Parkinsonism-related β oscillations in the primate basal ganglia networks – Recent advances and clinical implications

https://doi.org/10.1016/j.parkreldis.2018.12.015Get rights and content

Highlights

  • The striatum and the subthalamic nucleus (STN) are the basal ganglia (BG) inputs.

  • Parkinsonism-related BG β oscillations resonate through the STN, not the striatum.

  • BG β oscillations are episodic but not necessarily pathological.

  • Episodic BG β oscillatory activity is more prevalent in parkinsonism.

  • Longer STN β episodes are a biomarker of abnormal neuronal activity in parkinsonism.

Abstract

Today, the basal ganglia (BG) network can be viewed as a three-layer neural network in which the striatum and the subthalamic nucleus (STN) are the two BG input structures and together innervate BG downstream structures using GABA and glutamate, respectively. The striatum is larger than the STN and is the main site of dopamine depletion in Parkinson's disease (PD). However, STN is the prime target for deep brain stimulation (DBS) of patients with advanced PD. Traditionally, the efficacy of STN-DBS is attributed to the suppression of the pathological synchronous β oscillations along the cortico-thalamo BG network. In conventional DBS, stimulation is delivered continuously and equally influences normal and pathological neural activity. A DBS protocol would be therefore more effective if stimulation was only applied when necessary. We recently showed in the non-human primate model of PD that parkinsonism-related β oscillations resonate across the BG network through the STN, not the striatum. Moreover, we also demonstrated that BG β oscillations are episodic and albeit extended in parkinsonism also exists in the healthy condition. Thus, not all parkinsonian β oscillatory episodes are necessarily pathological. Remarkably, the duration of BG β episodes is more highly impacted than their magnitude in parkinsonism and may be more reliable metric - especially in STN - to discriminate between normal (“good”) and pathological (“bad”) β episodes. Thus, prolonged STN β episodes is suggested as one of the biomarkers of the pathological neuronal activity in parkinsonism that could be used as a trigger for adaptive DBS.

Section snippets

Basal ganglia model 1.0 – the D1/D2 direct/indirect pathway model of the basal ganglia

Basal ganglia (BG) are a set of interconnected subcortical nuclei involved in behavioral control whose dysfunction leads to motor (e.g., Parkinson's disease, Huntington disease and dystonia) and non-motor (e.g., obsessive compulsive disorders, depression and schizophrenia) disorders. Most of neurology and neuroscience textbooks describe the BG network as two segregated direct and indirect internal BG pathways [1,2] (Fig. 1A). Both BG pathways start in the striatum that is innervated by nearly

Basal ganglia model 2.0 – the three-layer basal ganglia network

Both the striatum and STN receive considerable glutamatergic inputs from diverse areas of the cortex and the thalamus [12,13] (Fig. 1B). Although cortical projections to the STN originate mostly from motor, premotor and prefrontal areas [14,15], the importance of these (hyper) direct projections from the cortex to the STN [[15], [16], [17], [18]] indicate that STN should no longer be considered a relay station of the BG “indirect pathway”. Like the striatum, the STN is a BG input structure. The

STN vs. striatum in the control of the activity of BG downstream structures

Despite evidence of subthalamic dopamine depletion in PD and its role in the pathophysiology of the disease [[31], [32], [33]] the striatum remains the main site of dopamine depletion in PD patients and animal models of PD. In addition, the striatum is much larger than the STN (107 vs. 105 neurons in non-human primates (NHPs), respectively [34]). Nevertheless, the STN, not the striatum, is the prime target for deep brain stimulation (DBS) of patients with advanced PD [35,36]. Moreover, it has

Striatal projections neurons do not express parkinsonism-related β oscillations as do the STN and BG downstream structures

In PD, the degeneration of midbrain dopaminergic neurons leads to substantial dopamine depletion throughout the BG (especially in the striatum) which provokes abnormal BG neuronal activity and notably the emergence of synchronized β oscillatory activity in the BG network [40,41]. Abnormal synchronized β oscillatory activity has been found at multiple levels of the BG network, within and between BG nuclei, in both PD patients and animal models of PD (e.g.,

BG β oscillatory activity is episodic and not necessarily pathological

An earlier study on PD patients showed that STN neurons exhibit long, non-continuous, 8–20 Hz oscillatory spiking activity that is coherent with their background MUA [76]. Similarly, examination of the dynamics of the β oscillatory spike-LFP synchrony in the STN of PD patients revealed that synchronized β oscillatory activity in human parkinsonian STN is interrupted by irregular short de-synchronization events [77]. Recently, β bursts have also been detected in the LFPs recorded in the STN of

Prolonged STN β oscillatory episodes are a reliable biomarker for parkinsonism –discriminating between normal and pathological β oscillatory activity

Conventional (i.e., continuous high-frequency) STN-DBS, by influencing pathological but also physiological neural activity, can worsen motor functioning or induce side-effects in PD patients [87,88]. The DBS protocol may be more effective when stimulation is applied only when necessary as in a closed-loop adaptive DBS strategy [[89], [90], [91], [92]]. For optimal adaptive DBS to be achieved, stimulation should be triggered by the most relevant biomarker of the pathological neuronal activity in

Concluding remarks

Binary ON/OFF approach for adaptive DBS may provoke side-effects (e.g., paresthesia) caused by the rapid increase of stimulation voltage [94]. However, this important issue can be resolved by incorporating a soft-start (ramping) stimulation. We posit that the success of early studies on adaptive stimulation in PD patients [78,79,90,91,93] could be due to the soft-start (ramping) nature of the stimulation following detection of the STN β episodes, leading exclusively to effective stimulation at

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