Efficient Estimation of the Human Circadian Phase via Kalman Filtering.

Circadian rhythms play a vital role in maintaining a person's well-being but remain difficult to quantify accurately. Numerous approaches exist to measure these rhythms, but they often suffer from performance issues on the individual level. This work implements a Steady-State Kalman Filter as a method for estimating the circadian phase shifts from biometric signals. Our framework can automatically fit the filter's parameters to biometric data obtained for each individual, and we were able to consistently estimate the phase shift within 1 hour of melatonin estimates on 100% of all subjects in this study. The estimation method opens up the possibility of real-time control and assessment of the circadian system, as well as chronotherapeutic intervention.Clinical relevance- This establishes a near real-time alternative to melatonin measurements for the estimation of circadian phase shifts, with potential applications in feedback circadian control and chronotherapeutics.

Fast tuning of observer-based circadian phase estimator using biometric data.

Circadian rhythms play a vital role in maintaining an individual's well-being, and they have been shown to be the product of the master oscillator in the suprachiasmatic nuclei (SCN) located in the brain. The SCN however, is inaccessible for assessment, so existing standards for circadian phase estimation often focus on the use of indirect measurements as proxies for the circadian state. These methods often suffer from severe delays due to invasive methods of sample collection, making online estimation impossible. In this paper, we propose a linear state observer as an elegant solution for continuous phase estimation. This observer-based filter is used in isolating the frequency components of input biometric signals, which are then taken to be the circadian state. We start the design process by fixing the observer's oscillatory frequency at 24 hours, and then we tune its gains using an evolutionary optimization algorithm to extract the target components from individuals' data. The resulting filter was able to provide phase estimates with an average absolute error within 1.5 hours on all test subjects, given their minute-to-minute actigraphy data collected in ambulatory conditions.

Actigraphy-based parameter tuning process for adaptive notch filter and circadian phase shift estimation.

We report herein the application of an adaptive notch filter (ANF) algorithm to minute-by-minute actigraphy data to estimate the continuous circadian phase of eight healthy adults. As the adaptation rates and damping factor of the ANF algorithm have large impacts on the ANF states and circadian phase estimation results, we propose a method for optimizing these parameters. The ANF with optimal parameters is further used to estimate the circadian phase shift from the actigraphy data. Dim light melatonin onset (DLMO), considered the "gold standard" method for identification of circadian phase, was determined by a serial collection of salivary samples analyzed for melatonin per standard protocol simultaneously with the collection of actigraphic data. We demonstrate our ANF algorithm, when applied to the actigraphy data, is able to estimate the circadian phase as determined by the DLMO. These results demonstrate that applying our ANF with a well-defined parameter tuning process to actigraphic data can provide accurate measurements of the circadian phase and its shift without resorting to salivary melatonin collections.

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.

Parkinson's disease rigidity: relation to brain connectivity and motor performance.

OBJECTIVE: (1) To determine the brain connectivity pattern associated with clinical rigidity scores in Parkinson's disease (PD) and (2) to determine the relation between clinically assessed rigidity and quantitative metrics of motor performance. BACKGROUND: Rigidity, the resistance to passive movement, is exacerbated in PD by asking the subject to move the contralateral limb, implying that rigidity involves a distributed brain network. Rigidity mainly affects subjects when they attempt to move; yet the relation between clinical rigidity scores and quantitative aspects of motor performance are unknown. METHODS: Ten clinically diagnosed PD patients (off-medication) and 10 controls were recruited to perform an fMRI squeeze-bulb tracking task that included both visually guided and internally guided features. The direct functional connectivity between anatomically defined regions of interest was assessed with Dynamic Bayesian Networks (DBNs). Tracking performance was assessed by fitting Linear Dynamical System (LDS) models to the motor performance, and was compared to the clinical rigidity scores. A cross-validated Least Absolute Shrinkage and Selection Operator (LASSO) regression method was used to determine the brain connectivity network that best predicted clinical rigidity scores. RESULTS: The damping ratio of the LDS models significantly correlated with clinical rigidity scores (p = 0.014). An fMRI connectivity network in subcortical and primary and premotor cortical regions accurately predicted clinical rigidity scores (p < 10(-5)). CONCLUSION: A widely distributed cortical/subcortical network is associated with rigidity observed in PD patients, which reinforces the importance of altered functional connectivity in the pathophysiology of PD. PD subjects with higher rigidity scores tend to have less overshoot in their tracking performance, and damping ratio may represent a robust, quantitative marker of the motoric effects of increasing rigidity.

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.

Assessing manual pursuit tracking in Parkinson's disease via linear dynamical systems.

Quantitative assessment of motor performance is important for diseases of motor control, such as Parkinson's disease (PD). Manual tracking tasks are well suited for motor assessment, as they can be performed concomitantly with brain mapping techniques. Here we propose utilizing second-order linear dynamical systems to assess manual pursuit tracking performance. With the desired trajectory as the input, and the subject's actual motor response as the output, a linear model characterized by natural frequency and damping ratio is identified for each subject. We applied this method to 10 PD subjects (on and off L: -dopa medication) and 10 normal subjects performing a multi-frequency sinusoidal tracking task. Model parameters were more sensitive than overall tracking errors in determining significant differences between groups. The effect of L: -dopa medication was to reduce the damping ratio and make the range in natural frequency across individuals approach that of normal subjects. We interpret the changes in damping ratio and natural frequency as possibly related to suppression of compensatory cerebellar activity and/or improvement of motor program selection, and the changes in natural frequency as an implicit strategy to maintain settling time in the face of reduce damping ratio. Our results suggest that simple linear dynamical system models can be a powerful method to assess tracking performance in Parkinson's disease because of the additional insight they can provide into neurological processes.

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.

L-dopa induces under-damped visually guided motor responses in Parkinson's disease.

Parkinson's disease preferentially affects internally generated movements, e.g., movements recalled from memory, while externally cued movements are relatively preserved. However, L-dopa may have effects on visually guided movements as well as error-related processing. Fourteen Parkinson's disease (PD) subjects (on and off L-dopa medication) as well as ten normal controls performed a tracking task using a joystick. During discrete 30 s blocks, the visual feedback of the actual tracking errors were attenuated, amplified or unaltered. Second order dynamical system models, with the desired trajectory as the input and the actual motor performance as the output, were used to characterize the motor performance by the each subject under each condition. Although the overall root-mean-square tracking error did not significantly differ between groups, the nature of the motor performance differed significantly across groups. A clear dissociation was made between manipulations of error feedback--which altered the natural frequency of the models--and the effects of L-dopa, which affected damping. Compared to normal controls, PD subjects were significantly overdamped before medication and underdamped after medication. We interpret our results as being suggestive of L: -dopa normalization of compensatory overactive cerebellar activity in PD.