Changes in neuronal firing rate in the subthalamic nucleus with Parkinson's disease

The neuronal basis of hyperkinetic movement disorders has long been unclear. We now test the hypothesis that changes in the firing pattern of neurons in the globus pallidus internus (GPi) are related to dyskinesias induced by low doses of apomorphine in patients with advanced Parkinson's disease (PD). During pallidotomy for advanced PD, the activity of single neurons was studied both before and after administration of apomorphine at doses just adequate to induce dyskinesias (21 neurons, 17 patients). After the apomorphine injection, these spike trains demonstrated an initial fall in firing from baseline. In nine neurons, the onset of on was simultaneous with that of dyskinesias. In these spike trains, the initial fall in firing rate preceded and was larger than the fall at the onset of on with dyskinesias. Among the three neurons in which the onset of on occurred before that of dyskinesias, the firing rate did not change at the time of onset of dyskinesias. After injection of apomorphine, dyskinesias during on with dyskinesias often fluctuated between transient periods with dyskinesias and those without. Average firing rates were not different between these two types of transient periods. Transient periods with dyskinesias were characterized by interspike interval (ISI) independence, stationary spike trains, and higher variability of ISIs. A small but significant group of neurons demonstrated recurring ISI patterns during transient periods of on with dyskinesias. These results suggest that mild dyskinesias resulting from low doses of apomorphine are related to both low GPi neuronal firing rates and altered firing patterns.

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Unsupervised clustering reveals spatially varying single neuronal firing patterns in the subthalamic nucleus of patients with Parkinson's disease

Clinical Parkinsonism & Related Disorders ◽

10.1016/j.prdoa.2019.100032 ◽

2020 ◽

Vol 3 ◽

pp. 100032 ◽

Cited By ~ 1

Author(s):

Heet Kaku ◽

Musa Ozturk ◽

Ashwin Viswanathan ◽

Joohi Shahed ◽

Sameer A. Sheth ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Subthalamic Nucleus ◽

Unsupervised Clustering ◽

Neuronal Firing ◽

Firing Patterns ◽

Spatially Varying

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Multistable properties of human subthalamic nucleus neurons in Parkinson’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1912128116 ◽

2019 ◽

Vol 116 (48) ◽

pp. 24326-24333 ◽

Cited By ~ 1

Author(s):

Jeremy W. Chopek ◽

Hans Hultborn ◽

Robert M. Brownstone

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Subthalamic Nucleus ◽

Neural Circuits ◽

Silent Period ◽

Neuronal Firing ◽

Awake Surgery ◽

Finite State ◽

Subthalamic Neurons ◽

Firing Properties

To understand the function and dysfunction of neural circuits, it is necessary to understand the properties of the neurons participating in the behavior, the connectivity between these neurons, and the neuromodulatory status of the circuits at the time they are producing the behavior. Such knowledge of human neural circuits is difficult, at best, to obtain. Here, we study firing properties of human subthalamic neurons, using microelectrode recordings and microstimulation during awake surgery for Parkinson’s disease. We demonstrate that low-amplitude, brief trains of microstimulation can lead to persistent changes in neuronal firing behavior including switching between firing rates, entering silent periods, or firing several bursts then entering a silent period. We suggest that these multistable states reflect properties of finite state machines and could have implications for the function of circuits involving the subthalamic nucleus. Furthermore, understanding these states could lead to therapeutic strategies aimed at regulating the transitions between states.

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Effects of Apomorphine on Subthalamic Nucleus and Globus Pallidus Internus Neurons in Patients With Parkinson's Disease

Journal of Neurophysiology ◽

10.1152/jn.2001.86.1.249 ◽

2001 ◽

Vol 86 (1) ◽

pp. 249-260 ◽

Cited By ~ 188

Author(s):

R. Levy ◽

J. O. Dostrovsky ◽

A. E. Lang ◽

E. Sime ◽

W. D. Hutchison ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Firing Rate ◽

Globus Pallidus ◽

Subthalamic Nucleus ◽

Current Model ◽

Passive Movement ◽

Spontaneous Discharge ◽

Dopamine Receptor Agonist ◽

Firing Rates

This study examines the effect of apomorphine (APO), a nonselective D1- and D2-dopamine receptor agonist, on the firing activity of neurons in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) in patients with Parkinson's disease (PD). Single-unit microelectrode recordings were conducted in 13 patients undergoing implantation of deep brain stimulation electrodes in STN and 6 patients undergoing a pallidotomy. Doses of APO (2.5–8 mg) were sufficient to produce anon state, but not intended to induce dyskinetic movements. Following baseline recordings from a single neuron, APO was administered and the activity of the neuron followed for an average of 15 min. The spontaneous discharge of neurons encountered before ( n = 309), during ( n = 146, 10–60 min), and after the effect of APO had waned ( n = 127, >60 min) was also sampled, and the response to passive joint movements was noted. In both nuclei, APO increased the overall proportion of spikes in burst discharges (as detected with Poisson “surprise” analysis), and a greater proportion of cells with an irregular discharge pattern was observed. APO significantly decreased the overall firing rates of GPi neurons ( P < 0.01), but there was no change in the overall firing rate of neurons in the STN ( P = 0.68). However, the mean firing rates of STN neurons during APO-induced movements (choreic or dystonic dyskinesias) that occurred in four patients were significantly lower thanoff-period baseline values ( P < 0.05). Concurrent with a reduction in limb tremor, the percentage of cells with tremor-related activity (TCs) was found to be significantly reduced from 19 to 6% in the STN and 14 to 0% in the GPi following APO administration. APO also decreased the firing rate of STN TCs ( P < 0.05). During the off state, more than 15% of neurons tested (STN = 93, GPi = 63) responded to passive movement of two or more joints. After APO, this proportion decreased significantly to 7% of STN cells and 4% of GPi cells (STN = 28, GPi = 26). These findings suggest that the APO-induced amelioration of parkinsonian symptoms is not solely due to a decrease in overall activity in the GPi or STN as predicted by the current model of basal ganglia function in PD.

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Increased Gamma Oscillatory Activity in the Subthalamic Nucleus During Tremor in Parkinson's Disease Patients

Journal of Neurophysiology ◽

10.1152/jn.90837.2008 ◽

2009 ◽

Vol 101 (2) ◽

pp. 789-802 ◽

Cited By ~ 76

Author(s):

M. Weinberger ◽

W. D. Hutchison ◽

A. M. Lozano ◽

M. Hodaie ◽

J. O. Dostrovsky

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Subthalamic Nucleus ◽

Field Potential ◽

Gamma Oscillations ◽

Neuronal Firing ◽

Oscillatory Activity ◽

Frequency Range ◽

Resting Tremor ◽

Gamma Frequency

Rest tremor is one of the main symptoms in Parkinson's disease (PD), although in contrast to rigidity and akinesia, the severity of the tremor does not correlate well with the degree of dopamine deficiency or the progression of the disease. Studies suggest that akinesia in PD patients is related to abnormal increased beta (15–30 Hz) and decreased gamma (35–80 Hz) synchronous oscillatory activity in the basal ganglia. Here we investigated the dynamics of oscillatory activity in the subthalamic nucleus (STN) during tremor. We used two adjacent microelectrodes to simultaneously record neuronal firing and local field potential (LFP) activity in nine PD patients who exhibited resting tremor during functional neurosurgery. We found that neurons exhibiting oscillatory activity at tremor frequency are located in the dorsal region of STN, where neurons with beta oscillatory activity are observed, and that their activity is coherent with LFP oscillations in the beta frequency range. Interestingly, in 85% of the 58 sites examined, the LFP exhibited increased oscillatory activity in the low gamma frequency range (35–55 Hz) during periods with stronger tremor. Furthermore, in 17 of 26 cases where two LFPs were recorded simultaneously, their coherence in the gamma range increased with increased tremor. When averaged across subjects, the ratio of the beta to gamma coherence was significantly lower in periods with stronger tremor compared with periods of no or weak tremor. These results suggest that resting tremor in PD is associated with an altered balance between beta and gamma oscillations in the motor circuits of STN.

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