The role of the cerebellum in schizophrenia: from cognition to molecular pathways

Beside its role in motor coordination, the cerebellum is involved in cognitive function such as attention, working memory, verbal learning, and sensory discrimination. In schizophrenia, a disturbed prefronto-thalamo-cerebellar circuit has been proposed to play a role in the pathophysiology. In addition, a deficit in the glutamatergic N-methyl-D-aspartate (NMDAf) receptor has been hypothesized. The risk gene neuregulin 1 may play a major role in this process. We demonstrated a higher expression of the NMDA receptor subunit 2D in the right cerebellar regions of schizophrenia patients, which may be a secondary upregulation due to a dysfunctional receptor. In contrast, the neuregulin 1 risk variant containing at least one C-allele was associated with decreased expression of NMDA receptor subunit 2C, leading to a dysfunction of the NMDA receptor, which in turn may lead to a dysfunction of the gamma amino butyric acid (GABA) system. Accordingly, from post-mortem studies, there is accumulating evidence that GABAergic signaling is decreased in the cerebellum of schizophrenia patients. As patients in these studies are treated with antipsychotics long term, we evaluated the effect of long-term haloperidol and clozapine treatment in an animal model. We showed that clozapine may be superior to haloperidol in restoring a deficit in NMDA receptor subunit 2C expression in the cerebellum. We discuss the molecular findings in the light of the role of the cerebellum in attention and cognitive deficits in schizophrenia.

Disfunção pré-frontoparietal durante o processamento de informação visuoauditiva em pacientes idosos com esquizofrenia crônica e efeitos da medicação / Parieto-prefrontal dysfunction during visuo-auditory information processing in elderly, chronic schizophrenic patients and medication effects

OBJETIVOS: Em pacientes com primeiro episódio de esquizofrenia, estudos com ressonância magnética funcional (RMf) têm demonstrado disfunção pré-frontoparietal durante estimulação acústica e visual. O objetivo do presente estudo foi investigar a rede pré-frontoparietal em pacientes idosos com esquizofrenia utilizando o mesmo paradigma. Adicionalmente, foram presumidos efeitos favoráveis na ativação cerebral pelo antipsicótico atípico clozapina em comparação a neurolépticos típicos. MÉTODOS: Foram investigados 18 pacientes com esquizofrenia crônica e 21 controles saudáveis idosos. Nove pacientes com esquizofrenia haviam sido medicados com clozapina e nove haviam recebido neurolépticos típicos por décadas. Concomitantemente às avaliações com escalas psicopatológicas e neuropsicológicas foi utilizado um paradigma de estimulação auditiva e visual em um aparelho de ressonância magnética de 1,5 Tesla para investigar a resposta BOLD em diferentes áreas cerebrais. RESULTADOS: Comparados a controles saudáveis, os pacientes com esquizofrenia apresentaram diminuição na ativação cerebral nos córtices pré-frontal e parietal, assim como no giro do cíngulo anterior medial. Nessas regiões, os pacientes medicados com clozapina apresentaram resposta BOLD aumentada em comparação aos pacientes tratados com neurolépticos típicos. DISCUSSÃO: O presente estudo confirmou a presença de distúrbios na rede pré-frontoparietal em pacientes idosos com esquizofrenia, apontando assim para a preservação de déficits de ativação cerebrais e a influência de distúrbios do desenvolvimento neural em esquizofrenia crônica até a velhice. CONCLUSÃO: O antipsicótico atípico clozapina parece facilitar a ativação de áreas cerebrais mesmo em pacientes idosos com esquizofrenia crônica.

OBJECTIVES: In first-episode schizophrenia patients, functional magnetic resonance imaging (fMRI) has shown prefronto-parietal dysfunction during acoustic and visual stimulation. The aim of this study was to investigate the prefronto-parietal network in elderly schizophrenia patients using the same paradigm. Additionally, we hypothesized favourable effects on brain activation by the atypical antipsychotic clozapine compared to typical neuroleptics. METHODS: We investigated 18 elderly, chronic schizophrenia patients and 21 elderly healthy controls. Nine schizophrenia patients had been medicated with clozapine and 9 had been receiving typical neuroleptics over decades. In addition to assessments with psychopathological and neuropsychological rating scales we used an acoustic and visual stimulation paradigm in a 1.5 Tesla MRI scanner to investigate BOLD-response in different brain areas. RESULTS: Compared to healthy controls schizophrenia patients showed decreased brain activation in the prefrontal and parietal cortex as well as medial anterior cingulate gyrus compared to healthy controls. In these regions, patients medicated with clozapine showed increased BOLD-response compared to patients treated with typical neuroleptics. DISCUSSION: Our study confirmed prefronto-parietal network disturbances in elderly schizophrenia patients thus pointing to the preservation of brain activation deficits and the influence of neurodevelopmental disturbances in chronic schizophrenia until old-age. CONCLUSION: The atypical antipsychotic clozapine seems to facilitate brain activation even in elderly, chronic schizophrenia patients.