Cerebellar motor learning deficits in medicated and medication-free men with recent-onset schizophrenia.

BACKGROUND: The notion that cerebellar deficits may underlie clinical symptoms in people with schizophrenia is tested by evaluating 2 forms of cerebellar learning in patients with recent-onset schizophrenia. A potential medication effect is evaluated by including patients with or without antipsychotics. METHODS: We assessed saccadic eye movement adaptation and eyeblink conditioning in men with recent-onset schizophrenia who were taking antipsychotic medication or who were antipsychotic-free and in age-matched controls. RESULTS: We included 39 men with schizophrenia (10 who were taking clozapine, 16 who were taking haloperidol and 13 who were antipsychotic-free) and 29 controls in our study. All participants showed significant saccadic adaptation. Adaptation strength did not differ between healthy controls and men with schizophrenia. The speed of saccade adaptation, however, was significantly lower in men with schizophrenia. They showed a significantly lower increase in the number of conditioned eyeblink responses. Over all experiments, no consistent effects of medication were observed. These outcomes did not correlate with age, years of education, psychopathology or dose of antipsychotics. LIMITATIONS: As patients were not randomized for treatment, an influence of confounding variables associated with medication status cannot be excluded. Individual patients also varied along the schizophrenia spectrum despite the relative homogeneity with respect to onset of illness and short usage of medication. Finally, the relatively small number of participants may have concealed effects as a result of insufficient statistical power. CONCLUSION: We found several cerebellar learning deficits in men with schizophrenia that we cannot attribute to the use of antipsychotics. Although this finding, combined with the fact that deficits are already present in patients with recent-onset schizophrenia, could suggest that cerebellar impairments are a trait deficit in people with schizophrenia. This should be confirmed in longitudinal studies.

Transcranial magnetic stimulation and motor plasticity in human lateral cerebellum: dual effect on saccadic adaptation.

The cerebellum is a key area for movement control and sensory-motor plasticity. Its medial part is considered as the exclusive cerebellar center controlling the accuracy and adaptive calibration of saccadic eye movements. However, the contribution of other zones situated in its lateral part is unknown. We addressed this question in healthy adult volunteers by using magnetic resonance imaging (MRI)-guided transcranial magnetic stimulation (TMS). The double-step target paradigm was used to adaptively lengthen or shorten saccades. TMS pulses over the right hemisphere of the cerebellum were delivered at 0, 30, or 60 ms after saccade detection in separate recording sessions. The effects on saccadic adaptation were assessed relative to a fourth session where TMS was applied to Vertex as a control site. First, TMS applied upon saccade detection before the adaptation phase reduced saccade accuracy. Second, TMS applied during the adaptation phase had a dual effect on saccadic plasticity: adaptation after-effects revealed a potentiation of the adaptive lengthening and a depression of the adaptive shortening of saccades. For the first time, we demonstrate that TMS on lateral cerebellum can influence plasticity mechanisms underlying motor performance. These findings also provide the first evidence that the human cerebellar hemispheres are involved in the control of saccade accuracy and in saccadic adaptation, with possibly different neuronal populations concerned in adaptive lengthening and shortening. Overall, these results require a reappraisal of current models of cerebellar contribution to oculomotor plasticity.

Motor learning in children with neurofibromatosis type I.

The aim of this study was to quantify the frequently observed problems in motor control in Neurofibromatosis type 1 (NF1) using three tasks on motor performance and motor learning. A group of 70 children with NF1 was compared to age-matched controls. As expected, NF1 children showed substantial problems in visuo-motor integration (Beery VMI). Prism-induced hand movement adaptation seemed to be mildly affected. However, no significant impairments in the accuracy of simple eye or hand movements were observed. Also, saccadic eye movement adaptation, a cerebellum dependent task, appeared normal. These results suggest that the motor problems of children with NF1 in daily life are unlikely to originate solely from impairments in motor learning. Our findings, therefore, do not support a general dysfunction of the cerebellum in children with NF1.

Cortical and cerebellar activation induced by reflexive and voluntary saccades.

Reflexive saccades are driven by visual stimulation whereas voluntary saccades require volitional control. Behavioral and lesional studies suggest that there are two separate mechanisms involved in the generation of these two types of saccades. This study investigated differences in cerebral and cerebellar activation between reflexive and self-paced voluntary saccadic eye movements using functional magnetic resonance imaging. In two experiments (whole brain and cerebellum) using the same paradigm, differences in brain activations induced by reflexive and self-paced voluntary saccades were assessed. Direct comparison of the activation patterns showed that the frontal eye fields, parietal eye field, the motion-sensitive area (MT/V5), the precuneus (V6), and the angular and the cingulate gyri were more activated in reflexive saccades than in voluntary saccades. No significant difference in activation was found in the cerebellum. Our results suggest that the alleged separate mechanisms for saccadic control of reflexive and self-paced voluntary are mainly observed in cerebral rather than cerebellar areas.

An fMRI study on smooth pursuit and fixation suppression of the optokinetic reflex using similar visual stimulation.

This study compares brain activation patterns evoked by smooth pursuit and by fixation suppression of the optokinetic reflex (OKR) using similar retinal stimulation. Functional magnetic resonance imaging (fMRI) was performed during smooth pursuit stimulation in which a moving target was presented on a stationary pattern of stripes, and during fixation suppression of OKR in which a stationary target was presented on a moving pattern of stripes. All subjects could effectively ignore the background pattern and were able to keep the target continuously on the fovea with few saccades, in both experiments. Smooth pursuit evoked activation in the frontal eye fields (FEF), the supplementary eye fields (SEF), the parietal eye fields (PEF), the motion-sensitive area (MT/V5), and in lobules and vermis VI of the cerebellum (oculomotor areas). Fixation suppression of OKR induced activation in the FEF, PEF, and MT/V5. The direct comparison analysis revealed more activation in the right lobule VI of the cerebellum and in the right lingual and calcarine gyri during smooth pursuit than during fixation suppression of OKR. Using similar retinal stimulation, our results show that smooth pursuit and fixation suppression of the OKR appear to activate largely overlapping pathways. The increased activity in the oculomotor areas of the cerebellum during smooth pursuit is probably due to the presence of an active eye movement component.

fMRI of optokinetic eye movements with and without a contribution of smooth pursuit.

BACKGROUND AND PURPOSE: Optokinetic eye movements are elicited when tracking a moving pattern. It can be argued that a moving pattern of stripes invokes both the optokinetic and the smooth pursuit eye movement system, which may confound the observed brain activation patterns using functional magnetic resonance imaging (fMRI). A moving pattern of limited-lifetime-dot stimulation does not target the smooth pursuit eye movement system. METHODS: fMRI was used to compare the cortical activity elicited by an optokinetic eye movement response evoked by a moving pattern of stripes and a moving pattern of limited lifetime dots. RESULTS: The eye movement behavior showed that both types of stimuli evoked an adequate and similar optokinetic eye movement response, but stimulation with stripes evoked more activation in the frontal and parietal eye fields, MT/V5, and in the cerebellar area VI than stimulation with limited-lifetime dots. CONCLUSIONS: These brain areas are implicated in smooth pursuit eye movements. Our results suggest that indeed both the optokinetic and the smooth pursuit eye movement system are involved in tracking a moving pattern of stripes.

Comparing two diagnostic laboratory tests for Williams syndrome: fluorescent in situ hybridization versus multiplex ligation-dependent probe amplification.

Most people with Williams syndrome (WS) have a heterozygous 1.55 Mb deletion on chromosome 7q11.23. For diagnostic purposes, fluorescence in situ hybridisation (FISH) with commercial FISH probes is commonly used to detect this deletion. We investigated whether multiplex ligation-dependent probe amplification (MLPA) is a reliable alternative for FISH. The MLPA kit (SALSA P029) contains probes for eight genes in the WS critical region: FKBP6, FZD9, TBL2, STX1A, ELN, LIMK1, RFC2, and CYLN2. The experimental FISH assay that was used consists of four probes covering the WS critical region. A total number of 63 patients was tested; in 53 patients, a deletion was detected both with FISH and MLPA(P029), in 10 patients both techniques failed to demonstrate a deletion. In only one patient, a deletion was detected which was not previously detected by two commercial FISH probes. This patient appeared to carry a small, atypical deletion. We conclude that MLPA is a reliable technique to detect WS. Compared with FISH, MLPA is less time consuming and has the possibility to detect also smaller, atypical deletions and duplications in the WS critical region.

Saccade adaptation in Williams-Beuren Syndrome.

PURPOSE: To investigate the capacity for rapid saccade adaptation in Williams-Beuren Syndrome (WBS), a genetic neurodevelopmental disorder, in which it has been observed that saccadic accuracy is severely reduced. METHODS: Saccade amplitude modification was elicited by backward steps (30% of target eccentricity) during the primary saccade in a classic saccade-adaptation paradigm. RESULTS: Patients with WBS showed a significant decrease in saccade amplitude. Furthermore, we observed that higher saccade accuracy before adaptation was related to more adaptation. CONCLUSIONS: The increased variability in motor performance does not abolish the ability for saccadic adaptation in subjects with WBS. Our results are congruent with the notion that part of the behavioral deficits observed in WBS may have a cerebellar origin.

Neuronal substrate of the saccadic inhibition deficit in schizophrenia investigated with 3-dimensional event-related functional magnetic resonance imaging.

BACKGROUND: Several studies have shown that the ability to suppress automatic saccadic eye movements is impaired in patients with schizophrenia as well as in their first-degree relatives, and suggest that this impairment is a potential vulnerability marker for schizophrenia. The neurobiological mechanisms underlying normal saccade production and inhibition, revealed in primate studies, indicate that the impairment may result from a failure of the oculomotor system to effectively exert inhibitory control over brainstem structures. Functional localization of the affected brain structure(s) potentially provides a physiological measure for the investigation of vulnerability markers in schizophrenia. METHODS: The hemodynamic response to discrete visual stimuli was measured during prosaccades (saccades toward a peripheral stimulus), antisaccades (saccades toward a position opposite to a peripheral stimulus), and active fixation (holding fixation and ignoring a peripheral stimulus) in 16 patients with schizophrenia receiving atypical neuroleptics and 17 healthy control subjects using an event-related functional magnetic resonance imaging task design. RESULTS: Brain responses were detected in the frontal and parietal regions of the oculomotor system in all 3 tasks. Patients made more errors during inhibition tasks and exhibited a selective failure to activate the striatum during the inhibition of saccades. In other regions that were active during inhibition, specifically the supplementary and frontal eye fields, no difference was found between patients and control subjects. CONCLUSIONS: A frontostriatal network is engaged in the suppression of automatic eye movements. The results indicate that abnormalities in this network, rather than the selective dysfunction of prefrontal brain regions, underlie the saccade inhibition deficit in schizophrenia.

Differences between smooth pursuit and optokinetic eye movements using limited lifetime dot stimulation: a functional magnetic resonance imaging study.

In this study, we examined possible differences in brain activation between smooth pursuit and optokinetic reflexive (OKR) eye movements using functional magnetic resonance imaging (fMRI). Eighteen healthy subjects performed two different eye movement paradigms. In the first paradigm, smooth pursuit eye movements were evoked by a single moving dot. In the second paradigm, optokinetic eye movements without a foveal smooth pursuit component were evoked by a moving pattern of multiple dots with a limited lifetime. As expected, the two eye movement systems show overlapping pathways, but the direct comparison of the activation patterns between the two experiments showed that the frontal eye field, MT/V5 and cerebellar area VI appear to be more activated during smooth pursuit than during optokinetic eye movements. These results showed that the smooth pursuit and optokinetic eye movement systems can be differentiated with fMRI using limited lifetime dots as an effective OKR stimulus.

Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies.

Patients with Hodgkin's disease can develop paraneoplastic cerebellar ataxia because of the generation of autoantibodies against mGluR1 (mGluR1-Abs). Yet, the pathophysiological mechanisms underlying their motor coordination deficits remain to be elucidated. Here, we show that application of IgG purified from the patients' serum to cerebellar slices of mice acutely reduces the basal activity of Purkinje cells, whereas application to the flocculus of mice in vivo evokes acute disturbances in the performance of their compensatory eye movements. In addition, the mGluR1-Abs block induction of long-term depression in cultured mouse Purkinje cells, whereas the cerebellar motor learning behavior of the patients is affected in that they show impaired adaptation of their saccadic eye movements. Finally, postmortem analysis of the cerebellum of a paraneoplastic cerebellar ataxia patient showed that the number of Purkinje cells was significantly reduced by approximately two thirds compared with three controls. We conclude that autoantibodies against mGluR1 can cause cerebellar motor coordination deficits caused by a combination of rapid effects on both acute and plastic responses of Purkinje cells and chronic degenerative effects.