A Neuroanatomically Grounded Optimal Control Model of the Compensatory Eye Movement System in Mice.

We present a working model of the compensatory eye movement system in mice. We challenge the model with a data set of eye movements in mice (n =34) recorded in 4 different sinusoidal stimulus conditions with 36 different combinations of frequency (0.1-3.2 Hz) and amplitude (0.5-8°) in each condition. The conditions included vestibular stimulation in the dark (vestibular-ocular reflex, VOR), optokinetic stimulation (optokinetic reflex, OKR), and two combined visual/vestibular conditions (the visual-vestibular ocular reflex, vVOR, and visual suppression of the VOR, sVOR). The model successfully reproduced the eye movements in all conditions, except for minor failures to predict phase when gain was very low. Most importantly, it could explain the interaction of VOR and OKR when the two reflexes are activated simultaneously during vVOR stimulation. In addition to our own data, we also reproduced the behavior of the compensatory eye movement system found in the existing literature. These include its response to sum-of-sines stimuli, its response after lesions of the nucleus prepositus hypoglossi or the flocculus, characteristics of VOR adaptation, and characteristics of drift in the dark. Our model is based on ideas of state prediction and forward modeling that have been widely used in the study of motor control. However, it represents one of the first quantitative efforts to simulate the full range of behaviors of a specific system. The model has two separate processing loops, one for vestibular stimulation and one for visual stimulation. Importantly, state prediction in the visual processing loop depends on a forward model of residual retinal slip after vestibular processing. In addition, we hypothesize that adaptation in the system is primarily adaptation of this model. In other words, VOR adaptation happens primarily in the OKR loop.

Impairment of Long-Term Plasticity of Cerebellar Purkinje Cells Eliminates the Effect of Anodal Direct Current Stimulation on Vestibulo-Ocular Reflex Habituation.

Anodal direct current stimulation (DCS) of the cerebellum facilitates adaptation tasks, but the mechanism underlying this effect is poorly understood. We have evaluated whether the effects of DCS effects depend on plasticity of cerebellar Purkinje cells (PCs). Here, we have successfully developed a mouse model of cerebellar DCS, allowing us to present the first demonstration of cerebellar DCS driven behavioral changes in rodents. We have utilized a simple gain down vestibulo-ocular reflex (VOR) adaptation paradigm, that stabilizes a visual image on the retina during brief head movements, as behavioral tool. Our results provide evidence that anodal stimulation has an acute post-stimulation effect on baseline gain reduction of VOR (VOR gain in sham, anodal and cathodal groups are 0.75 ± 0.12, 0.68 ± 0.1, and 0.78 ± 0.05, respectively). Moreover, this anodal induced decrease in VOR gain is directly dependent on the PP2B medicated synaptic long-term potentiation (LTP) and intrinsic plasticity pathways of PCs.

Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial.

OBJECTIVE: To investigate whether mammalian target of rapamycin complex 1 (mTORC1) inhibitors could reduce seizure frequency in children with tuberous sclerosis complex (TSC). METHODS: Due to slow inclusion rate, target inclusion of 30 children was not reached. Twenty-three children with TSC and intractable epilepsy (age 1.8-10.9 years) were randomly assigned (1:1) to open-label, add-on sirolimus treatment immediately or after 6 months. Sirolimus was titrated to trough levels of 5-10 ng/mL. Primary endpoint was seizure frequency change during the sixth month of sirolimus treatment. RESULTS: Intention-to-treat analysis showed sirolimus treatment resulted in 41% seizure frequency decrease (95% confidence interval [CI] -69% to +14%; p = 0.11) compared to the standard-care period. Per protocol analysis of 14 children who reached sirolimus target trough levels in the sixth sirolimus month showed a seizure frequency decrease of 61% (95% CI -86% to +6%; p = 0.06). Cognitive development did not change. All children had adverse events. Five children discontinued sirolimus prematurely. CONCLUSIONS: We describe a randomized controlled trial for a non-antiepileptic drug that directly targets a presumed causal mechanism of epileptogenesis in a genetic disorder. Although seizure frequency decreased, especially in children reaching target trough levels, we could not show a significant benefit. Larger trials or meta-analyses are needed to investigate if patients with TSC with seizures benefit from mTORC1 inhibition. This trial was registered at trialregister.nl (NTR3178) and supported by the Dutch Epilepsy Foundation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that sirolimus does not significantly reduce seizure frequency in children with TSC and intractable epilepsy. The study lacked the precision to exclude a benefit from sirolimus.

Superposition Violations in the Compensatory Eye Movement System.

PURPOSE: Compensatory eye movements (CEM) maintain a stable image on the retina by minimizing retinal slip. The optokinetic reflex (OKR) and vestibulo-ocular reflex (VOR) compensate for low and high velocity stimuli, respectively. The OKR system is known to be highly nonlinear. The VOR is generally modeled as a linear system and assumed to satisfy the superposition and homogeneity principles. To probe CEM violation of the superposition principle, we recorded eye movement responses in C57BL/6 mice to sum of sine (SoS) stimulation, a combination of multiple nonharmonic inputs. METHODS: We tested the VOR, OKR, VVOR (visually enhanced VOR), and SVOR (suppressed VOR). We used stimuli containing 0.6 Hz, 0.8 Hz, 1.0 Hz, and 1.9 Hz. Power spectra of SoS stimuli did not yield distortion products. Gains and delays of SoS and single sine (SS) responses were compared to yield relative gains and delays. RESULTS: We find the superposition principle is violated primarily in the OKR, VOR, and SVOR conditions. In OKR, we observed relative gain suppression of the lower SoS stimulus frequency component irrespective of the absolute frequency. Conversely, SVOR and VOR results showed gain enhancement of the lower frequency component and overall decrease in lead. Visually enhanced VOR results showed trends for overall gain suppression and delay decrease. CONCLUSIONS: Compensatory eye movements arguably depend on predictive signals. These results may reflect better prediction for SS stimuli. Natural CEM system stimulation generally involves complex frequency spectra. Use of SoS stimuli is a step toward unravelling the signals that really drive CEM and the predictive algorithms they depend on.

Arm-trunk coordination as a measure of vestibulospinal efficiency.

When arm and trunk segments are involved in reaching for objects within arm's reach, vestibulospinal pathways compensate for trunk motion influence on arm movement. This compensatory arm-trunk synergy is characterised by a gain coefficient of 0 to 1. Vestibular patients have less efficient arm-trunk synergies and lower gains. To assess the clinical usefulness of the gain measure, we used a portable ultrasound-based device to characterize arm-trunk coordination deficits in vestibular patients. Arm-trunk coordination without vision was measured in a Stationary Hand Task where hand position was maintained during trunk movement, and a Reaching Task with and without trunk motion. Twenty unilateral vestibular patients and 16 controls participated. For the Stationary Hand task, patient gains ranged from g=0.94 (good compensation) to 0.31 (poor compensation) and, on average, were lower than in controls (patients: 0.67 ± 0.19; controls: 0.85 ± 0.07; p< 0.01). Gains were significantly correlated with clinical tests (Sensory Organization; r=0.62, p< 0.01, Foam Romberg Eyes Closed; r=0.65, p< 0.01). For the Reaching Task, blocking trunk movement during reaching modified hand position significantly more in patients (8.2 ± 4.3 cm) compared to controls (4.5 ± 1.7 cm, p< 0.02) and the amount of hand position deviation was correlated with the degree of vestibular loss in a sub-group (n=14) of patients. Measurement of the Stationary Task arm-trunk gain and hand deviations during the Reaching Task can help characterize sensorimotor problems in vestibular-deficient patients and track recovery following therapeutic interventions. The ultrasound-based portable device is suitable for measuring vestibulospinal deficits in arm-trunk coordination in a clinical setting.