Clinical accuracy of instrument-based SARS-CoV-2 antigen diagnostic tests: a systematic review and meta-analysis.

BACKGROUND: During the COVID-19 pandemic, antigen diagnostic tests were frequently used for screening, triage, and diagnosis. Novel instrument-based antigen tests (iAg tests) hold the promise of outperforming their instrument-free, visually-read counterparts. Here, we provide a systematic review and meta-analysis of the SARS-CoV-2 iAg tests' clinical accuracy. METHODS: We systematically searched MEDLINE (via PubMed), Web of Science, medRxiv, and bioRxiv for articles published before November 7th, 2022, evaluating the accuracy of iAg tests for SARS-CoV-2 detection. We performed a random effects meta-analysis to estimate sensitivity and specificity and used the QUADAS-2 tool to assess study quality and risk of bias. Sub-group analysis was conducted based on Ct value range, IFU-conformity, age, symptom presence and duration, and the variant of concern. RESULTS: We screened the titles and abstracts of 20,431 articles and included 114 publications that fulfilled the inclusion criteria. Additionally, we incorporated three articles sourced from the FIND website, totaling 117 studies encompassing 95,181 individuals, which evaluated the clinical accuracy of 24 commercial COVID-19 iAg tests. The studies varied in risk of bias but showed high applicability. Of 24 iAg tests from 99 studies assessed in the meta-analysis, the pooled sensitivity and specificity compared to molecular testing of a paired NP swab sample were 76.7% (95% CI 73.5 to 79.7) and 98.4% (95% CI 98.0 to 98.7), respectively. Higher sensitivity was noted in individuals with high viral load (99.6% [95% CI 96.8 to 100] at Ct-level ≤ 20) and within the first week of symptom onset (84.6% [95% CI 78.2 to 89.3]), but did not differ between tests conducted as per manufacturer's instructions and those conducted differently, or between point-of-care and lab-based testing. CONCLUSION: Overall, iAg tests have a high pooled specificity but a moderate pooled sensitivity, according to our analysis. The pooled sensitivity increases with lower Ct-values (a proxy for viral load), or within the first week of symptom onset, enabling reliable identification of most COVID-19 cases and highlighting the importance of context in test selection. The study underscores the need for careful evaluation considering performance variations and operational features of iAg tests.

Comparing SARS-CoV-2 antigen-detection rapid diagnostic tests for COVID-19 self-testing/self-sampling with molecular and professional-use tests: a systematic review and meta-analysis.

Self-testing is an effective tool to bridge the testing gap for several infectious diseases; however, its performance in detecting SARS-CoV-2 using antigen-detection rapid diagnostic tests (Ag-RDTs) has not been systematically reviewed. This study aimed to inform WHO guidelines by evaluating the accuracy of COVID-19 self-testing and self-sampling coupled with professional Ag-RDT conduct and interpretation. Articles on this topic were searched until November 7th, 2022. Concordance between self-testing/self-sampling and fully professional-use Ag-RDTs was assessed using Cohen's kappa. Bivariate meta-analysis yielded pooled performance estimates. Quality and certainty of evidence were evaluated using QUADAS-2 and GRADE tools. Among 43 studies included, twelve reported on self-testing, and 31 assessed self-sampling only. Around 49.6% showed low risk of bias. Overall concordance with professional-use Ag-RDTs was high (kappa 0.91 [95% confidence interval (CI) 0.88-0.94]). Comparing self-testing/self-sampling to molecular testing, the pooled sensitivity and specificity were 70.5% (95% CI 64.3-76.0) and 99.4% (95% CI 99.1-99.6), respectively. Higher sensitivity (i.e., 93.6% [95% CI 90.4-96.8] for Ct < 25) was estimated in subgroups with higher viral loads using Ct values as a proxy. Despite high heterogeneity among studies, COVID-19 self-testing/self-sampling exhibits high concordance with professional-use Ag-RDTs. This suggests that self-testing/self-sampling can be offered as part of COVID-19 testing strategies.Trial registration: PROSPERO: CRD42021250706.

Accuracy of rapid point-of-care antigen-based diagnostics for SARS-CoV-2: An updated systematic review and meta-analysis with meta-regression analyzing influencing factors.

BACKGROUND: Comprehensive information about the accuracy of antigen rapid diagnostic tests (Ag-RDTs) for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is essential to guide public health decision makers in choosing the best tests and testing policies. In August 2021, we published a systematic review and meta-analysis about the accuracy of Ag-RDTs. We now update this work and analyze the factors influencing test sensitivity in further detail. METHODS AND FINDINGS: We registered the review on PROSPERO (registration number: CRD42020225140). We systematically searched preprint and peer-reviewed databases for publications evaluating the accuracy of Ag-RDTs for SARS-CoV-2 until August 31, 2021. Descriptive analyses of all studies were performed, and when more than 4 studies were available, a random-effects meta-analysis was used to estimate pooled sensitivity and specificity with reverse transcription polymerase chain reaction (RT-PCR) testing as a reference. To evaluate factors influencing test sensitivity, we performed 3 different analyses using multivariable mixed-effects meta-regression models. We included 194 studies with 221,878 Ag-RDTs performed. Overall, the pooled estimates of Ag-RDT sensitivity and specificity were 72.0% (95% confidence interval [CI] 69.8 to 74.2) and 98.9% (95% CI 98.6 to 99.1). When manufacturer instructions were followed, sensitivity increased to 76.3% (95% CI 73.7 to 78.7). Sensitivity was markedly better on samples with lower RT-PCR cycle threshold (Ct) values (97.9% [95% CI 96.9 to 98.9] and 90.6% [95% CI 88.3 to 93.0] for Ct-values <20 and <25, compared to 54.4% [95% CI 47.3 to 61.5] and 18.7% [95% CI 13.9 to 23.4] for Ct-values ≥25 and ≥30) and was estimated to increase by 2.9 percentage points (95% CI 1.7 to 4.0) for every unit decrease in mean Ct-value when adjusting for testing procedure and patients' symptom status. Concordantly, we found the mean Ct-value to be lower for true positive (22.2 [95% CI 21.5 to 22.8]) compared to false negative (30.4 [95% CI 29.7 to 31.1]) results. Testing in the first week from symptom onset resulted in substantially higher sensitivity (81.9% [95% CI 77.7 to 85.5]) compared to testing after 1 week (51.8%, 95% CI 41.5 to 61.9). Similarly, sensitivity was higher in symptomatic (76.2% [95% CI 73.3 to 78.9]) compared to asymptomatic (56.8% [95% CI 50.9 to 62.4]) persons. However, both effects were mainly driven by the Ct-value of the sample. With regards to sample type, highest sensitivity was found for nasopharyngeal (NP) and combined NP/oropharyngeal samples (70.8% [95% CI 68.3 to 73.2]), as well as in anterior nasal/mid-turbinate samples (77.3% [95% CI 73.0 to 81.0]). Our analysis was limited by the included studies' heterogeneity in viral load assessment and sample origination. CONCLUSIONS: Ag-RDTs detect most of the individuals infected with SARS-CoV-2, and almost all (>90%) when high viral loads are present. With viral load, as estimated by Ct-value, being the most influential factor on their sensitivity, they are especially useful to detect persons with high viral load who are most likely to transmit the virus. To further quantify the effects of other factors influencing test sensitivity, standardization of clinical accuracy studies and access to patient level Ct-values and duration of symptoms are needed.

Accuracy of novel antigen rapid diagnostics for SARS-CoV-2: A living systematic review and meta-analysis.

BACKGROUND: SARS-CoV-2 antigen rapid diagnostic tests (Ag-RDTs) are increasingly being integrated in testing strategies around the world. Studies of the Ag-RDTs have shown variable performance. In this systematic review and meta-analysis, we assessed the clinical accuracy (sensitivity and specificity) of commercially available Ag-RDTs. METHODS AND FINDINGS: We registered the review on PROSPERO (registration number: CRD42020225140). We systematically searched multiple databases (PubMed, Web of Science Core Collection, medRvix, bioRvix, and FIND) for publications evaluating the accuracy of Ag-RDTs for SARS-CoV-2 up until 30 April 2021. Descriptive analyses of all studies were performed, and when more than 4 studies were available, a random-effects meta-analysis was used to estimate pooled sensitivity and specificity in comparison to reverse transcription polymerase chain reaction (RT-PCR) testing. We assessed heterogeneity by subgroup analyses, and rated study quality and risk of bias using the QUADAS-2 assessment tool. From a total of 14,254 articles, we included 133 analytical and clinical studies resulting in 214 clinical accuracy datasets with 112,323 samples. Across all meta-analyzed samples, the pooled Ag-RDT sensitivity and specificity were 71.2% (95% CI 68.2% to 74.0%) and 98.9% (95% CI 98.6% to 99.1%), respectively. Sensitivity increased to 76.3% (95% CI 73.1% to 79.2%) if analysis was restricted to studies that followed the Ag-RDT manufacturers' instructions. LumiraDx showed the highest sensitivity, with 88.2% (95% CI 59.0% to 97.5%). Of instrument-free Ag-RDTs, Standard Q nasal performed best, with 80.2% sensitivity (95% CI 70.3% to 87.4%). Across all Ag-RDTs, sensitivity was markedly better on samples with lower RT-PCR cycle threshold (Ct) values, i.e., <20 (96.5%, 95% CI 92.6% to 98.4%) and <25 (95.8%, 95% CI 92.3% to 97.8%), in comparison to those with Ct ≥ 25 (50.7%, 95% CI 35.6% to 65.8%) and ≥30 (20.9%, 95% CI 12.5% to 32.8%). Testing in the first week from symptom onset resulted in substantially higher sensitivity (83.8%, 95% CI 76.3% to 89.2%) compared to testing after 1 week (61.5%, 95% CI 52.2% to 70.0%). The best Ag-RDT sensitivity was found with anterior nasal sampling (75.5%, 95% CI 70.4% to 79.9%), in comparison to other sample types (e.g., nasopharyngeal, 71.6%, 95% CI 68.1% to 74.9%), although CIs were overlapping. Concerns of bias were raised across all datasets, and financial support from the manufacturer was reported in 24.1% of datasets. Our analysis was limited by the included studies' heterogeneity in design and reporting. CONCLUSIONS: In this study we found that Ag-RDTs detect the vast majority of SARS-CoV-2-infected persons within the first week of symptom onset and those with high viral load. Thus, they can have high utility for diagnostic purposes in the early phase of disease, making them a valuable tool to fight the spread of SARS-CoV-2. Standardization in conduct and reporting of clinical accuracy studies would improve comparability and use of data.

Role of psychiatric hospitals during a pandemic: introducing the Munich Psychiatric COVID-19 Pandemic Contingency Plan.

BACKGROUND: Psychiatry is facing major challenges during the current coronavirus disease 2019 (COVID)-19 pandemic. These challenges involve its actual and perceived role within the medical system, in particular how psychiatric hospitals can maintain their core mission of attending to people with mental illness while at the same time providing relief to overstretched general medicine services. Although psychiatric disorders comprise the leading cause of the global burden of disease, mental healthcare has been deemphasised in the wake of the onslaught of the pandemic: to make room for emergency care, psychiatric wards have been downsized, clinics closed, psychiatric support systems discontinued and so on. To deal with this pressing issue, we developed a pandemic contingency plan with the aim to contain, decelerate and, preferably, avoid transmission of COVID-19 and to enable and maintain medical healthcare for patients with mental disorders. AIMS: To describe our plan as an example of how a psychiatric hospital can share in providing acute care in a healthcare system facing an acute and highly infectious pandemic like COVID-19 and at the same time provide support for people with mental illness, with or without a COVID-19 infection. METHOD: This was a descriptive study. RESULTS: The plan was based on the German national pandemic strategy and several legal recommendations and was implemented step by step on the basis of the local COVID-19 situation. In addition, mid- and long-term plans were developed for coping with the aftermath of the pandemic. CONCLUSIONS: The plan enabled the University Hospital to maintain medical healthcare for patients with mental disorders. It has offered the necessary flexibility to adapt its implementation to the first and second waves of the COVID-19 pandemic in Germany. The plan is designed to serve as an easily adaptable blueprint for psychiatric hospitals around the world.

Muscarinic receptors 2 and 5 regulate bitter response of urethral brush cells via negative feedback.

We have recently identified a cholinergic chemosensory cell in the urethral epithelium, urethral brush cell (UBC), that, upon stimulation with bitter or bacterial substances, initiates a reflex detrusor activation. Here, we elucidated cholinergic mechanisms that modulate UBC responsiveness. We analyzed muscarinic acetylcholine receptor (M1-5 mAChR) expression by using RT-PCR in UBCs, recorded [Ca2+]i responses to a bitter stimulus in isolated UBCs of wild-type and mAChR-deficient mice, and performed cystometry in all involved strains. The bitter response of UBCs was enhanced by global cholinergic and selective M2 inhibition, diminished by positive allosteric modulation of M5, and unaffected by M1, M3, and M4 mAChR inhibitors. This effect was not observed in M2 and M5 mAChR-deficient mice. In cystometry, M5 mAChR-deficient mice demonstrated signs of detrusor overactivity. In conclusion, M2 and M5 mAChRs attenuate the bitter response of UBC via a cholinergic negative autocrine feedback mechanism. Cystometry suggests that dysfunction, particularly of the M5 receptor, may lead to such symptoms as bladder overactivity.-Deckmann, K., Rafiq, A., Erdmann, C., Illig, C., Durschnabel, M., Wess, J., Weidner, W., Bschleipfer, T., Kummer, W. Muscarinic receptors 2 and 5 regulate bitter response of urethral brush cells via negative feedback.

Permeability profile of poly(alkyl cyanoacrylate) nanocapsules.

The permeability profile of poly(alkyl cyanoacrylate) nanocapsules is studied using pulsed-field gradient NMR on a variety of tracer molecules of different size and polarity. In addition, the influence of the surfactant layer and of organic tracer molecules on the capsule membrane permeability for water is examined. The aim of the study is a detailed understanding of the dependencies between molecular properties of a given tracer and its capability to permeate the polymer membrane. As expected, the results clearly show that the capsule membrane permeability depends on the size of the tracer molecule: the exchange rate of polyethylene glycols continuously decreases with increasing chain length. However, the permeation rate also varies with the polarity of the tracer molecule: molecules of lower polarity exchange faster than more polar ones. In turn, the capsule membrane permeability is influenced by added organic compounds. Focusing on water as a characteristic permeate and depending on the type of the additive, the permeability can be varied by almost an order of magnitude, offering an opportunity to reversibly switch the uptake and release properties of the capsules.

Enhanced Optical Head Tracking for Cranial Radiation Therapy: Supporting Surface Registration by Cutaneous Structures.

PURPOSE: To support surface registration in cranial radiation therapy by structural information. The risk for spatial ambiguities is minimized by using tissue thickness variations predicted from backscattered near-infrared (NIR) light from the forehead. METHODS AND MATERIALS: In a pilot study we recorded NIR surface scans by laser triangulation from 30 volunteers of different skin type. A ground truth for the soft-tissue thickness was segmented from MR scans. After initially matching the NIR scans to the MR reference, Gaussian processes were trained to predict tissue thicknesses from NIR backscatter. Moreover, motion starting from this initial registration was simulated by 5000 random transformations of the NIR scan away from the MR reference. Re-registration to the MR scan was compared with and without tissue thickness support. RESULTS: By adding prior knowledge to the backscatter features, such as incident angle and neighborhood information in the scanning grid, we showed that tissue thickness can be predicted with mean errors of <0.2 mm, irrespective of the skin type. With this additional information, the average registration error improved from 3.4 mm to 0.48 mm by a factor of 7. Misalignments of more than 1 mm were almost thoroughly (98.9%) pushed below 1 mm. CONCLUSIONS: For almost all cases tissue-enhanced matching achieved better results than purely spatial registration. Ambiguities can be minimized if the cutaneous structures do not agree. This valuable support for surface registration increases tracking robustness and avoids misalignment of tumor targets far from the registration site.

Microstructure of the superior longitudinal fasciculus predicts stimulation-induced interference with on-line motor control.

A cortical visuomotor network, comprising the medial intraparietal sulcus (mIPS) and the dorsal premotor area (PMd), encodes the sensorimotor transformations required for the on-line control of reaching movements. How information is transmitted between these two regions and which pathways are involved, are less clear. Here, we use a multimodal approach combining repetitive transcranial magnetic stimulation (rTMS) and diffusion tensor imaging (DTI) to investigate whether structural connectivity in the 'reaching' circuit is associated to variations in the ability to control and update a movement. We induced a transient disruption of the neural processes underlying on-line motor adjustments by applying 1Hz rTMS over the mIPS. After the stimulation protocol, participants globally showed a reduction of the number of corrective trajectories during a reaching task that included unexpected visual perturbations. A voxel-based analysis revealed that participants exhibiting higher fractional anisotropy (FA) in the second branch of the superior longitudinal fasciculus (SLF II) suffered less rTMS-induced behavioral impact. These results indicate that the microstructural features of the white matter bundles within the parieto-frontal 'reaching' circuit play a prominent role when action reprogramming is interfered. Moreover, our study suggests that the structural alignment and cohesion of the white matter tracts might be used as a predictor to characterize the extent of motor impairments.

Emotional reactivity to threat modulates activity in mentalizing network during aggression.

Aggression is a common response to provocation, albeit with considerable interindividual differences. In this fMRI study, we investigated emotional reactivity to threat as possible link between provocation and aggression, as well as the neural correlates of this relationship. We hypothesized that emotional reactivity, measured as fear potentiation (FP) of the startle response, would be negatively associated with aggressive behavior and would modulate neural activity during an aggressive interaction. In 30 healthy female participants, FP was measured as the difference between blink amplitudes while watching threatening vs neutral pictures. Participants subsequently engaged in a variant of the Taylor Aggression Paradigm (TAP), while being scanned. During the TAP, participants selected a punishment level for either a highly provoking or a nonprovoking opponent. There was no difference in aggressive behavior between participants high and low in FP. However, we found a negative correlation between FP and the neural provocation effect in several regions of a network previously associated with mentalizing including the medial prefrontal cortex, precuneus and the temporo-parietal junction. Independently of the FP variability, aggressive behavior correlated with the provocation effect on activity in the caudate nucleus. Our results indicate that during a provocative confrontation, high emotional reactivity to threat suppresses recruitment of the mentalizing network.

Variation of stimulation intensity in transcranial magnetic stimulation with depth.

The quantification of stimulation intensity in transcranial magnetic stimulation (TMS) as a function of depth is of interest in order to adjust stimulator output when non-motor regions are stimulated. Currently, a linear increase of stimulator output to correct for depth has been suggested. This is contrary to the physical properties of the electric field that is induced by the stimulation coil as measured in vitro. For two stimulation coils, we determined the characteristics of their field in air. We then measured motor thresholds for the abductor hallucis muscle of 10 healthy subjects. Coil position, distance from the scalp, and orientation were controlled with a head tracking robotic system that corrected for head movements. In both coils an approximately exponential increase, rather than a linear increase, of the threshold with the scalp-coil distance was measured. The slope of the increase was slightly smaller than expected from the field characteristic, but overall in good agreement. With respect to the depth of the TMS target, different results were obtained from the threshold ratios of the coils and from the slopes of the threshold increase with distance. For the adjustment of stimulator output to scalp-to-cortex distances exponential functions with parameters motivated by physical properties of the coils should be used. Estimation of the target depth from the thresholds, with different coils, is not reliable. Our results resolve a conflict between physiological data and physical properties of TMS coils. They provide a more reliable base for depth dependent corrections for TMS stimulator output.

Neural activity related to self- versus externally generated painful stimuli reveals distinct differences in the lateral pain system in a parametric fMRI study.

Self-generated sensory stimulation can be distinguished from externally generated stimulation that is otherwise identical. To determine how the brain differentiates external from self-generated noxious stimulation and which structures of the lateral pain system use neural signals to predict the sensory consequences of self-generated painful stimulation, we used functional magnetic resonance imaging to examine healthy human subjects who received thermal-contact stimuli with noxious and non-noxious temperatures on the resting right hand in random order. These stimuli were internally (self-generated) or externally generated. Two additional conditions served as control conditions: to account for stimulus onset uncertainty, acoustic stimuli preceding the same thermal stimuli were used with variable or fixed delays but without any stimulus-eliciting movements. Whereas graded pain-related activity in the insula and secondary somatosensory cortex (SII) was independent of how the stimulus was generated, it was attenuated in the primary somatosensory cortex (SI) during self-generated stimulation. These data agree with recent concepts of the parallel processing of nociceptive signals to the primary and secondary somatosensory cortices. They also suggest that brain areas that encode pain intensity do not distinguish between internally or externally applied noxious stimuli, i.e., this adaptive biological mechanism prevents harm to the individual. The attenuated activation of SI during self-generated painful stimulation might be a result of the predictability of the sensory consequences of the pain-related action.

Parametric modulation of cortical activation during smooth pursuit with and without target blanking. an fMRI study.

Smooth pursuit eye movements (SPEM) are performed to track slowly moving visual targets and are accompanied by saccades whenever foveal representation is lost. In the present study, we correlated the cerebral activation as assessed by functional magnetic resonance imaging with parameters of eye movement performance in order to determine the cortical areas involved in the retinal and extraretinal processing of maintaining smooth pursuit velocity (SPV) and generating saccades in 16 healthy males. The stimulus consisted of a target moving at a constant velocity of 10 degrees/s with and without target blanking. During constant target presentation, SPV was positively correlated with the BOLD signal in the right V5 complex and negatively correlated with the BOLD response in the left dorsolateral prefrontal cortex (DLPFC). In the condition with target blanking, additional negative correlations with SPV were found in the left frontal eye field (FEF), the left parietoinsular vestibular cortex (PIVC) and the left angular gyrus. Saccadic frequency was negatively correlated with activations of the right mesial intraparietal sulcus (IPS) during both conditions and the right premotor area during continuous target presentation. We conclude that V5 is directly related to the maintenance of an optimal smooth pursuit velocity during visual feedback, whereas the FEF, PFC, angular gyrus and PIVC are involved in reconstitution and prediction whenever SPV decreases, especially during maintenance of smooth pursuit in the absence of a visual target. Furthermore, we suggest that parietal areas are related to the suppression of saccades during smooth pursuit.

Motor memory consolidation in sleep shapes more effective neuronal representations.

Learning a motor skill involves a latent process of consolidation that develops after training to enhance the skill in the absence of any practice and crucially depends on sleep. Here, we show that this latent consolidation during sleep changes the brain representation of the motor skill by reducing overall the neocortical contributions to the representation. Functional magnetic resonance brain imaging was performed during initial training and 48 h later, at retesting, on a sequential finger movement task with training followed by either a night of regular sleep or sleep deprivation. An additional night of sleep for all subjects served to rule out unspecific effects of sleep loss at retrieval testing. Posttraining sleep, but not sleep deprivation, led to improved motor skill performance at retrieval. This sleep-dependent improvement was linked to greatly reduced brain activation in prefrontal, premotor, and primary motor cortical areas, along with a stronger involvement of left parietal cortical regions. Our findings indicate that storing a motor skill during sleep reorganizes its brain representation toward enhanced efficacy.

Activation of cerebellar hemispheres in spatial memorization of saccadic eye movements: an fMRI study.

What mechanisms allow us to direct a precise saccade to a remembered target position in space? The cerebellum has been proposed to be involved not only in motor and oculomotor control, but also in perceptual and cognitive functions. We used functional MRI (Echoplanar imaging at 1.5 T) to investigate the role of the cerebellum in the control of externally triggered and internally generated saccadic eye movements of high and low memory impact, in six healthy volunteers. Memory-guided saccades to remembered locations of 3 targets (triple-step saccades) in contrast to either central fixation or to visually guided saccades activated the cerebellar hemispheres predominantly within lobuli VI-crus I. The same areas were activated when an analogous visuospatial working memory task was contrasted to the triple-step saccades. Visually guided saccades activated the posterior vermis and the triple-step saccades, contrasted to the working memory task, activated predominantly the posterior vermis and paravermal regions. Our data confirm the primary involvement of the posterior vermis for visually-triggered saccadic eye movements and present novel evidence for a role of the cerebellar hemispheres in the mnemonic and visuospatial control of memory-guided saccades.

Cortical mechanisms of smooth pursuit eye movements with target blanking. An fMRI study.

Smooth pursuit eye movements are evoked by retinal image motion of visible moving objects and can also be driven by the internal representation of a target due to extraretinal mechanisms (e.g. efference copy). To delineate the corresponding neuronal correlates, functional magnetic resonance imaging at 1.5 T was applied during smooth pursuit at 10 degrees /s with continuous target presentation and target blanking for 1 s to 16 right-handed healthy males. Eye movements were assessed during scanning sessions by infra-red reflection oculography. Smooth pursuit performance was optimal when the target was visible but decreased to a residual velocity of about 30% of the velocity observed during continuous target presentation. Random effects analysis of the imaging data yielded an activation pattern for smooth pursuit in the absence of a visual target (in contrast to continuous target presentation) which included a number of cortical areas in which extraretinal information is available such as the frontal eye field, the superior parietal lobe, the anterior and the posterior intraparietal sulcus and the premotor cortex, and also the supplementary and the presupplementary eye field, the supramarginal gyrus, the dorsolateral prefrontal cortex, cerebellar areas and the basal ganglia. We suggest that cortical mechanisms such as prediction, visuo-spatial attention and transformation, multimodal visuomotor control and working memory are of special importance for maintaining smooth pursuit eye movements in the absence of a visible target.

The role of the fastigial nucleus in saccadic eye oscillations.

For the first time, we provide functional magnetic resonance imaging evidence for a recent hypothesis that saccadic oscillations in opsoclonus may result from a disinhibition of the cerebellar fastigial nuclei. Two patients with severe opsoclonus were examined during fixation in the light and during eye closure and in darkness where opsoclonus disappeared. Their activation during opsoclonus was compared with 10 healthy subjects performing visually guided and self-paced saccades in the light and darkness. In contrast to the control subjects, the patients showed a strong bilateral midline cerebellar activation that involved the deep cerebellar nuclei. This is probably not just a secondary finding in the fastigial nuclei due to the high frequent saccadic activity because there was, concomitantly, no oculomotor vermal activation, which is normally seen in healthy subjects. We propose that cerebellar activation of the fastigial nuclei may cause opsoclonus via their projections to the brainstem saccadic generator.

Modulation of cerebellar activation by predictive and non-predictive sequential finger movements.

We investigated the modulation of cerebellar activation by predictive and non-predictive sequential finger movements. It is hypothesized that the prediction of desired movement sequences and adaptation to new movement parameters is mediated by the cerebellum. Using functional MRI at 1.5 T, seven normal subjects performed sequential finger to thumb opposition movements, either in predictive (repeatedly 2,3,4,5) or non-predictive (randomized) fashion at a constant frequency of 1 Hz. Performance and error rates were monitored by simultaneous recording of the finger movements. Predictive sequential finger opposition movements activated a cerebellar network including the lobuli IV-VI ipsilateral to the movements, the contralateral lobuli IV-VI, the vermis, and lobuli VIIB-VIII ipsilaterally. Non-predictive compared to predictive finger opposition movements activated a broader area within the ipsi- and contralateral anterior cerebellum, lobuli IV-VI, the vermis, and the ipsilateral lobuli VIIB-VIII. Additional activation foci were found in the contralateral lobuli VIIA and VIIB-VIII. Our study demonstrates a modulated information processing within the cerebellar network dependent on the predictability of movement sequences.