Excessive Sensitivity to Uncertain Visual Input in L-DOPA-Induced Dyskinesias in Parkinson's Disease: Further Implications for Cerebellar Involvement.

UNLABELLED: When faced with visual uncertainty during motor performance, humans rely more on predictive forward models and proprioception and attribute lesser importance to the ambiguous visual feedback. Though disrupted predictive control is typical of patients with cerebellar disease, sensorimotor deficits associated with the involuntary and often unconscious nature of l-DOPA-induced dyskinesias in Parkinson's disease (PD) suggests dyskinetic subjects may also demonstrate impaired predictive motor control. METHODS: We investigated the motor performance of 9 dyskinetic and 10 non-dyskinetic PD subjects on and off l-DOPA, and of 10 age-matched control subjects, during a large-amplitude, overlearned, visually guided tracking task. Ambiguous visual feedback was introduced by adding "jitter" to a moving target that followed a Lissajous pattern. Root mean square (RMS) tracking error was calculated, and ANOVA, robust multivariate linear regression, and linear dynamical system analyses were used to determine the contribution of speed and ambiguity to tracking performance. RESULTS: Increasing target ambiguity and speed contributed significantly more to the RMS error of dyskinetic subjects off medication. l-DOPA improved the RMS tracking performance of both PD groups. At higher speeds, controls and PDs without dyskinesia were able to effectively de-weight ambiguous visual information. CONCLUSION: PDs' visually guided motor performance degrades with visual jitter and speed of movement to a greater degree compared to age-matched controls. However, there are fundamental differences in PDs with and without dyskinesia: subjects without dyskinesia are generally slow, and less responsive to dynamic changes in motor task requirements, but in PDs with dyskinesia, there was a trade-off between overall performance and inappropriate reliance on ambiguous visual feedback. This is likely associated with functional changes in posterior parietal-ponto-cerebellar pathways.

Noisy galvanic vestibular stimulation modulates the amplitude of EEG synchrony patterns.

Noisy galvanic vestibular stimulation has been associated with numerous cognitive and behavioural effects, such as enhancement of visual memory in healthy individuals, improvement of visual deficits in stroke patients, as well as possibly improvement of motor function in Parkinson's disease; yet, the mechanism of action is unclear. Since Parkinson's and other neuropsychiatric diseases are characterized by maladaptive dynamics of brain rhythms, we investigated whether noisy galvanic vestibular stimulation was associated with measurable changes in EEG oscillatory rhythms within theta (4-7.5 Hz), low alpha (8-10 Hz), high alpha (10.5-12 Hz), beta (13-30 Hz) and gamma (31-50 Hz) bands. We recorded the EEG while simultaneously delivering noisy bilateral, bipolar stimulation at varying intensities of imperceptible currents - at 10, 26, 42, 58, 74 and 90% of sensory threshold - to ten neurologically healthy subjects. Using standard spectral analysis, we investigated the transient aftereffects of noisy stimulation on rhythms. Subsequently, using robust artifact rejection techniques and the Least Absolute Shrinkage Selection Operator regression and cross-validation, we assessed the combinations of channels and power spectral features within each EEG frequency band that were linearly related with stimulus intensity. We show that noisy galvanic vestibular stimulation predominantly leads to a mild suppression of gamma power in lateral regions immediately after stimulation, followed by delayed increase in beta and gamma power in frontal regions approximately 20-25 s after stimulation ceased. Ongoing changes in the power of each oscillatory band throughout frontal, central/parietal, occipital and bilateral electrodes predicted the intensity of galvanic vestibular stimulation in a stimulus-dependent manner, demonstrating linear effects of stimulation on brain rhythms. We propose that modulation of neural oscillations is a potential mechanism for the previously-described cognitive and motor effects of vestibular stimulation, and noisy galvanic vestibular stimulation may provide an additional non-invasive means for neuromodulation of functional brain networks.

Dyskinetic Parkinson's disease patients demonstrate motor abnormalities off medication.

The pathophysiology of L-dopa-induced dyskinesias (LIDs) in Parkinson's disease (PD) remains poorly understood. The presence of superimposed LIDs clearly differentiates motor performance of dyskinetic from non-dyskinetic PD subjects when they are on medication, but here, we investigated whether their respective motor performance differs while subjects are off L-dopa medication and LIDs are not apparent. We assessed the motor performance of nine dyskinetic and ten non-dyskinetic PD subjects off L-dopa, and of ten age-matched control subjects, during a visually guided tracking task. As previous studies have suggested that linear dynamical system (LDS) models are useful to assess motor performance in PD in addition to overall tracking error, we used LDS models to assess the damping ratio parameter of motor behavior while controlling for disease severity. While overall tracking error did not significantly differ across groups, dyskinetic PD subjects demonstrated a significantly decreased mean damping ratio compared with control and non-dyskinetic PD subjects. For both groups, greater disease severity significantly predicted a lower damping ratio, but even after controlling for disease severity, the damping ratio for dyskinetic subjects was significantly lower. Our results demonstrate, somewhat counter-intuitively, that motor performance of dyskinetic and non-dyskinetic PD subjects differ, even off L-dopa when no dyskinesias are seen. A decreased damping ratio is indicative of a tendency to overshoot a target during motor performance, similar to the dysmetria found in cerebellar patients. We discuss the possibility of motor abnormalities in dyskinetic PD patients off medication in relation to altered functional cerebellar changes described in PD.

Altered directional connectivity in Parkinson's disease during performance of a visually guided task.

Recent animal studies have suggested that cortical areas may play a greater role in the modulation of abnormal oscillatory activity in Parkinson's disease (PD) than previously recognized. We investigated task and medication-dependent, EEG-based directional cortical connectivity in the θ (4-7Hz), α (8-12Hz), ß (13-30Hz) and low γ (31-50Hz) frequency bands in 10 PD subjects and 10 age-matched controls. All subjects performed a visually guided task previously shown to modulate abnormal oscillatory activity in PD subjects. We examined the connectivity in the simultaneously-recorded EEG between 5 electrode regions of interest (fronto-central, left and right sensorimotor, central and occipital) using a sparse, multivariate, autoregressive-based partial directed coherence method. For comparison, we utilized traditional Fourier analysis to evaluate task-dependent frequency spectra modulation in these same regions. While the spectral analysis revealed some overall differences between PD and control subjects, it demonstrated relatively modest changes between regions. In contrast, the partial directed coherence-based analysis revealed multifaceted, regionally and directionally-dependent alterations of connectivity in PD subjects during both movement preparation and execution. Connectivity was particularly altered posteriorly, suggesting abnormalities in visual and visuo-motor processing in PD. Moreover, connectivity measures in the α, ß and low γ frequency ranges correlated with motor Unified Parkinson's Disease Rating Scores in PD subjects withdrawn from medication. Levodopa administration only partially restored connectivity, and in some cases resulted in further exacerbation of abnormalities. Our results support the notion that PD is associated with significant alterations in connectivity between brain regions, and that these changes can be non-invasively detected in the EEG using partial directed coherence methods. Thus, the role of EEG to monitor PD may need to be further expanded.

Response to sensory uncertainty in Parkinson's disease: a marker of cerebellar dysfunction?

Motor performance is profoundly influenced by sensory information, yet sensory input can be noisy and uncertain. The basal ganglia and the cerebellum are important in processing sensory uncertainty, as the basal ganglia incorporate the uncertainty of predictive reward cues to reinforce motor programs, and the cerebellum and its connections mitigate the effect of ambiguous sensory input on motor performance through the use of forward models. Although Parkinson's disease (PD) is classically considered a primary disease of the basal ganglia, alterations in cerebellar activation are also observed, which may have consequences for the processing of sensory uncertainty. The aim of this study was to investigate the effect of visual uncertainty on motor performance in 15 PD patients and ten age-matched control subjects. Subjects performed a visually guided tracking task, requiring large-amplitude arm movements, by tracking with their index finger a moving target along a smooth trajectory. To induce visual uncertainty, the target position randomly jittered about the desired trajectory with increasing amplitudes. Tracking error was related to target ambiguity to a significantly greater degree in PD subjects off medication compared with control subjects, indicative of susceptibility to visual uncertainty in PD. l-Dopa partially ameliorated this deficit. We interpret our findings as suggesting an inability of PD subjects to create adequate forward models and/or de-weight less informative visual input. As these computations are normally associated with the cerebellum and connections, we suggest that alterations in normal cerebellar functioning may be a significant contributor to altered motor performance in PD.

Systemic and ocular findings in 100 patients with optic nerve hypoplasia.

To describe associated ocular, neurologic, and systemic findings in a population of children with optic nerve hypoplasia, a retrospective chart review of 100 patients with optic nerve hypoplasia for the presence of neurologic, radiologic, and endocrine abnormalities was performed. Neuroimaging and endocrine studies were obtained in 65 cases. Visual acuity and associated ocular, neurologic, endocrine, systemic, and structural brain abnormalities were recorded. Seventy-five percent had bilateral optic nerve hypoplasia. Conditions previously associated with optic nerve hypoplasia and present in our patients include premature birth in 21%, fetal alcohol syndrome in 9%, maternal diabetes in 6%, and endocrine abnormalities in 6%. Developmental delay was present in 32%, cerebral palsy in 13%, and seizures in 12%. Of those imaged, 60% had an abnormal study. Neuroimaging showed abnormalities in ventricles or white- or gray-matter development in 29 patients, septo-optic dysplasia in 10, hydrocephalus in 10, and corpus callosum abnormalities in 8. There was an associated clinical neurologic abnormality in 57% of patients with bilateral optic nerve hypoplasia and in 32% of patients with unilateral optic nerve hypoplasia. Patients with unilateral and bilateral optic nerve hypoplasia frequently have a wide range and common occurrence of concomitant neurologic, endocrine, and systemic abnormalities.