Autonomous oscillations and phase-locking in a biophysically detailed model of the STN-GPe network

AbstractThe aim of this study was to understand the relative role of autonomous oscillations and patterning by exogenous oscillatory inputs in the generation of pathological oscillatory activity within the subthalamic nucleus (STN) - external globus pallidus (GPe) network in Parkinson’s disease. A biophysically detailed model that accounts for the integration of synaptic currents and their interaction with intrinsic membrane currents in dendritic structures within the STN and GPe was developed. The model was used to investigate the development of beta-band synchrony and bursting within the STN-GPe network by changing the balance of excitation and inhibition in both nuclei, and by adding exogenous oscillatory inputs with varying phase relationships through the hyperdirect cortico-subthalamic and indirect striato-pallidal pathways. The model showed an intrinsic susceptibility to beta-band oscillations that was manifest in weak autonomously generated oscillations within the STN-GPe network and in selective amplification of exogenous beta-band synaptic inputs near the network’s endogenous oscillation frequency. The resonant oscillation frequency was determined by the net level of excitatory drive in the loop. Intrinsically generated oscillations were too weak to support a pacemaker role for the STN-GPe network, however, they were considerably amplified by sparse cortical beta inputs when their frequency range overlapped and were further amplified by striatal beta inputs that promoted anti-phase firing of the cortex and GPe, resulting in maximum transient inhibition of STN neurons. The model elucidates a mechanism of cortical patterning of the STN-GPe network through feedback inhibition whereby intrinsic susceptibility to beta-band oscillations can lead to phase locked spiking under parkinsonian conditions. These results point to resonance of endogenous oscillations with exogenous patterning of the STN-GPe network as a mechanism of pathological synchronization, and a role for the pallido-striatal feedback loop in amplifying beta oscillations.Author summaryExaggerated beta-frequency neuronal synchrony is observed throughout the basal ganglia in Parkinson’s disease and is reduced with medication and during deep brain stimulation. The power of beta-band oscillations is increasingly used as a biomarker to guide antiparkinsonian therapies. Despite their importance as a clinical target, the mechanisms by which pathological beta-band oscillations are generated are not yet clearly understood. In vitro electrophysiological recordings support a theory of enhanced phase locking of the reciprocally connected subthalamo-pallidal network to beta-band cortical inputs but this has not yet been clearly demonstrated in a model. We present a new model of the subthalamo-pallidal network consisting of biophysically detailed cell models that captures the interaction between synaptic and intrinsic currents in dendritic structures. The model shows how phase locking of subthalamic and pallidal neurons and exaggerated bursting in subthalamic neurons can arise from the interaction of these currents when the balance of excitation and inhibition is changed and how phase locking is amplified under specific phase relationships between cortical and striatal beta inputs.

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Parkinson's disease and pathological oscillatory activity: Is the beta band the bad guy? — New lessons learned from low-frequency deep brain stimulation

Experimental Neurology ◽

10.1016/j.expneurol.2011.10.022 ◽

2012 ◽

Vol 233 (1) ◽

pp. 123-125 ◽

Cited By ~ 14

Author(s):

Lars Timmermann ◽

Esther Florin

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Deep Brain Stimulation ◽

Brain Stimulation ◽

Low Frequency ◽

Lessons Learned ◽

Oscillatory Activity ◽

Beta Band ◽

Deep Brain

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Attenuated beta rebound to proprioceptive afferent feedback in Parkinson’s disease

10.1101/334565 ◽

2018 ◽

Author(s):

Mikkel C. Vinding ◽

Panagiota Tsitsi ◽

Harri Piitulainen ◽

Josefine Waldthaler ◽

Veikko Jousmäki ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Passive Movement ◽

Afferent Feedback ◽

Oscillatory Activity ◽

Cortical Processing ◽

Beta Band ◽

Proprioceptive Stimulation ◽

Proprioceptive Function

AbstractMotor symptoms are defining traits in the diagnosis of Parkinson’s disease (PD). A crucial component in motor function and control of movements is the integration of efferent signals from the motor network to the peripheral motor system, and afferent proprioceptive sensory feedback. Previous studies have indicated abnormal movement-related cortical oscillatory activity in PD, but the role of the proprioceptive afference on abnormal oscillatory activity in PD has not been elucidated. In the present study, we examine the role of proprioception by studying the cortical processing of proprioceptive stimulation in PD patients, ON/OFF levodopa medication, as compared to that of healthy controls (HC). We used a proprioceptive stimulator that generated precisely controlled passive movements of the index finger and measured the induced cortical oscillatory responses following the proprioceptive stimulation using magnetoencephalography (MEG). Both PD patients and HC showed a typical initial mu/beta-band (8–30 Hz) desynchronization during the passive movement. However, the subsequent beta rebound after the passive movement that was apparent in HC was much attenuated and almost absent in PD patients. Furthermore, we found no difference in the degree of beta rebound attenuation between patients ON and OFF levodopa medication. Our results hence demonstrate a disease-related deterioration in cortical processing of proprioceptive afference in PD, and further suggest that such disease-related loss of proprioceptive function is due to processes outside the dopaminergic system affected by levodopa medication.

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Neuronal beta band oscillatory activity in the basal ganglia reflecting rigidity in Parkinson’s disease patients

Journal of the Neurological Sciences ◽

10.1016/j.jns.2017.08.3596 ◽

2017 ◽

Vol 381 ◽

pp. 493

Author(s):

H. Iwamuro ◽

Y. Shimo ◽

A. Umemura ◽

A. Nakajima ◽

G. Oyama ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Basal Ganglia ◽

Oscillatory Activity ◽

Beta Band

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Dopamine and beta-band oscillations differentially link to striatal value and motor control

Science Advances ◽

10.1126/sciadv.abb9226 ◽

2020 ◽

Vol 6 (39) ◽

pp. eabb9226

Author(s):

H. N. Schwerdt ◽

K. Amemori ◽

D. J. Gibson ◽

L. L. Stanwicks ◽

T. Yoshida ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Oscillatory Activity ◽

Beta Band ◽

Performance History ◽

Multimodal Systems ◽

Long Time ◽

Normative Rule ◽

Time Frames ◽

Band Activity

Parkinson’s disease is characterized by decreased dopamine and increased beta-band oscillatory activity accompanying debilitating motor and mood impairments. Coordinate dopamine-beta opposition is considered a normative rule for basal ganglia function. We report a breakdown of this rule. We developed multimodal systems allowing the first simultaneous, chronic recordings of dopamine release and beta-band activity in the striatum of nonhuman primates during behavioral performance. Dopamine and beta signals were anticorrelated over seconds-long time frames, in agreement with the posited rule, but at finer time scales, we identified conditions in which these signals were modulated with the same polarity. These measurements demonstrated that task-elicited beta suppressions preceded dopamine peaks and that relative dopamine-beta timing and polarity depended on reward value, performance history, movement, and striatal domain. These findings establish a new view of coordinate dopamine and beta signaling operations, critical to guide novel strategies for diagnosing and treating Parkinson’s disease and related neurodegenerative disorders.

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Fine Temporal Structure of Beta Oscillations Synchronization in Subthalamic Nucleus in Parkinson's Disease

Journal of Neurophysiology ◽

10.1152/jn.00724.2009 ◽

2010 ◽

Vol 103 (5) ◽

pp. 2707-2716 ◽

Cited By ~ 62

Author(s):

Choongseok Park ◽

Robert M. Worth ◽

Leonid L. Rubchinsky

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Basal Ganglia ◽

Subthalamic Nucleus ◽

Phase Synchronization ◽

Phase Locking ◽

Temporal Structure ◽

High Temporal Resolution ◽

Beta Band ◽

Oscillatory Dynamics

Synchronous oscillatory dynamics in the beta frequency band is a characteristic feature of neuronal activity of basal ganglia in Parkinson's disease and is hypothesized to be related to the disease's hypokinetic symptoms. This study explores the temporal structure of this synchronization during episodes of oscillatory beta-band activity. Phase synchronization (phase locking) between extracellular units and local field potentials (LFPs) from the subthalamic nucleus (STN) of parkinsonian patients is analyzed here at a high temporal resolution. We use methods of nonlinear dynamics theory to construct first-return maps for the phases of oscillations and quantify their dynamics. Synchronous episodes are interrupted by less synchronous episodes in an irregular yet structured manner. We estimate probabilities for different kinds of these “desynchronization events.” There is a dominance of relatively frequent yet very brief desynchronization events with the most likely desynchronization lasting for about one cycle of oscillations. The chances of longer desynchronization events decrease with their duration. The observed synchronization may primarily reflect the relationship between synaptic input to STN and somatic/axonal output from STN at rest. The intermittent, transient character of synchrony even on very short time scales may reflect the possibility for the basal ganglia to carry out some informational function even in the parkinsonian state. The dominance of short desynchronization events suggests that even though the synchronization in parkinsonian basal ganglia is fragile enough to be frequently destabilized, it has the ability to reestablish itself very quickly.

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Temporal Evolution of Oscillations and Synchrony in GPi/Muscle Pairs in Parkinson's Disease

Journal of Neurophysiology ◽

10.1152/jn.00829.2004 ◽

2005 ◽

Vol 93 (3) ◽

pp. 1569-1584 ◽

Cited By ~ 61

Author(s):

José M. Hurtado ◽

Leonid L. Rubchinsky ◽

Karen A. Sigvardt ◽

Vicki L. Wheelock ◽

Conrad T. E. Pappas

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Phase Locking ◽

Phase Delay ◽

Phase Correlation ◽

Oscillatory Activity ◽

Sliding Windows ◽

Significant Difference ◽

The Times ◽

Coherent Pairs

Both standard spectral analysis and time-dependent phase correlation techniques were applied to 27 pairs of tremor-related single units in the globus pallidus internus (GPi) and EMG of patients with Parkinson's disease (PD) undergoing stereotactic neurosurgery. Over long time-scales (∼60 s), GPi tremor-related units were statistically coherent with restricted regions of the peripheral musculature displaying tremor. The distribution of pooled coherence across all pairs supports a classification of GPi cell/EMG oscillatory pairs into coherent or noncoherent. Analysis using ∼2-s sliding windows shows that oscillatory activity in both GPi tremor units and muscles occurs intermittently over time. For brain/muscle pairs that are coherent, there is partial overlap in the times of oscillatory activity but, in most cases, no significant correlation between the times of oscillatory subepisodes in the two signals. Phase locking between coherent pairs occurs transiently; however, the phase delay is similar for different phase-locking subepisodes. Noncoherent pairs also show episodes of transient phase locking, but they occurred less frequently, and no preferred phase delay was seen across subepisodes. Tremor oscillations in pallidum and EMGs are punctuated by phase slips, which were classified as synchronizing or desynchronizing depending on their effect on phase locking. In coherent pairs, the incidence of synchronizing slips is higher than desynchronizing slips, whereas no significant difference was seen for noncoherent pairs. The results of this quantitative characterization of parkinsonian tremor provide a foundation for hypotheses about the structure and dynamical functioning of basal ganglia motor control networks involved in tremor generation.

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Intraoperative localization of spatially and spectrally distinct resting-state networks in Parkinson’s disease

Journal of Neurosurgery ◽

10.3171/2018.11.jns181684 ◽

2020 ◽

Vol 132 (4) ◽

pp. 1234-1242 ◽

Cited By ~ 1

Author(s):

Paolo Belardinelli ◽

Ramin Azodi-Avval ◽

Erick Ortiz ◽

Georgios Naros ◽

Florian Grimm ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Network Effects ◽

Brain Activity ◽

Dynamic Imaging ◽

Oscillatory Activity ◽

Network Information ◽

Novel Approach ◽

Electrophysiological Recordings ◽

Intraoperative Localization

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for symptomatic Parkinson’s disease (PD); the clinical benefit may not only mirror modulation of local STN activity but also reflect consecutive network effects on cortical oscillatory activity. Moreover, STN-DBS selectively suppresses spatially and spectrally distinct patterns of synchronous oscillatory activity within cortical-subcortical loops. These STN-cortical circuits have been described in PD patients using magnetoencephalography after surgery. This network information, however, is currently not available during surgery to inform the implantation strategy.The authors recorded spontaneous brain activity in 3 awake patients with PD (mean age 67 ± 14 years; mean disease duration 13 ± 7 years) during implantation of DBS electrodes into the STN after overnight withdrawal of dopaminergic medication. Intraoperative propofol was discontinued at least 30 minutes prior to the electrophysiological recordings. The authors used a novel approach for performing simultaneous recordings of STN local field potentials (LFPs) and multichannel electroencephalography (EEG) at rest. Coherent oscillations between LFP and EEG sensors were computed, and subsequent dynamic imaging of coherent sources was performed.The authors identified coherent activity in the upper beta range (21–35 Hz) between the STN and the ipsilateral mesial (pre)motor area. Coherence in the theta range (4–6 Hz) was detected in the ipsilateral prefrontal area.These findings demonstrate the feasibility of detecting frequency-specific and spatially distinct synchronization between the STN and cortex during DBS surgery. Mapping the STN with this technique may disentangle different functional loops relevant for refined targeting during DBS implantation.

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