3D printed guide tube system for acute Neuropixels probe recordings in non-human primates.

Objective.Neuropixels (NP) probes are a significant advance in electrophysiological recording technology that enable monitoring of hundreds of neurons in the brain simultaneously at different depths. Application of this technology has been predominately in rodents, however widespread use in non-human primates (NHPs) such as rhesus macaques has been limited. In this study we sought to overcome two overarching challenges that impede acute NP implantation in NHPs: (1) traditional microdrive systems that mount to cephalic chambers are commonly used to access cortical areas for microelectrode recordings but are not designed to accommodate NP probes, and (2) NHPs have thick dura mater and tissue growth within the cephalic chambers which poses a challenge for insertion of the extremely fragile NP probe.Approach.In this study we present a novel NP guide tube system that can be adapted to commercial microdrive systems and demonstrate an implant method using the NP guide tube system. This system was developed using a combination of CAD design, 3D printing, and small part machining. Software programs, 3D Slicer and SolidWorks were used to target cortical areas, approximate recording depths and locations, and for in-silico implant testing.Main results.We performedin vivotesting to validate our methodology, successfully implanting, explanting, and reimplanting NP probes. We collected stable neurophysiological recordings in the premotor cortex of a rhesus macaque at rest and during performance of a reaching task.Significance.In this study we demonstrate a robust Neuropixels implant system that allows multiple penetrations with the same NP probe and share design files that will facilitate the adoption of this powerful recording technology for NHP studies.

Spatiotemporal scaling changes in gait in a progressive model of Parkinson's disease.

Objective: Gait dysfunction is one of the most difficult motor signs to treat in patients with Parkinson's disease (PD). Understanding its pathophysiology and developing more effective therapies for parkinsonian gait dysfunction will require preclinical studies that can quantitatively and objectively assess the spatial and temporal features of gait. Design: We developed a novel system for measuring volitional, naturalistic gait patterns in non-human primates, and then applied the approach to characterize the progression of parkinsonian gait dysfunction across a sequence of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatments that allowed for intrasubject comparisons across mild, moderate, and severe stages. Results: Parkinsonian gait dysfunction was characterized across treatment levels by a slower stride speed, increased time in both the stance and swing phase of the stride cycle, and decreased cadence that progressively worsened with overall parkinsonian severity. In contrast, decreased stride length occurred most notably in the moderate to severe parkinsonian state. Conclusion: The results suggest that mild parkinsonism in the primate model of PD starts with temporal gait deficits, whereas spatial gait deficits manifest after reaching a more severe parkinsonian state overall. This study provides important context for preclinical studies in non-human primates studying the neurophysiology of and treatments for parkinsonian gait.

Parkinsonism Alters Beta Burst Dynamics across the Basal Ganglia-Motor Cortical Network.

Elevated synchronized oscillatory activity in the beta band has been hypothesized to be a pathophysiological marker of Parkinson's disease (PD). Recent studies have suggested that parkinsonism is closely associated with increased amplitude and duration of beta burst activity in the subthalamic nucleus (STN). How beta burst dynamics are altered from the normal to parkinsonian state across the basal ganglia-thalamocortical (BGTC) motor network, however, remains unclear. In this study, we simultaneously recorded local field potential activity from the STN, internal segment of the globus pallidus (GPi), and primary motor cortex (M1) in three female rhesus macaques, and characterized how beta burst activity changed as the animals transitioned from normal to progressively more severe parkinsonian states. Parkinsonism was associated with an increased incidence of beta bursts with longer duration and higher amplitude in the low beta band (8-20 Hz) in both the STN and GPi, but not in M1. We observed greater concurrence of beta burst activity, however, across all recording sites (M1, STN, and GPi) in PD. The simultaneous presence of low beta burst activity across multiple nodes of the BGTC network that increased with severity of PD motor signs provides compelling evidence in support of the hypothesis that low beta synchronized oscillations play a significant role in the underlying pathophysiology of PD. Given its immersion throughout the motor circuit, we hypothesize that this elevated beta-band activity interferes with spatial-temporal processing of information flow in the BGTC network that contributes to the impairment of motor function in PD.SIGNIFICANCE STATEMENT This study fills a knowledge gap regarding the change in temporal dynamics and coupling of beta burst activity across the basal ganglia-thalamocortical (BGTC) network during the evolution from normal to progressively more severe parkinsonian states. We observed that changes in beta oscillatory activity occur throughout BGTC and that increasing severity of parkinsonism was associated with a higher incidence of longer duration, higher amplitude low beta bursts in the basal ganglia, and increased concurrence of beta bursts across the subthalamic nucleus, globus pallidus, and motor cortex. These data provide new insights into the potential role of changes in the temporal dynamics of low beta activity within the BGTC network in the pathogenesis of Parkinson's disease.