Understanding Parkinson’s disease and deep brain stimulation: Role of monkey models

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder affecting over 10 million people worldwide. In the 1930s and 1940s there was little understanding regarding what caused PD or how to treat it. In a desperate attempt to improve patients’ lives different regions of the neuraxis were ablated. Morbidity and mortality were common, but some patients’ motor signs improved with lesions involving the basal ganglia or thalamus. With the discovery ofl-dopa the advent of medical therapy began and surgical approaches became less frequent. It soon became apparent, however, that medical therapy was associated with side effects in the form of drug-induced dyskinesia and motor fluctuations and surgical therapies reemerged. Fortunately, during this time studies in monkeys had begun to lay the groundwork to understand the functional organization of the basal ganglia, and with the discovery of the neurotoxin MPTP a monkey model of PD had been developed. Using this model scientists were characterizing the physiological changes that occurred in the basal ganglia in PD and models of basal ganglia function and dysfunction were proposed. This work provided the rationale for the return of pallidotomy, and subsequently deep brain stimulation procedures. In this paper we describe the evolution of these monkey studies, how they provided a greater understanding of the pathophysiology underlying the development of PD and provided the rationale for surgical procedures, the search to understand mechanisms of DBS, and how these studies have been instrumental in understanding PD and advancing the development of surgical therapies for its treatment.

Disrupted basal ganglia output during movement preparation in hemi-parkinsonian mice accounts for behavioral deficits

“…Before directly comparing the effects of unilateral dopaminergic cell loss on the SG and IS movements required by our task, we sought to characterize the effects on each trial type individually. Given the rate-model prediction that SNr-recipient nuclei for contralateral movement are over-inhibited (Albin et al, 1989; DeLong, 1990; Obeso et al, 2008; Utter and Basso, 2008; McGregor and Nelson, 2019; Vitek and Johnson, 2019), and supported by our findings of greater ipsilateral bias on the rotation assay and an increase in mean SNr activity (Fig. 3B), we expected hemi-PD mice (as determined by the extent of dopaminergic cell loss; Fig.…”

“…Parkinson’s disease (PD) is a neurodegenerative disease of the basal ganglia (BG) in which motor impairments arise from disordered – typically, elevated – inhibitory BG output resulting from the loss of dopaminergic tone (DeLong, 1990; Wichmann et al, 1999; Ibanez-Sandoval et al, 2007; Utter and Basso, 2008; Wang et al, 2010a; Seeger-Armbruster and von Ameln-Mayerhofer, 2013; Brazhnik et al, 2014; Filyushkina et al, 2019; McGregor and Nelson, 2019). One predominant theoretical framework for BG pathology in PD is the “rate model”, which posits that motor centers downstream of the BG are over-inhibited, leading to disordered movements (Albin et al, 1989; DeLong, 1990; Obeso et al, 2008; Utter and Basso, 2008; McGregor and Nelson, 2019; Vitek and Johnson, 2019). However, it is not clear whether the rate model can account for context-dependent PD motor phenomena, including the intriguing clinical observation that not all forms of movement are equally affected by PD: when movements are guided by external stimuli (e.g., gait matching with a rhythmic auditory stimulus or visually patterned flooring, kinematics are less impaired than for otherwise identical movements made in the absence of guiding stimuli (Glickstein and Stein, 1991; McIntosh et al, 1997; Ballanger et al, 2006; Daroff, 2008; McDonald et al, 2015; Distler et al, 2016).…”

Reversal of hyperactive subthalamic circuits differentially mitigates pain hypersensitivity phenotypes in parkinsonian mice

“…Accumulating evidence shows that STN DBS effectively relieves musculoskeletal and dystonic pain in PD patients (28)(29)(30)(31)(32). Whether DBS at therapeutic frequencies causes inhibition or stimulation of STN neurons remains controversial (15,16,38,39); therefore, the antinociceptive effect of STN DBS in PD patients cannot be directly linked to inhibition of STN neurons. Empirically, the direct targets of DBS (50 to 100 μs) are axonal fibers (40).…”

Deep brain stimulation for psychiatric disorders: From focal brain targets to cognitive networks

“…Recent work from our lab suggests that circuit responses to DBS-like neurostimulation are sufficiently consistent across individuals to make this paradigm feasible ( Basu et al 2019 ). Similar approaches have been highly helpful in advancing DBS for movement disorders ( Vitek and Johnson 2019 ).…”