioning autistic disorder and in 11 age-matched normal controls. Morphometric measures were statistically compared between groups and correlated with age and scores on the Psychoeducational Profile-Revised and the Childhood Autism Rating Scale. A significant negative correlation was found between midsagittal area of the cerebrum and age in patients with autistic disorder, and a positive correlation was found between the midsagittal area of the midbrain and some subscales of the Psychoeducational Profile-Revised.     

Hypoplasia of the cerebellar vermis in neurogenetic syndromes

There are conflicting reports on the relationship between cerebellar vermal lobule hypoplasia and autism. Using quantitative magnetic resonance image analysis, we measured the cerebellar vermis in 125 normal individuals with a broad age range and 102 patients with a variety of neurogenetic abnormalities. We conclude that hypoplasia of cerebellar vermal lobules VI and VII is a nonspecific finding that even occurs in several conditions without autistic behavior. This suggests that it is not a specific neuroanatomical marker for autism, nor is cerebellar dys- genesis likely to be solely responsible for clinical autistic behaviors.     

Topography of cerebellar corticonuclear fibers of the albino rat. Vermis of anterior and posterior lobes.

The distribution of cerebellar corticonuclear fibers of the vermis of anterior and posterior lobes was determined for the albino rat using the Fink and Heimer method. Efferent fibers from vermal cortex terminate in the ipsilateral medial cerebellar nucleus (NM) in an organized circumferential manner. Rostral lobules (I--III) project to rostroventral and rostrocentral NM, more central lobules (IV, V, VI) project to rostrodorsal, dorsocentral and caudodorsal areas of the nucleus respectively, while caudal lobules (VII, VIII, IX) send fibers into caudal and ventrocaudal NM. No evidence was seen to corroborate the contention that individual lobules of the vermis may project essentially throughout the rostrocaudal extent of the nucleus. Although species differences are apparent the arrangement of terminal fields in the NM for vermal cortex of rats is similar to that reported for other mammals. Degenerated fibers from medial aspects of each lesion primarily enter the NM while those coursing into the juxtarestiform body originate from more lateral portions of the cortical injury. This suggests that the arrangement of cortical zones in rat is fundamentally similar to that described in other mammals.     

Cerebellar neurotransmission in attention-deficit/hyperactivity disorder: does dopamine neurotransmission occur in the cerebellar vermis?

Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have smaller cerebellar volumes, particularly in the posterior-inferior cerebellar vermis (lobules VIII-X). Functional activation of the human cerebellar vermis following stimulant administration has also been repeatedly demonstrated. There is no well-characterized dopaminergic pathway that projects to the posterior-inferior cerebellar vermis, although the dopamine transporter (DAT) and tyrosine hydroxylase (TH) have been localized in the posterior-inferior vermis in the non-human primate by immunohistochemistry. We hypothesized that DA neurotransmission may occur in localized "hot spots" in the cerebellar vermis, and if so, that differences in such neurotransmission might be relevant to the pathophysiology of ADHD. To investigate this hypothesis, cerebellar tissue was obtained from rats and non-human primates. Catecholamines were extracted and analyzed using HPLC with coulometric detection. A regional gradient of norepinephrine (NE) and DA was found throughout the cerebellum with NE levels always roughly 10-40-fold higher than DA in both rats and monkeys. In addition, in vivo microdialysis studies were performed in the rat posterior-inferior cerebellar vermis in anesthetized animals. Significant NE overflow was observed over baseline following reverse microdialysis induced release by potassium or d-amphetamine. DA overflow was not observed over baseline for potassium stimulation, but was significant for d-amphetamine stimulation. These studies refute the hypothesis that DA neurotransmission normally occurs in the rat cerebellar vermis, but highlight that vermal DA is released by d-amphetamine. The presence of DAT may therefore allow for enhanced regulation of NE and not regulation of released DA.     

Contribution of alcohol abuse to cerebellar volume deficits in men with schizophrenia

BACKGROUND: It is controversial whether cerebellar tissue volume deficits occur in schizophrenia and, if so, what regions and tissue types are affected. Complicating such investigations is the high incidence of alcoholism comorbidity in patients with schizophrenia that itself can contribute to cerebellar abnormalities. METHOD: We studied 61 healthy men (control subjects), 25 men with alcoholism, 27 men with schizophrenia, and 19 men comorbid for schizophrenia and alcoholism with the use of magnetic resonance imaging. Cerebellar structures were outlined manually, tissue classification was determined statistically, and regional volumes were corrected for normal variation in head size and age. RESULTS: Patients with schizophrenia alone had enlarged fourth ventricles (1.5 SD relative to controls) but showed no cerebellar tissue volume deficits. The alcoholic group had gray and white matter vermian deficits (-0.5 SD), most prominent in anterior superior lobules, and gray matter hemisphere deficits (-0.8 SD), but not fourth ventricle enlargement. The comorbid group had cerebellar hemisphere (-1.3 SD) and vermian gray matter volume deficits (-0.7 SD) and fourth ventricular enlargement (1.6 SD); these abnormalities were greater than in either single-diagnosis group, despite significantly lower levels of alcohol consumption compared with the alcoholic group. Gray matter volume in the anterior superior vermis correlated with lifetime alcohol consumption in the schizophrenic and comorbid groups when combined. CONCLUSIONS: Cerebellar tissue volume deficits were detected in schizophrenia only when accompanied by alcoholism. By contrast, fourth ventricular enlargement occurred in schizophrenia even without alcoholism, although it was exacerbated by alcoholism. These findings support a model of cerebellar supersensitivity to alcohol-related tissue volume deficits in schizophrenia.     

Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism.

BACKGROUND: Although limited environmental exploration in autism is an obvious behavioral feature and may be a manifestation of "restricted interests" as described in DSM-IV criteria, there have been no behavioral or neurobiological studies of this important aspect of the disorder. Given consistent reports of cerebellar abnormality in autism, combined with animal research showing a relationship between exploration and the cerebellum, this study aimed to test the possible link between cerebellar abnormality and exploration in autism. METHODS: The relationship between visuospatial exploration, stereotyped motor movements, and magnetic resonance imaging measures of the cerebellar vermis, whole brain volume, and frontal lobes in 14 autistic and 14 normal children was investigated. Children were exposed to a large room with several exploration containers and instructed to play. Exploration behavior was videotaped and scored for percentage of time engaged in exploration, number of containers explored, as well as stereotyped movements. RESULTS: Children with autism spent significantly less time in active exploration and explored fewer containers overall than normal children. Measures of decreased exploration were significantly correlated with the magnitude of cerebellar hypoplasia of vermal lobules VI-VII in the autistic children, but no relationship to vermis size was found with normal control children. Further, measures of rates of stereotyped behavior were significantly negatively correlated with area measures of cerebellar vermis lobules VI-VII and positively correlated with frontal lobe volume in the autism sample. CONCLUSIONS: Reduced environmental exploration and repetitive behavior may have particularly important developmental consequences for children with autism because it may lead them to miss learning opportunities that fall outside their scope of interest. Our findings represent the first documented link between the restricted range of interests and stereotyped behaviors pathognomonic of autism and particular neuroanatomic sites.     

Metabotrop glutamate receptor type 1a expressing unipolar brush cells in the cerebellar cortex of different species: a comparative quantitative study

Morphology, distribution and number of unipolar brush cells (UBCs) was studied in the cerebellar vermal lobules I-X of the chicken, rat, guinea pig, cat, and monkey using monoclonal mGluR1a antibody as a marker to visualise these recently described nerve cells (Mugnaini and Floris [1994] J. Comp. Neurol. 339:174-180; Mugnaini et al. [1994] Synapse 16:284-311). The morphological appearance of mGluR1a immunopositive UBCs is similar in all species investigated: they are small cells, having a single, relatively short and thick dendrite, terminating in brush-like dendrioles. Although this, probably excitatory, cell type can be found all over the cerebellar cortex, highest density of UBCs can be seen in the vermal cortex. The present study, therefore, was focused on the quantitative morphology and distribution of UBCs in the 10 lobules of the vermis. Calculating the number of UBCs/l Purkinje cell (PC), we have found differences in this value (average in vermal lobules I-X) from 1.04 in rat, 1.10 in chicken, 1.16 in guinea pig, 2.27 in monkey, and up to 2.44 in cat. The highest density of UBCs was observed in lobules I, IX, and X, whereas the lowest number of UBCs/l PC was found in lobules IV-VI (in the mammals) and in lobules VII-VIII (in the chicken). In mammals, particularly the monkey and cat, an increased presence of UBCs was observed in vermal sub-lobules VIc-VIIb,c, a region defined as the oculomotor vermis because of its role in the control of saccadic eye movement. There is also a basic difference between chicken and mammals in the distribution of UBCs within the lobules: in mammals, the lowest density of these nerve cells was found in the peripheral portion of the lobules, near to the pia, while in the chicken, in contrast, the density of UBCs was the highest subpially with fewer UBCs located in the deepest curvature of the lobules. Finally, the functional significance of the differences in the density and in the distribution pattern of UBCs in the cerebellar vermis between the phylogenetically different species investigated is briefly discussed.     

A quantitative MRI study of posterior fossa development in velocardiofacial syndrome.

BACKGROUND: Velocardiofacial syndrome (VCFS) has been identified as a risk factor for developing schizophrenia. Qualitative neuroimaging studies indicated that VCFS was frequently associated with abnormal development of structures in the posterior fossa of the brain. The objective of this investigation was to identify the specific structures affected in the posterior fossa and investigate the association of these neuroanatomic variations with behaviors potentially related to later-onset psychiatric disorders. METHODS: Twenty-four children and adolescents with VCFS individually matched for age and gender with 24 control subjects received magnetic resonance imaging scans. Analysis of covariance models were used to investigate regional brain differences. Association between brain areas and behaviors measured on the Child Behavior Checklist (CBCL) were assessed using simple regression models. RESULTS: Children with VCFS had significantly smaller size of vermal lobules VI--VII and the pons after adjusting for overall brain size. There were no significant associations between scores on the CBCL and measures of neuroanatomic variation within the VCFS group. CONCLUSIONS: Structural alterations of the posterior fossa in VCFS are specifically limited to cerebellar vermis lobules VI--VII and pons. Previous literature has suggested that the vermis is involved in social cognition, and alteration of lobules VI--VII could therefore partially explain the neurobehavioral profile associated with VCFS.     

Reduced cerebellar hemisphere size and its relationship to vermal hypoplasia in autism

Cerebellar hemisphere size was calculated in 10 autistic and 8 normal control subjects by summing the cross-sectional areas of cerebellar hemisphere tissue measured on paramidline sagittal magnetic resonance images. The areas of two cerebellar vermal regions (lobules I through V and lobules VI through VII) were also measured using the midsagittal image. Our cumulative slice area measure of cerebellar hemisphere size was significantly smaller in the autistic subjects than in the control group. The cumulative slice area correlated positively with the area of vermal lobules VI through VII only in the autistic subjects. Our results indicated that the decreased size of the cerebellar hemispheres and vermal lobules VI through VII was associated with autism.     

Fixation instability and oculomotor abnormalities in Friedreich's ataxia

Eye movements were studied in 13 patients with Friedreich's ataxia and correlated with MRI findings to investigate whether oculomotor abnormalities can be traced to cerebellar disturbances in this disease. One of the most prominent eye signs was fixation instability (square-wave jerks, SWJ.). Besides SWJ the patients showed various combinations of cerebellar, vestibular and brain-stem oculomotor signs. Our patients did not comprise a homogeneous group with regard to their oculomotor findings. There was no correlation between the severity of any of the so-called cerebellar oculomotor disturbances and the number of SWJ. We tried to correlate the extent of oculomotor disturbances with floccular atrophy and atrophy of the dorsal vermis on MRI in seven of the patients. None of the oculomotor features (including SWJ) correlated with flocculus or dorsal vermis size. Furthermore, floccular and vermal measurements on MRI were normal. Accordingly, we think it unlikely that the oculomotor disturbances, including SWJ, are attributable to cerebellar pathology per se.     

The brain in infantile autism: are posterior fossa structures abnormal?

We conducted a detailed MRI study of posterior fossa structures in 13 autistic children, 10 without seizures and three with seizures, and 28 controls, 17 without seizures and 11 with seizures, using computer-assisted planimetry, and measured midsagittal areas of cerebellar vermal lobule group I-V, vermal lobule group VI-VII, the pons, and fourth ventricle height. There were no significant differences between autistic and control subjects in any of the four regions measured, or in the ratio of areas of vermal lobules VI-VII to I-V.     

Magnetic resonance imaging in degenerative ataxic disorders.

MRI of the brain was performed in 53 patients with a variety of degenerative ataxias and related disorders and 96 control subjects. Atrophy of intracranial structures was not seen in patients with the pure type of hereditary spastic paraplegia, or in early cases of Friedreich's ataxia. In advanced Friedreich's ataxia there was atrophy of the vermis and medulla. The MRI features of early onset cerebellar ataxia with retained reflexes were variable, and suggest heterogeneity. In autosomal dominant cerebellar ataxias, most patients had cerebellar and brainstem atrophy, probably reflecting the pathological process of olivopontocerebellar atrophy; there was no clearly defined group with both clinical and imaging features of isolated cerebellar involvement. The MRI abnormalities in idiopathic late onset cerebellar ataxia were predominantly those of cerebellar and brainstem atrophy or pure cerebellar atrophy. The clinical and imaging features of brainstem abnormalities were discordant in several patients. Pure cerebellar atrophy was associated with slower progression of disability. Cerebral atrophy was common in the late onset ataxias. Cerebral white matter lesions, although usually few in number, were observed in significantly more patients than controls, particularly those aged over 50 years.     

Transverse zones in the vermis of the mouse cerebellum

The mouse cerebellar cortex is subdivided by an elaborate array of parasagittal and transverse boundaries. The relationship between these two orthogonal patterns of compartmentation is understood poorly. We have combined the use of adult and perinatal molecular markers of compartmentation—zebrin II, calbindin, and an L7/pcp-2-lacZ transgene—to resolve some of these issues. Our results indicate that the adult cerebellar vermis is divided along the rostrocaudal axis by three transverse boundaries: through the rostral face of lobule VI, in the caudal half of lobule VII, and across the posterolateral fissure between lobules IX and X. These three boundaries subdivide the vermis into four transverse zones: the anterior zone (lobules I–V), the central zone (lobules VI–VII), the posterior zone (lobules VIII–IX), and the nodular zone (lobule X). The same zones and boundaries also can be identified in the newborn cerebellum. The parasagittal organization is different in each zone: a unique combination of Purkinje cell phenotypes is found in each transverse zone both in the neonate and the adult, and different zones have distinct developmental time tables. Furthermore, the parasagittal bands of Purkinje cells revealed in the adult cerebellar cortex by using antizebrin II immunocytochemistry are discontinuous across the transverse boundaries. These data suggest that the transverse zones of the vermis form first during development and that parasagittal compartmentation develops independently in each transverse zone. J. Comp. Neurol. 412:95–111, 1999. © 1999 Wiley-Liss, Inc.