Relationships between Freezing of Gait Severity and Cognitive Deficits in Parkinson’s Disease

Freezing of gait (FOG) is one of the most debilitating motor symptoms experienced by patients with Parkinson’s disease (PD), as it can lead to falls and a reduced quality of life. Evidence supports an association between FOG severity and cognitive functioning; however, results remain debatable. PD patients with (PDFOG+, n = 41) and without FOG (PDFOG–, n = 39) and control healthy subjects (n = 41) participated in this study. The NIH toolbox cognition battery, the Montreal Cognitive Assessment (MoCA), and the interval timing task were used to test cognitive domains. Measurements were compared between groups using multivariable models and adjusting for covariates. Correlation analyses, linear regression, and mediation models were applied to examine relationships among disease duration and severity, FOG severity, and cognitive functioning. Significant differences were observed between controls and PD patients for all cognitive domains. PDFOG+ and PDFOG– exhibited differences in Dimensional Change Card Sort (DCCS) test, interval timing task, and MoCA scores. After adjusting for covariates in two different models, PDFOG+ and PDFOG– differed in both MoCA and DCCS scores. In addition, significant relationships between FOG severity and cognitive function (MoCA, DCCS, and interval timing) were also found. Regression models suggest that FOG severity may be a predictor of cognitive impairment, and mediation models show the effects of cognitive impairment on the relationship between disease severity and FOG severity. Overall, this study provides insight into the relationship between cognitive and FOG severity in patients with PD, which could aid in the development of therapeutic interventions to manage both.

Dopamine mediates the bidirectional update of interval timing

The role of dopamine as a reward prediction error signal in reinforcement learning tasks has been well-established over the past decades. Recent work has shown that the reward prediction error interpretation can also account for the effects of dopamine on interval timing by controlling the speed of subjective time. According to this theory, the timing of the dopamine signal relative to reward delivery dictates whether subjective time speeds up or slows down: Early DA signals speed up subjective time and late signals slow it down. To test this bidirectional prediction, we reanalyzed measurements of dopaminergic neurons in the substantia nigra pars compacta of mice performing a self-timed movement task. Using the slope of ramping dopamine activity as a read-out of subjective time speed, we found that trial-by-trial changes in the slope could be predicted from the timing of dopamine activity on the previous trial. This result provides a key piece of evidence supporting a unified computational theory of reinforcement learning and interval timing.

Using adaptive psychophysics to identify the neural network reset time in subsecond interval timing

State-dependent network models of sub-second interval timing propose that duration is encoded in states of neuronal populations that need to reset prior to a novel timing operation to maintain optimal timing performance. Previous research has shown that the approximate boundary of this reset interval can be inferred by varying the inter-stimulus interval between two to-be-timed intervals. However, the estimated boundary of this reset interval is broad (250–500 ms) and remains under-specified with implications for the characteristics of state-dependent network dynamics sub-serving interval timing. Here, we probed the interval specificity of this reset boundary by manipulating the inter-stimulus interval between standard and comparison intervals in two sub-second auditory duration discrimination tasks (100 and 200 ms) and a control (pitch) discrimination task using adaptive psychophysics. We found that discrimination thresholds improved with the introduction of a 333 ms inter-stimulus interval relative to a 250 ms inter-stimulus interval in both duration discrimination tasks, but not in the control task. This effect corroborates previous findings of a breakpoint in the discrimination performance for sub-second stimulus interval pairs as a function of an incremental inter-stimulus delay but more precisely localizes the minimal inter-stimulus delay range. These results suggest that state-dependent networks sub-serving sub-second timing require approximately 250–333 ms for the network to reset to maintain optimal interval timing.

Altered cerebellar oscillations in Parkinson's disease patients during cognitive and motor tasks

Structural and functional abnormalities in the cerebellar region have been shown in patients with Parkinson's disease (PD). Since the cerebellar region has been associated with cognitive and lower-limb motor functions, it is imperative to study cerebellar oscillations in PD. Here, we evaluated cerebellar electroencephalography (EEG) during cognitive processing and lower-limb motor performances in PD. Cortical and cerebellar EEG were collected from 74 PD patients and 37 healthy control subjects during a 7-second interval timing task, 26 PD patients and 13 controls during a lower-limb pedaling task, and 23 PD patients during eyes-open/closed resting conditions. Analyses were focused on the mid-cerebellar Cbz electrode and further compared to the mid-occipital Oz and mid-frontal Cz electrodes. Increased alpha-band power was observed during the eyes-closed resting-state condition over Oz, but no change in alpha power was observed over Cbz. PD patients showed higher dispersion when performing the 7-second interval timing cognitive task and executed the pedaling motor task with reduced speed compared to controls. PD patients exhibited attenuated cue-triggered theta-band power over Cbz during both the interval timing and pedaling motor tasks. Connectivity measures between Cbz and Cz showed theta-band differences, but only during the pedaling motor task. Cbz oscillatory activity also differed from Oz across multiple frequency bands in both groups during both tasks. Our cerebellar EEG data along with previous magnetoencephalography and animal model studies clearly show the alteration in the cerebellar oscillations during cognitive and motor processing in PD.

Conceptually plausible Bayesian inference in interval timing

In a world that is uncertain and noisy, perception makes use of optimization procedures that rely on the statistical properties of previous experiences. A well-known example of this phenomenon is the central tendency effect observed in many psychophysical modalities. For example, in interval timing tasks, previous experiences influence the current percept, pulling behavioural responses towards the mean. In Bayesian observer models, these previous experiences are typically modelled by unimodal statistical distributions, referred to as the prior. Here, we critically assess the validity of the assumptions underlying these models and propose a model that allows for more flexible, yet conceptually more plausible, modelling of empirical distributions. By representing previous experiences as a mixture of lognormal distributions, this model can be parametrized to mimic different unimodal distributions and thus extends previous instantiations of Bayesian observer models. We fit the mixture lognormal model to published interval timing data of healthy young adults and a clinical population of aged mild cognitive impairment patients and age-matched controls, and demonstrate that this model better explains behavioural data and provides new insights into the mechanisms that underlie the behaviour of a memory-affected clinical population.

Interval timing and midfrontal delta oscillations are impaired in Parkinson's disease patients with freezing of gait

Gait abnormalities and cognitive dysfunction are common in patients with Parkinson's disease (PD) and get worst with disease progression. Recent evidence has suggested a strong relationship between gait abnormalities and cognitive dysfunction in PD patients and impaired cognitive control could be one of the causes for abnormal gait patterns. However, the pathophysiological mechanisms of cognitive dysfunction in PD patients with gait problems are unclear. Here, we collected scalp electroencephalography (EEG) signals during a 7-second interval timing task to investigate the cortical mechanisms of cognitive dysfunction in PD patients with (PDFOG+, n=34) and without (PDFOG-, n=37) freezing of gait, as well as control subjects (n=37). Results showed that the PDFOG+ group exhibited the lowest maximum response density at around 7 seconds compared to PDFOG- and control groups, and this response density peak correlated with gait abnormalities as measured by FOG scores. EEG data demonstrated that PDFOG+ had decreased midfrontal delta-band power at the onset of the target cue, which was also correlated with maximum response density and FOG scores. In addition, our classifier performed better at discriminating PDFOG+ from PDFOG- and controls with an area under the curve of 0.93 when midfrontal delta power was chosen as a feature. These findings suggest that abnormal midfrontal activity in PDFOG+ is related to cognitive dysfunction and describe the mechanistic relationship between cognitive and gait functions in PDFOG+. Overall, these results could advance the development of novel biosignatures and brain stimulation approaches for PDFOG+.