Timing variability and midfrontal ~4 Hz rhythms correlate with cognition in Parkinson’s disease

Abstract

Patients with Parkinson’s disease (PD) can have significant cognitive dysfunction; however, the mechanisms for these cognitive symptoms are unknown. Here, we used scalp electroencephalography (EEG) to investigate the cortical basis for PD-related cognitive impairments during interval timing, which requires participants to estimate temporal intervals of several seconds. Time estimation is an ideal task demand for investigating cognition in PD because it is simple, requires medial frontal cortical areas, and recruits basic executive processes such as working memory and attention. However, interval timing has never been systematically studied in PD patients with cognitive impairments. We report three main findings. First, 71 PD patients had increased temporal variability compared to 37 demographically matched controls, and this variability correlated with cognitive dysfunction as measured by the Montreal Cognitive Assessment (MOCA). Second, PD patients had attenuated ~4 Hz EEG oscillatory activity at midfrontal electrodes in response to the interval-onset cue, which was also predictive of MOCA. Finally, trial-by-trial linear mixed-effects modeling demonstrated that cue-triggered ~4 Hz power predicted subsequent temporal estimates as a function of PD and MOCA. Our data suggest that impaired cue-evoked midfrontal ~4 Hz activity predicts increased timing variability that is indicative of cognitive dysfunction in PD. These findings link PD-related cognitive dysfunction with cortical mechanisms of cognitive control, which could advance novel biomarkers and neuromodulation for PD.

Novelty-induced frontal-STN networks in Parkinson’s disease

“…All intraoperative research procedures were approved by the UI IRB (#201402730). All patients were tested on levodopa as our past work has shown that levodopa does not reliably modulate midfrontal ~4 Hz rhythms (Singh et al, 2018(Singh et al, , 2021. Levodopa-equivalent doses (LEDD) are presented in Table 2.…”

Experience‐related enhancements in striatal temporal encoding

“…Indeed, PD patients can have specific challenges in learning (Frank et al., 2004; Nieuwboer et al., 2009) and in performing functions for which they have extensive experience (Uc et al., 2006, 2007). PD patients have impairments in interval timing (Malapani et al., 1998, 2002; Merchant et al., 2008; Singh et al., 2021). In animal models, dopamine depletion can profoundly change striatal firing patterns and promote aberrant synchrony that is not entirely normalized by dopamine agonists (Alberico et al., 2017; Jáidar et al., 2019; Lara‐González et al., 2019).…”

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

“…Potential limitations of the interval timing cognitive task, lower-limb pedaling motor task, and both tasks-related cortical EEG have been discussed extensively in our prior reports (Singh et al, 2020;Singh et al, 2021) since cortical and cerebellar EEG data were collected from the same participants and under similar conditions. In addition, there were several limitations to this study.…”

“…We also recruited 5 PD patients to collect cerebellar EEG and electromyography (EMG) signals from the nearby muscles during resting and body actions. In our previous reports, all clinical details of the patients and control groups who participated in the cognitive task (Singh et al, 2021) and lower-limb pedaling motor task (Singh et al, 2020) are described and have been summarized in Table 1. All participants performed the interval timing cognitive and lower-limb pedaling motor tasks with levodopa medication.…”