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Neuronal oscillations at beta frequencies (20-50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in Parkinson's disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy., Introduction A cardinal feature of Parkinson's disease (PD) is slow movements, known as bradykinesia. The neuronal activities related to bradykinesia are two electrophysiological landmarks in PD: oscillations, the pathological augmentation [...]

Parkinson's disease (PD) is the most prevalent hypokinetic movement disorder, and symptomatic PD pathogenesis has been ascribed to imbalances between the direct and indirect pathways in the basal ganglia circuitry. Here, we applied glutamate receptor blockers to the subthalamic nucleus (STN) of parkinsonian rats and evaluated locomotor behaviors via single-unit and local-field recordings. Using this model, we found that inhibition of NMDAergic cortico -subthalamic transmission ameliorates parkinsonian motor deficits without eliciting any vivid turning behavior and abolishes electrophysiological abnormalities, including excessive subthalamic bursts, cortico-subthalamic synchronization, and in situ beta synchronization in both the motor cortex and STN. Premotor cortex stimulation revealed that cortico-subthalamic transmission is deranged in PD and directly responsible for the excessive stimulation-dependent bursts and time-locked spikes in the STN, explaining the genesis of PD-associated pathological bursts and synchronization, respectively. Moreover, application of a dopaminergic agent via a microinfusion cannula localized the therapeutic effect to the STN, without correcting striatal dopamine deficiency. Finally, optogenetic overactivation and synchronization of cortico-subthalamic transmission alone sufficiently and instantaneously induced parkinsonian-associated locomotor dysfunction in normal mice. In addition to the classic theory emphasizing the direct-indirect pathways, our data suggest that deranged cortico-subthalamic transmission via the NMDA receptor also plays a central role in the pathophysiology of parkinsonian motor deficits., Introduction According to the classic view, the basal ganglia circuitry is composed of 2 major pathways (1, 2). The excitatory direct pathway and the inhibitory indirect pathway are counterbalanced to [...]

An increase in neuronal burst activities in the subthalamic nucleus (STN) is a well-documented electrophysiological feature of Parkinson disease (PD). However, the causal relationship between subthalamic bursts and PD symptoms and the ionic mechanisms underlying the bursts remain to be established. Here, we have shown that T- type C [a.sup.2+] channels are necessary for subthalamic burst firing and that pharmacological blockade of T-type C[a.sup.2+] channels reduces motor deficits in a rat model of PD. N[i.sup.2+], mibefradil, NNC 55-0396, and efonidipine, which inhibited T-type C[a.sup.2+] currents in acutely dissociated STN neurons, but not C[d.sup.2+] and nifedipine, which preferentially inhibited L-type or the other non-T-type C[a.sup.2+] currents, effectively diminished burst activ-ity in STN slices. Topical administration of inhibitors of T-type C[a.sup.2+] channels decreased in vivo STN burst activity and dramatically reduced the locomotor deficits in a rat model of PD. C[d.sup.2+] and nifedipine showed no such electrophysiological and behavioral effects. While low-frequency deep brain stimulation (DBS) has been considered ineffective in PD, we found that lengthening the duration of the low-frequency depolarizing pulse effectively improved behavioral measures of locomotion in the rat model of PD, presumably by decreasing the availability of T-type C[a.sup.2+] channels. We therefore conclude that modulation of subthalamic T-type C[a.sup.2+] cur-rents and consequent burst discharges may provide new strategies for the treatment of PD., Introduction Parkinson disease (PD) is closely related to aberrant corticobasal ganglia loop functions in a state of dopamine deficiency (1, 2). The subthalamic nucleus (STN) has been proposed to play [...]