Modulation of Neuronal Activity in the Motor Thalamus during GPi-DBS in the MPTP Nonhuman Primate Model of Parkinson's Disease

Muralidharan, Abirami; Zhang, Jianyu; Ghosh, Debabrata; Johnson, Matthew D.; Baker, Kenneth B.; Vitek, Jerrold L.

doi:10.1016/j.brs.2016.10.005

Cited by 20 publications

(19 citation statements)

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“…). However, parkinsonism is associated with relatively minor changes in firing in the basal ganglia receiving portion of the thalamus . Whereas traditional models predict that interventions aimed at the basal ganglia–receiving portion of the ventral motor thalamus “should” impact bradykinesia or akinesia, these predictions have not been confirmed in parkinsonian animals or human patients with the disease (e.g., see an earlier work) .…”

Section: Evolving Topicsmentioning

confidence: 99%

“…However, parkinsonism is associated with relatively minor changes in firing in the basal ganglia receiving portion of the thalamus. [248][249][250][251][252] Whereas traditional models predict that interventions aimed at the basal ganglia-receiving portion of the ventral motor thalamus "should" impact bradykinesia or akinesia, these predictions have not been confirmed in parkinsonian animals or human patients with the disease (e.g., see an earlier work). 35 These findings suggest that the branching GPi projections to brainstem nuclei, such as the PPN, 253,254 may be more important for the development of bradykinesia or akinesia than traditionally assumed.…”

Section: Role Of Brainstem Nucleimentioning

confidence: 99%

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Changing views of the pathophysiology of Parkinsonism

Wichmann

2019

Movement Disorders

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Studies of the pathophysiology of parkinsonism (specifically akinesia and bradykinesia) have a long history and primarily model the consequences of dopamine loss in the basal ganglia on the function of the basal ganglia/thalamocortical circuit(s). Changes of firing rates of individual nodes within these circuits were originally considered central to parkinsonism. However, this view has now given way to the belief that changes in firing patterns within the basal ganglia and related nuclei are more important, including the emergence of burst discharges, greater synchrony of firing between neighboring neurons, oscillatory activity patterns, and the excessive coupling of oscillatory activities at different frequencies. Primarily focusing on studies obtained in nonhuman primates and human patients with Parkinson's disease, this review summarizes the current state of this field and highlights several emerging areas of research, including studies of the impact of the heterogeneity of external pallidal neurons on parkinsonism, the importance of extrastriatal dopamine loss, parkinsonism‐associated synaptic and morphologic plasticity, and the potential role(s) of the cerebellum and brainstem in the motor dysfunction of Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society

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Section: Evolving Topicsmentioning

confidence: 99%

Section: Role Of Brainstem Nucleimentioning

confidence: 99%

Changing views of the pathophysiology of Parkinsonism

Wichmann

2019

Movement Disorders

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“…2 E-H). Interestingly, it has been demonstrated that STN, GPi, and GPe stimulation, although producing similar behavioral improvement in motor signs, may impose different changes in the network (74,75,78,82,83), suggestive of the idea that the therapeutic mechanisms of DBS may vary depending on the target and location of the DBS lead within that target.…”

Section: Dbs and The Role Of Monkey Researchmentioning

confidence: 99%

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

Vitek

Johnson

2019

Proc. Natl. Acad. Sci. U.S.A.

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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.

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“…This suggests that in Parkinson's disease higher-order correlations are relevant for motor symptoms, which offers some insight into the potential mechanisms by which deep-brain stimulation (DBS) might alleviate some of the motor symptoms such as rigidity and tremor. DBS in the STN and GPi has complex and diverse effects on the firing rate of neurons in SNr/GPi (Bar-Gad et al, 2004;Zimnik et al, 2015) and thalamus (Muralidharan et al, 2017). According to our model strong increases in SNr and GPi firing rates observed after STN DBS (Hashimoto et al, 2003;Maurice et al, 2003), would decrease the duration of the spontaneous pauses in the population activity ( Figure 3C).…”

Section: Effects Of Deep Brain Stimulationmentioning

confidence: 59%

Basal ganglia and cortical control of thalamic rebound spikes

Nejad

Rotter

Schmidt

2018

Preprint

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Basal ganglia output neurons transmit motor signals by decreasing their firing rate during movement. This decrease can lead to post-inhibitory rebound spikes in thalamocortical neurons in motor thalamus (Mthal). While in healthy animals neural activity in the basal ganglia is markedly uncorrelated, in Parkinson's disease neural activity becomes pathologically correlated. Here we investigated the impact of correlations in the basal ganglia output on the transmission of motor signals to Mthal using a Hodgkin-Huxley model of a thalamocortical neuron. We found that correlations in the basal ganglia output disrupt the transmission of motor signals via rebound spikes by increasing the signal-to-noise ratio and trial-to-trial variability. We further examined the role of brief sensory responses in basal ganglia output neurons and the effect of cortical excitation of Mthal in modulating rebound spiking. Interestingly, both the sensory responses and cortical inputs could either promote or suppress the generation of rebound spikes depending on their timing relative to the motor signal. Finally, in the model rebound spiking occurred despite the presence of moderate levels of excitation, indicating that rebound spiking might be feasible in a parameter regime relevant also in vivo. Overall, our model provides novel insights into the transmission of motor signals from the basal ganglia to Mthal by suggesting new functional roles for active decorrelation and sensory responses in the basal ganglia, as well as cortical excitation of Mthal. Author summaryThe output of the basal ganglia might act like a brake on our brain's motor circuits such as motor thalamus. When we move, this brake is released, letting motor thalamus execute the selected movement. However, the neural processes that underlie the communication of the basal ganglia with the motor thalamus during movement are unclear. We utilise a computational model of a neuron in motor thalamus to investigate how this transmission might work, how it can be modulated by sensory and cortical inputs, and how it is compromised in Parkinson's disease. Our results explain how pathological correlations in the neural activity in Parkinson's disease disturb the transmission of motor signals, which might underlie some of the motor symptoms. 2 voluntary movements [1-4]. Classic "box-and-arrow" models of the BG [5, 6] presume a 3 propagation of motor signals through the so-called direct pathway. Increased activity in 4 the striatum, the input region of the BG, reduces the activity in BG output regions 5 (e.g. substantia nigra pars reticulata, SNr), which in turn disinhibits the motor 6 thalamus (Mthal) [7], and thereby enables movement. BG output neurons often have 7 high baseline firing rates and decrease their rate during movement in both rodents and 8 primates [8-11]. However, recent studies have suggested a more complex picture on how 9 BG output affects Mthal and motor cortex [12, 13].10Three different modes have been proposed for how the BG output can affect 11 thalamic targets [13]. I...

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Modulation of Neuronal Activity in the Motor Thalamus during GPi-DBS in the MPTP Nonhuman Primate Model of Parkinson's Disease

Cited by 20 publications

References 64 publications

Changing views of the pathophysiology of Parkinsonism

Changing views of the pathophysiology of Parkinsonism

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

Basal ganglia and cortical control of thalamic rebound spikes

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