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