Modeling the motor striatum under Deep Brain Stimulation in normal and MPTP conditions

Abstract

Striatum (STR) is the major input stage of the basal ganglia (BG). It combines information from cortex, subthalamic nucleus (STN) and external globus pallidus (GPe), and projects to the output stages of the BG, where selection between concurrent motor programs is performed. Parkinson's disease (PD) reduces the concentration of dopamine (DA, a neurotransmitter) in STR and changes in the level of DA correlate with the onset of PD motor disorders. Though STR plays a pivotal role in BG, its behavior under PD and Deep Brain Stimulation (DBS) is still unclear. We develop point-process models of the STR neurons as a function of the activity in GPe, cortex, and DBS. We use single unit recordings from a monkey under STN DBS at different frequencies before and after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) to develop PD motor symptoms. The models suggest that STR neurons have prominent bursting activity in normal conditions, positive correlation with cortex (3-10 ms delay), and mild negative correlation with GPe (1-5 ms lag). DA depletion evokes 30-60 Hz oscillations, and increases the propensity of each neuron to be inhibited by surrounding neurons. DBS elicits antidromical activation, masks existent dynamics, reinforces dependencies between nuclei, and entrains at the stimulation frequency in both conditions.

Fig. 1

BG (white boxes), thalamus and sCTX with some connections. Black arrows are excitatory (bold) and inhibitory (dashed) projections.

Fig. 2

PPM for a MPTP (a–d) and a normal (e–h) STR neuron: a), e) e^α; b), f) e^β_r, r = 1, …,18 vs. history bins for a generic time bin k; c), g) $e^{{\delta }_{\mathrm{h},q}^E}$, h = 1, …,18 vs. history bins for a specific q and time bin k. c), g) $e^{{\delta }_{\mathrm{h},q}^C}$, h = 1, …,18 vs. history bins for a specific q and time bin k. Parameters are black lines, 95% confidence intervals are shaded green areas, e⁰ = 1 is a red line.

Fig. 3

PPM for normal neurons with 50 (a–e) and 100 Hz (f–l) DBS: a), f) e^α; b), g) $e^{{\delta }_{\mathrm{h},q}^G}$, h = 1, …,18 vs. history bins for a given q and a generic time bin k; c), h) $e^{{\delta }_{\mathrm{h},q}^C}$, h = 1, …,18 vs. history bins for a given q and time bin k; d), i) e^γ_ν, ν = 1, …,8 vs. history bins and time bin k. e), l) PSTHs (normalization to z-score based on the prestimulation activity [19]). Histograms <−1.96 or >1.96 (red lines) mean significant inhibition or excitation respectively. Legend for a–d), f–i) as in Fig.2.

Fig. 4

PPM for a MPTP (a–d) and a normal (e–h) STR neuron under 130 Hz DBS: a), e) e^α; b), f) e^β_r, r = 1, …,18 vs. history bins for a generic time bin k; c), g) e^γ_ν, ν = 1, …,8 vs. history bins for time bin k. d), h) PSTHs. Details as in Fig.3.