Internal Pallidal Neuronal Activity During Mild Drug-Related Dyskinesias in Parkinson's Disease: Decreased Firing Rates and Altered Firing Patterns

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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Deep brain stimulation entrains local neuronal firing in human globus pallidus internus

Journal of Neurophysiology ◽

10.1152/jn.00420.2012 ◽

2013 ◽

Vol 109 (4) ◽

pp. 978-987 ◽

Cited By ~ 38

Author(s):

Daniel R. Cleary ◽

Ahmed M. Raslan ◽

Jonathan E. Rubin ◽

Diaa Bahgat ◽

Ashwin Viswanathan ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Deep Brain Stimulation ◽

Globus Pallidus ◽

Neuronal Activity ◽

Brain Stimulation ◽

Spike Trains ◽

Neuronal Firing ◽

Firing Patterns ◽

Deep Brain

Deep brain stimulation (DBS) in the internal segment of the globus pallidus (GPi) relieves the motor symptoms of Parkinson's disease, yet the mechanism of action remains uncertain. To address the question of how therapeutic stimulation changes neuronal firing in the human brain, we studied the effects of GPi stimulation on local neurons in unanesthetized patients. Eleven patients with idiopathic Parkinson's disease consented to participate in neuronal recordings during stimulator implantation surgery. A recording microelectrode and a DBS macroelectrode were advanced through the GPi in parallel until a single neuron was isolated. After a baseline period, stimulation was initiated with varying voltages and different stimulation sites. The intra-operative stimulation parameters (1–8 V, 88–180 Hz, 0.1-ms pulses) were comparable with the postoperative DBS settings. Stimulation in the GPi did not silence local neuronal activity uniformly, but instead loosely entrained firing and decreased net activity in a voltage-dependent fashion. Most neurons had decreased activity during stimulation, although some increased or did not change firing rate. Thirty-three of 45 neurons displayed complex patterns of entrainment during stimulation, and burst-firing was decreased consistently after stimulation. Recorded spike trains from patients were used as input into a model of a thalamocortical relay neuron. Only spike trains that occurred during therapeutically relevant voltages significantly reduced transmission error, an effect attributable to changes in firing patterns. These data indicate that DBS in the human GPi does not silence neuronal activity, but instead disrupts the pathological firing patterns through loose entrainment of neuronal activity.

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Neuronal Firing Rates and Patterns in the Globus Pallidus Internus of Patients With Cervical Dystonia Differ From Those With Parkinson's Disease

Journal of Neurophysiology ◽

10.1152/jn.01107.2006 ◽

2007 ◽

Vol 98 (2) ◽

pp. 720-729 ◽

Cited By ~ 91

Author(s):

Joyce K. H. Tang ◽

Elena Moro ◽

Neil Mahant ◽

William D. Hutchison ◽

Anthony E. Lang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Firing Rate ◽

Globus Pallidus ◽

Cervical Dystonia ◽

Neuronal Firing ◽

Globus Pallidus Internus ◽

Motor Symptoms ◽

Firing Rates ◽

Irregular Pattern

Cervical dystonia (CD) is a movement disorder that involves involuntary turning and twisting of the neck caused by abnormal muscle contraction. Deep brain stimulation (DBS) in the globus pallidus internus (GPi) is used to treat both CD and the motor symptoms of Parkinson's disease (PD). It has been suggested that the differing motor symptoms in CD and PD may arise from a decreased GPi output in CD and elevation of output in PD. To test this hypothesis, extracellular recordings of GPi neuronal activity were obtained during stereotactic surgery for the implantation of DBS electrodes in seven idiopathic CD and 14 PD patients. The mean GPi neuronal firing rate recorded from CD patients was lower than that in PD patients ( P < 0.001; means ± SE: 71.4 ± 2.2 and 91.7 ± 3.0 Hz, respectively). Furthermore, GPi neurons fired in a more irregular pattern consisting of more frequent and longer pauses in CD compared with PD patients. When comparisons were done based on locations of recordings, these differences in firing rates and patterns were limited to the ventral portion of the GPi. In contrast, no difference in firing rate or pattern was observed in the globus pallidus externus between the two groups. These findings suggest that alterations in both firing rate and firing pattern may underlie the differing motor symptoms associated with these two movement disorders.

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Neuronal Entropy-Rate Feature of Entopeduncular Nucleus in Rat Model of Parkinson’s Disease

International Journal of Neural Systems ◽

10.1142/s0129065715500380 ◽

2016 ◽

Vol 26 (02) ◽

pp. 1550038 ◽

Cited By ~ 10

Author(s):

Olivier Darbin ◽

Xingxing Jin ◽

Christof Von Wrangel ◽

Kerstin Schwabe ◽

Atsushi Nambu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Basal Ganglia ◽

Normal Condition ◽

Rat Model ◽

Neuronal Firing ◽

Entopeduncular Nucleus ◽

Motor Processing ◽

Firing Rates ◽

Sensory Motor

The function of the nigro-striatal pathway on neuronal entropy in the basal ganglia (BG) output nucleus, i.e. the entopeduncular nucleus (EPN) was investigated in the unilaterally 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease (PD). In both control subjects and subjects with 6-OHDA lesion of dopamine (DA) the nigro-striatal pathway, a histological hallmark for parkinsonism, neuronal entropy in EPN was maximal in neurons with firing rates ranging between 15 and 25[Formula: see text]Hz. In 6-OHDA lesioned rats, neuronal entropy in the EPN was specifically higher in neurons with firing rates above 25[Formula: see text]Hz. Our data establishes that the nigro-striatal pathway controls neuronal entropy in motor circuitry and that the parkinsonian condition is associated with abnormal relationship between firing rate and neuronal entropy in BG output nuclei. The neuronal firing rates and entropy relationship provide putative relevant electrophysiological information to investigate the sensory-motor processing in normal condition and conditions such as movement disorders.

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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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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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