Neuronal firing patterns in the subthalamic nucleus in patients with akinetic-rigid-type Parkinson’s disease

AbstractIntroductionSubthalamic nucleus (STN) is an effective target for deep brain stimulation (DBS) to reduce the motor symptoms of Parkinson’s disease (PD). It is important to identify firing patterns within the structure for a better understanding of the electro-pathophysiology of the disease. Using recently established metrics, our study aims to autonomously identify the discharge patterns of individual cells and examine their spatial distribution within the STN.MethodsWe recorded single unit activity (SUA) from 12 awake PD patients undergoing a standard clinical DBS surgery. Three extracted features from raw SUA (local variation, bursting index and prominence of peak) were used with k-means clustering to achieve the aforementioned unsupervised grouping of firing patterns.Results279 neurons were isolated and four distinct firing patterns were identified across patients: tonic (11%), irregular (55%), periodic (9%) and non-periodic bursts (25%). The mean firing rates for irregular discharges were significantly lower (p<0.05) than the rest. Tonic firings were significantly ventral (p<0.05) while periodic (p<0.05) and non-periodic (p<0.01) bursts were dorsal. The percentage of periodically bursting neurons in dorsal region and entire STN were significantly correlated with off state UPDRS tremor scores (r=0.51, p=0.04) and improvement in bradykinesia and rigidity (r=0.57, p=0.02) respectively.ConclusionStrengthening the application of unsupervised clustering for firing patterns of individual cells, this study shows a unique spatial affinity of tonic activity towards the ventral and bursting activity towards the dorsal region of STN in PD patients. This spatial preference, together with the correlation of clinical scores, can provide a clue towards understanding Parkinsonian symptom generation.

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

Journal of Neurophysiology ◽

10.1152/jn.00443.2006 ◽

2007 ◽

Vol 97 (4) ◽

pp. 2627-2641 ◽

Cited By ~ 29

Author(s):

J. I. Lee ◽

L. Verhagen Metman ◽

S. Ohara ◽

P. M. Dougherty ◽

J. H. Kim ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Firing Rate ◽

Spike Trains ◽

Neuronal Firing ◽

Low Doses ◽

Significant Group ◽

Firing Patterns ◽

Firing Rates ◽

Before And After

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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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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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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Subthalamic nucleus neuronal firing rate increases with Parkinson's disease progression

Movement Disorders ◽

10.1002/mds.23708 ◽

2011 ◽

Vol 26 (9) ◽

pp. 1657-1662 ◽

Cited By ~ 29

Author(s):

Michael S. Remple ◽

Courtney H. Bradenham ◽

C. Chris Kao ◽

P. David Charles ◽

Joseph S. Neimat ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Firing Rate ◽

Disease Progression ◽

Subthalamic Nucleus ◽

Neuronal Firing ◽

Neuronal Firing Rate

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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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