Modulations in Oscillatory Frequency and Coupling in Globus Pallidus with Increasing Parkinsonian Severity

Abstract

While beta oscillations often occur within the parkinsonian basal ganglia, how these oscillations emerge from a naive state and change with disease severity is not clear. To address this question, a progressive, nonhuman primate model of Parkinson's disease was developed using staged injections of MPTP. Within each parkinsonian state (naive, mild, moderate, and severe), spontaneous local field potentials were recorded throughout the sensorimotor globus pallidus. In the naive state, beta oscillations (11-32 Hz) occurred in half of the recordings, indicating spontaneous beta oscillations in globus pallidus are not pathognomonic. Mild and moderate states were characterized by a narrower distribution of beta frequencies that shifted toward the 8 -15 Hz range. Additionally, coupling between the phase of beta and the amplitude of highfrequency oscillations (256 -362 Hz) emerged in the mild state and increased with severity. These findings provide a novel mechanistic framework to understand how progressive loss of dopamine translates into abnormal information processing in the pallidum through alterations in oscillatory activity. The results suggest that rather than the emergence of oscillatory activity in one frequency spectrum or the other, parkinsonian motor signs may relate more to the development of altered coupling across multiple frequency spectrums.

Subthalamic local field potentials in Parkinson's disease and isolated dystonia: An evaluation of potential biomarkers

“…In several rodent models of PD, dopamine depletion does result in an increase in the amplitude of beta oscillations in several structures in the basal ganglia-thalamocortical loop (Costa et al, 2006; Mallet et al, 2008). However, other studies using progressive model of parkinsonism in rodents and non-human primates showed equivocal changes in beta oscillations (Connolly et al, 2015; Devergnas et al, 2014; Leblois et al, 2007; Leventhal et al, 2012). Although the amplitude of beta oscillations in the LFP power spectrum is reduced by successful therapy in humans, this reduction should not necessarily be interpreted as returning the STN to its “normal” state.…”

“…However, one of these studies also showed that a discrete peak was found consistently in the 11–30 Hz range in both disease groups, and that synchronization of neuronal firing with LFP oscillations is a more prominent feature in PD than in dystonia (Weinberger et al, 2012). In a recent study of MPTP-induced parkinsonism in nonhuman primates, resting state beta oscillations were present in the naïve pallidum, and after induction of parkinsonism, beta band power was not correlated with disease severity (Connolly et al, 2015). Future studies comparing LFP oscillations and spike-field relationships in different movement disorders may clarify the disease specificity of biomarkers in the pallidum.…”

“…This does not rule out the possibility that beta-HFO PAC could be an important marker in other basal ganglia nuclei. In MPTP-induced nonhuman primate model of Parkinsonism, emergence of beta-HFO coupling in the pallidum occurred in the mild state and increased with symptom severity (Connolly et al, 2015). …”

Physiological changes in the pallidum in a progressive model of Parkinson's disease: Are oscillations enough?

“…Oscillatory synchronization in the 8-30 Hz (beta) band has been observed in the STN, GPi and primary motor cortex in humans undergoing DBS surgery (Kuhn et al , 2009), in the MPTP non-human primate model of Parkinson's disease (Devergnas et al , 2014), and in rats treated with 6-hydroxydopamine (Gradinaru et al , 2009). Other studies however, have questioned a causative role of beta band oscillations in the pathogenesis of Parkinson's disease finding that such oscillations occur in the naïve state (Connolly et al, 2015b; Courtemanche et al, 2003; Leventhal et al, 2012; Murthy and Fetz, 1992), that motor signs may precede the occurrence of oscillatory activity in the GPi and STN (Leblois et al , 2007), and that these oscillations are not found in all Parkinson's disease patients (Rosa et al , 2011). Thus, the precise nature of changes in neuronal activity within the basal ganglia and their role in the development of Parkinson's disease motor signs remains unclear.…”

Motor behaviors in the sheep evoked by electrical stimulation of the subthalamic nucleus

“…Effective DBS also suppresses the exaggerated low-frequency brain oscillations in both rodent and NHP models of PD [94]. In fact, the extent of the low-frequency oscillations correlates with disease severity in the MPTP NHP PD model [95]. Although the results from studying DBS in preclinical disease models are overall consistent with the clinical findings, they also fall short of distinguishing whether the abnormal low-frequency brain activity is a cause or only a symptom of the associated motor dysfunction.…”