Summary Disrupted mesocortical dopamine contributes to cognitive symptoms of Parkinson’s disease (PD). Past work has implicated medial frontal neurons expressing D1 dopamine receptors (D1DRs) in temporal processing. Here, we investigate if these neurons can compensate for behavioral deficits resulting from midbrain dopamine dysfunction. We report three main results. First, both PD patients and mice with ventral tegmental area (VTA) dopamine depletion had attenuated delta activity (1–4 Hz) in the medial frontal cortex (MFC) during interval timing. Second, we found that optogenetically stimulating MFC D1DR neurons could increase ramping activity among MFC neurons. Finally, stimulating MFC D1DR neurons specifically at delta frequencies (2 Hz) compensated for deficits in temporal control of action caused by VTA dopamine depletion. Our results suggest that cortical networks can be targeted by frequency-specific brain stimulation to improve dopamine-dependent cognitive processing.

Cognitive dysfunction is a pervasive and disabling aspect of schizophrenia without adequate treatments. A recognized correlate to cognitive dysfunction in schizophrenia is attenuated frontal theta oscillations. Neuromodulation to normalize these frontal rhythms represents a potential novel therapeutic strategy. Here, we evaluate whether noninvasive neuromodulation of the cerebellum in patients with schizophrenia can enhance frontal theta oscillations, with the future goal of targeting the cerebellum as a possible therapy for cognitive dysfunction in schizophrenia. We stimulated the midline cerebellum using transcranial pulsed current stimulation (tPCS), a non-invasive transcranial direct current that can be delivered in a frequency specific manner. A single 20-minute session of theta frequency stimulation was delivered in 9 patients with schizophrenia (cathode on right shoulder). Delta frequency tPCS was also delivered as a control to evaluate for frequency specific effects. EEG signals from midfrontal electrode Cz were analyzed before and after cerebellar tPCS while patients estimated the passage of 3 and 12 second intervals. Theta oscillations were significantly larger following theta frequency cerebellar tPCS in the midfrontal region, which was not seen with delta frequency stimulation. As previously reported, patients with schizophrenia showed a baseline reduction in accuracy estimating 3 and 12 second intervals relative to control subjects, which did not significantly improve following a single session theta or delta frequency cerebellar tPCS. These preliminary results suggest that single session theta

Interval timing refers to the ability to perceive and remember intervals in the seconds to minutes range. Our contemporary understanding of interval timing is derived from relatively small-scale, isolated studies that investigate a limited range of intervals with a small sample size, usually based on a single task. Consequently, the conclusions drawn from individual studies are not readily generalizable to other tasks, conditions, and task parameters. The current paper presents a live database that presents raw data from interval timing studies (currently composed of 68 datasets from eight different tasks incorporating various interval and temporal order judgments) with an online graphical user interface to easily select, compile, and download the data organized in a standard format. The Timing Database aims to promote and cultivate key and novel analyses of our timing ability by making published and future datasets accessible as open-source resources for the entire research community. In the current paper, we showcase the use of the database by testing various core ideas based on data compiled across studies (i.e., temporal accuracy, scalar property, location of the point of subjective equality, malleability of timing precision). The Timing Database will serve as the repository for interval timing studies through the submission of new datasets.