Gene expression of NMDA receptor subunits in the cerebellum of elderly patients with schizophrenia

To determine if NMDA receptor alterations are present in the cerebellum in schizophrenia, we measured NMDA receptor binding and gene expression of the NMDA receptor subunits in a post-mortem study of elderly patients with schizophrenia and non-affected subjects. Furthermore, we assessed influence of genetic variation in the candidate gene neuregulin-1 (NRG1) on the expression of the NMDA receptor in an exploratory study. Post-mortem samples from the cerebellar cortex of ten schizophrenic patients were compared with nine normal subjects. We investigated NMDA receptor binding by receptor autoradiography and gene expression of the NMDA receptor subunits NR1, NR2A, NR2B, NR2C and NR2D by in situ hybridization. For the genetic study, we genotyped the NRG1 polymorphism rs35753505 (SNP8NRG221533). Additionally, we treated rats with the antipsychotics haloperidol or clozapine and assessed cerebellar NMDA receptor binding and gene expression of subunits to examine the effects of antipsychotic treatment. Gene expression of the NR2D subunit was increased in the right cerebellum of schizophrenic patients compared to controls. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of the NR2C subunit in the right cerebellum, compared to individuals homozygous for the T allele. Correlation with medication parameters and the animal model revealed no treatment effects. In conclusion, increased NR2D expression results in a hyperexcitable NMDA receptor suggesting an adaptive effect due to receptor hypofunction. The decreased NR2C expression in NRG1 risk variant may cause a deficit in NMDA receptor function. This supports the hypothesis of an abnormal glutamatergic neurotransmission in the right cerebellum in the pathophysiology of schizophrenia

Lateralized organization of the cerebellum in a silent verbal fluency task: a functional magnetic resonance imaging study in healthy volunteers

Functionally, the cerebellum is not only involved in motor control but is also thought to influence higher cognitive function including language. Anatomical data would suggest crossed reciprocal connections between the cerebellum and higher order cortical association areas. In the following study, one left- and one right-handed female volunteer underwent functional magnetic resonance imaging in a conventional block design. Regions of activation were detected after performance of a silent verbal fluency task inside the scanner. In the right-handed volunteer we found an activation of the left fronto-parietal cortex and the right cerebellar hemisphere, while in the left-handed volunteer the activation was seen in the right fronto-parieto-temporal cortex and the left cerebellar hemisphere. These initial results demonstrate that cerebellar activation is contralateral to the activation of the frontal cortex even under conditions of different language dominance. They provide evidence for the hypothesis of a lateralized organization of the cerebellum crossed to the cerebral hemispheres in supporting higher cognitive function

Cortical response to motor stimulation in neuroleptic-naive first episode schizophrenics

The purpose of the present study was to evaluate the cortical response to motor stimulation in neuroleptic-naive first episode schizophrenics in comparison to matched controls using a high speed functional magnetic resonance imaging technique (fMRI). Twelve patients satisfying ICD 10 criteria (F20.0) for schizophrenia (paranoid subtype) as well as sex- and age-matched healthy volunteers participated in this study. All subjects underwent fMRI examination on a conventional 1.5 T MR unit equipped with an echo-planar imaging booster. The blood oxygen level dependent (BOLD) response of the sensorimotor cortex and the higher order SMA region was evaluated during performance of a left hand sequential finger opposition task. Special care was taken to minimize performance and motion artifacts. Patients and controls showed no notable difference with respect to laterality, changes of signal intensity or spatial extent of activation within the primary and higher order motor regions. Using high speed fMRI no fundamental motor cortical dysfunction was evident in a group of paranoid neuroleptic-naive first episode schizophrenic patients. In contrast to data previously reported for chronic disorganized medicated patients, these results suggest that motor dysfunction is not part of the phenomenology of acute paranoid first episode patients

Antipsychotic drug effects on motor activation measured by functional magnetic resonance imaging in schizophrenic patients

Brain function and laterality in schizophrenia were investigated by means of a simple motor task with a self-generated left-hand sequential finger opposition (SFO) using a whole-brain high-speed (100 ms per slice) functional imaging technique. Neuroleptic-naive, acutely ill schizophrenic patients were compared to schizophrenic patients under stable neuroleptic medication and matched controls. The goal was to evaluate both the motor function in first-episode patients and possible effects of different neuroleptic treatments on functional MRI results. Forty patients satisfying ICD 10 criteria (F20.x) for schizophrenia and sex- and age-matched healthy volunteers participated in this study. All subjects underwent fMRI examinations on a conventional 1.5 T MR unit. The primary sensorimotor cortex and the high-order supplementary motor area (SMA) were evaluated. There was a close similarity in the activation of the primary and high-order (SMA) sensorimotor areas between first-episode schizophrenic patients and controls. In contrast, a significant reduction in the overall blood oxygen level dependent (BOLD) response was seen in sensorimotor cortices (contra- and ipsilateral) in schizophrenic patients under stable medication with typical neuroleptics. This effect was not present in patients treated with atypical antipsychotics. Both antipsychotic treatments, however, led to a significant reduction in activation of the SMA region compared to controls and neuroleptic-naive subjects. Thus, the present study provides no evidence for the localized involvement of the primary motor cortex or the SMA as a relatively stable vulnerability marker in schizophrenia. There is, however, strong evidence that neuroleptics themselves influence fMRI activation patterns and that there are major differences between typical neuroleptics and atypical antipsychotics

Grey Matter Volume in the Cerebellum is Related to the Processing of Grammatical Rules in a Second Language: A Structural Voxel-based Morphometry Study

The experience of learning and using a second language (L2) has been shown to affect the grey matter (GM) structure of the brain. Importantly, GM density in several cortical and subcortical areas has been shown to be related to performance in L2 tasks. Here, we show that bilingualism can lead to increasedGMvolume in the cerebellum, a structure that has been related to the processing of grammatical rules. Additionally, the cerebellar GM volume of highly proficient L2 speakers is correlated to their performance in a task tapping on grammatical processing in an L2, demonstrating the importance of the cerebellum for the establishment and use of grammatical rules in an L2

The cerebellum and language: the story so far.

The cerebellum was traditionally considered to be exclusively involved in the coordination of voluntary movement, gait, posture, balance and motor speech. However, this view was challenged by recent neuroanatomical, neuroimaging and clinical findings, providing preliminary evidence of a cerebellar contribution to linguistic functioning.Journal ArticleResearch Support, Non-U.S. Gov'tReviewSCOPUS: cp.jinfo:eu-repo/semantics/publishe

Cerebellar lesions: is there a lateralisation effect on memory deficits?

BACKGROUND: Until recently, neurosurgeons eagerly removed cerebellar lesions without consideration of future cognitive impairment that might be caused by the resection. In children, transient cerebellar mutism after resection has lead to a diminished use of midline approaches and vermis transection, as well as reduced retraction of the cerebellar hemispheres. The role of the cerebellum in higher cognitive functions beyond coordination and motor control has recently attracted significant interest in the scientific community, and might change the neurosurgical approach to these lesions. The aim of this study was to investigate the specific effects of cerebellar lesions on memory, and to assess a possible lateralisation effect. METHODS: We studied 16 patients diagnosed with a cerebellar lesion, from January 1997 to April 2005, in the "Centre Hospitalier Universitaire Vaudois (CHUV)", Lausanne, Switzerland. Different neuropsychological tests assessing short term and anterograde memory, verbal and visuo-spatial modalities were performed pre-operatively. RESULTS: Severe memory deficits in at least one modality were identified in a majority (81%) of patients with cerebellar lesions. Only 1 patient (6%) had no memory deficit. In our series lateralisation of the lesion did not lead to a significant difference in verbal or visuo-spatial memory deficits. FINDINGS: These findings are consistent with findings in the literature concerning memory deficits in isolated cerebellar lesions. These can be explained by anatomical pathways. However, the cross-lateralisation theory cannot be demonstrated in our series. The high percentage of patients with a cerebellar lesion who demonstrate memory deficits should lead us to assess memory in all patients with cerebellar lesions