Striatal origin of the pathologic beta oscillations in Parkinson's disease

Abstract

Enhanced oscillations at beta frequencies (8-30 Hz) are a signature neural dynamic pathology in the basal ganglia and cortex of Parkinson's disease patients. The mechanisms underlying these pathological beta oscillations remain elusive. Here, using mathematical models, we find that robust beta oscillations can emerge from inhibitory interactions between striatal medium spiny neurons. The interaction of the synaptic GABAa currents and the intrinsic membrane M-current promotes population oscillations in the beta frequency range. Increased levels of cholinergic drive, a condition relevant to the parkinsonian striatum, lead to enhanced beta oscillations in the striatal model. We show experimentally that direct infusion of the cholinergic agonist carbachol into the striatum, but not into the neighboring cortex, of the awake, normal rodent induces prominent beta frequency oscillations in the local field potential. These results provide evidence for amplification of normal striatal network dynamics as a mechanism responsible for the enhanced beta frequency oscillations in Parkinson's disease.computational model | acetylcholine | muscarinic | mouse E nhanced beta frequency oscillations are correlated with bradykinesia, a disabling movement abnormality in Parkinson's disease patients (1). Improvement of bradykinesia correlates with a decrease in the enhanced beta frequency oscillations in the subthalamic nucleus (STN) and cortex of Parkinson's disease patients (2). However, the function of the beta oscillations in parkinsonian pathology remains elusive, and the source of these oscillations is unknown. Two predominating theories exist about the origin of these enhanced beta rhythms. One hypothesis proposes that oscillations arise from the interaction of the STN and the external segment of the globus pallidus (GPe); this is known as the STN/GPe pacemaker hypothesis (3). Evidence for the STN/ GPe pacemaker hypothesis comes from a study showing that GPe and STN are able to generate synchronized oscillatory bursting activity in the range of 0.4-1.8 Hz in organotypic cultures of cortex-striatum-STN-GPe (4). A second theory of beta generation in Parkinson's disease entails cortical patterning of the STN (3). This theory derives partly from studies on anesthetized rats showing that, with dopamine depletion, oscillatory spiking activity in STN and GPe is correlated with and largely dependent on cortical slow-wave (∼1 Hz) activity (5). For the cortical patterning, but not the STN/GPe hypothesis, there is experimental evidence for intrinsic production of the beta rhythm (6).Degeneration of dopaminergic neurons that project to the striatum is a hallmark of Parkinson's disease pathology (7), but the striatum has been largely ignored as a possible source of beta frequency rhythms in Parkinson's disease. There are several reasons for ignoring the striatum. The striatum consists of an almost entirely inhibitory network of cells (99.7% are GABAergic and 0.3% are cholinergic in the rat neostriatum) (8). Furthermore, the predominant striat...

Neural mechanisms of transient neocortical beta rhythms: Converging evidence from humans, computational modeling, monkeys, and mice

“…An intermediate view, supported by the model presented here, is that beta emerges in the neocortex but is dependent on extrinsic synaptic drive that could originate from basal ganglia/ thalamus. Consistent with the first view, beta has been robustly observed in LFP signals from basal ganglia nuclei including the subthalamic nucleus, striatum, and globus pallidus (18,19), and computational models have proposed mechanisms by which beta rhythms can emerge via interactions within and between these circuits (20,21). Other studies have suggested that the neocortex itself has unique properties that generate beta rhythms through spike-mediated synaptic and electrical interactions within local circuits (22)(23)(24)(25) or that beta in early-sensory neocortical areas could be driven in a top-down manner from frontal cortex during attentive states (26).…”

“…This mechanism may not account for beta at different recording scales or behavioral states [e.g., motor hold conditions (27,28) or up-states (47)] or in other brain networks, particularly those without spatially aligned PNs such as inhibitory networks in the striatum, where other mechanisms have been proposed (21). Prior modeling and experiments, primarily from slice recordings, have established that neocortical beta rhythms can emerge from the spiking interactions of local excitatory and inhibitory populations (22)(23)(24)(25)(26).…”

“…A 20-Hz drive does not account for beta events. A prevailing theory on the origin of neocortical beta in humans is that it originates in the basal ganglia (20,21) and is propagated via thalamus to neocortex. The ventral-medial (VM) nucleus of the thalamus receives direct basal ganglia input and predominantly contacts supragranular layers broadly across the neocortex (40).…”

“…These findings make several predictions about optimal states for perceptual and motor performance and guide causal interventions to modulate beta for optimal function. beta rhythm | magnetoencephalography | computational modeling | sensorimotor processing | Parkinson's disease B eta band rhythms (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) are a commonly observed activity pattern in the brain. They are found with magnetoencephalography (MEG) (1)(2)(3)(4), EEG (5,6), and local field potential (LFP) recordings from neocortex (7)(8)(9) and are preserved across species (10).…”

Introduction to Focus Issue: Rhythms and Dynamic Transitions in Neurological Disease: Modeling, Computation, and Experiment

“…25,[40][41][42][43][44] Transitions between dynamic regimes have been observed during sleep, and abnormal transitions have been associated with sleep disorders. 26,[45][46][47][48][49][50][51] Finally, the slow waves of cortical spreading depression 52 underlie the reduction of excitability in neuronal tissue associated with migraine, 53,54 in particular, migraine with aura. 52 On the three fronts of modeling, computation, and experiment, there have been a series of important recent advances, and many new avenues of research have emerged.…”