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.

Background: Motor and cognitive dysfunction has been linked in patients with Parkinson's disease (PD). EEG theta and beta rhythms are reliably associated with cognitive and motor functions, respectively. We tested the hypothesis that PD patients with lower-limb abnormalities would exhibit abnormal beta and theta rhythms in the mid-frontal region during action initiation. Methods:We recruited thirty-nine subjects, including PD patients with FOG (PDFOG+; n=13) and without FOG (PDFOG-; n=13), and demographically-matched healthy subjects (n=13).Scalp electroencephalogram (EEG) signals were collected during a lower-limb pedaling motor task, which required intentional initiation and stopping of a motor movement.Results: FOG scores were correlated with disease severity and cognition. PDFOG+ patients pedaled with reduced speed and decreased acceleration compared to PDFOG-patients and to controls. PDFOG+ patients exhibited attenuated theta-band (4-8 Hz) power and increased betaband (13-30 Hz) power at mid-frontal electrode Cz during pedaling. Frontal theta-and beta-band oscillations also correlated with lower-limb movement in PD patients. Conclusions:Frontal theta and beta oscillations are predictors of lower-limb motor symptoms in PD. These data provide insight into the mechanism of lower-limb dysfunction in PD, and could be used to design neuromodulation for PD-related lower-limb abnormalities.

Background: Motor function and aberrant cognition have been linked in patients with Parkinson's disease (PD), but it is unknown if these are distinct symptoms or if they are correlated outcomes of a single dysfunctional latent process. EEG theta and beta rhythms are reliably associated with cognitive and motor functions, respectably. We tested the hypothesis that PD patients with lowerlimb abnormalities would exhibit abnormal beta and theta rhythms in the mid-frontal region during action initiation. Methods:We recruited thirty-nine subjects, including PD patients with FOG (PDFOG+; n=13) and without FOG (PDFOG-; n=13), and demographically-matched healthy subjects (n=13). Scalp electroencephalogram (EEG) signals were collected during a lower-limb pedaling motor task, which required intentional initiation and stopping of a motor movement.Results: FOG scores were correlated with disease severity and cognition. PDFOG+ patients pedaled with reduced speed and decreased acceleration compared to PDFOG-patients and to controls. PDFOG+ patients exhibited attenuated theta-band (4-8 Hz) power and increased betaband (13-30 Hz) power at mid-frontal electrode Cz during pedaling. Frontal theta-and beta-band oscillations also correlated with lower-limb movement in PD patients. Conclusions:Frontal theta and beta oscillations are predictors of lower-limb motor symptoms in PD. These data provide insight into the mechanism of lower-limb dysfunction in PD, and could be used to design neuromodulation for PD-related lower-limb abnormalities.

Patients with Parkinson's disease (PD) can have significant cognitive dysfunction; however, the mechanism of 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.

Evaluating and responding to new information requires cognitive control. Here, we studied novelty-response mechanisms in Parkinson's disease (PD). In PD patient-volunteers, we recorded from cortical circuits with scalp-based electroencephalography (EEG) and from subcortical circuits using intraoperative neurophysiology during surgeries for implantation of deep-brain stimulation (DBS) electrodes. We report three major results. First, novel auditory stimuli triggered midfrontal ~4-Hz rhythms, which were attenuated in PD patients but were not linked with cognitive function or novelty-associated slowing. Second, 32% of subthalamic nucleus (STN) neurons were response-modulated; nearly all (94%) of these were also modulated by novel stimuli. Finally, response-modulated STN neurons were coherent with midfrontal low-frequency activity. These findings link scalp-based measurements of neural activity with neuronal activity in the STN. Our results provide insight into midfrontal cognitive control mechanisms and how hyperdirect circuits evaluate new information.