Cholinergic mechanisms of high-frequency stimulation in entopeduncular nucleus

Chronic, high-frequency (>100 Hz) electrical stimulation, known as deep brain stimulation (DBS), of the internal segment of the globus pallidus (GPi) is a highly effective therapy for Parkinson's disease (PD) and dystonia. Despite some understanding of how it works acutely in PD models, there remain questions about its mechanisms of action. Several hypotheses have been proposed, such as depolarization blockade, activation of inhibitory synapses, depletion of neurotransmitters, and/or disruption/alteration of network oscillations. In this study we investigated the cellular mechanisms of high-frequency stimulation (HFS) in entopeduncular nucleus (EP; rat equivalent of GPi) neurons using whole cell patch-clamp recordings. We found that HFS applied inside the EP nucleus induced a prolonged afterdepolarization that was dependent on stimulation frequency, pulse duration, and current amplitude. The high frequencies (>100 Hz) and pulse widths (>0.15 ms) used clinically for dystonia DBS could reliably induce these afterdepolarizations, which persisted under blockade of ionotropic glutamate (kynurenic acid, 2 mM), GABAA (picrotoxin, 50 μM), GABAB (CGP 55845, 1 μM), and acetylcholine nicotinic receptors (DHβE, 2 μM). However, this effect was blocked by atropine (2 μM; nonselective muscarinic antagonist) or tetrodotoxin (0.5 μM). Finally, the muscarinic-dependent afterdepolarizations were sensitive to Ca2+-sensitive nonspecific cationic (CAN) channel blockade. Hence, these data suggest that muscarinic receptor activation during HFS can lead to feedforward excitation through the opening of CAN channels. This study for the first time describes a cholinergic mechanism of HFS in EP neurons and provides new insight into the underlying mechanisms of DBS.

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Cellular mechanisms of fatigue in skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.1991.261.2.c195 ◽

1991 ◽

Vol 261 (2) ◽

pp. C195-C209 ◽

Cited By ~ 259

Author(s):

H. Westerblad ◽

J. A. Lee ◽

J. Lannergren ◽

D. G. Allen

Keyword(s):

Skeletal Muscle ◽

Sarcoplasmic Reticulum ◽

High Frequency ◽

Force Production ◽

High Frequency Stimulation ◽

Tetanic Stimulation ◽

Cellular Mechanisms ◽

Frequency Stimulation ◽

T Tubules ◽

Underlying Mechanisms

Prolonged activation of skeletal muscle leads to a decline of force production known as fatigue. In this review we outline the ionic and metabolic changes that occur in muscle during prolonged activity and focus on how these changes might lead to reduced force. We discuss two distinct types of fatigue: fatigue due to continuous high-frequency stimulation and fatigue due to repeated tetanic stimulation. The causes of force decline are considered under three categories: 1) reduced Ca2+ release from the sarcoplasmic reticulum, 2) reduced myofibrillar Ca2+ sensitivity, and 3) reduced maximum Ca(2+)-activated tension. Reduced Ca2+ release can be due to impaired action potential propagation in the T tubules, and this is a principal cause of the tension decline with continuous tetanic stimulation. Another type of failing Ca2+ release, which is homogeneous across the fibers, is prominent with repeated tetanic stimulation; the underlying mechanisms of this reduction are not fully understood, although several possibilities emerge. Changes in intracellular metabolites, particularly increased concentration of Pi and reduced pH, lead to reduced Ca2+ sensitivity and reduced maximum tension, which make an important contribution to the force decline, especially with repeated tetanic stimulation.

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Electroceutically induced subthalamic high-frequency oscillations and evoked compound activity may explain the mechanism of therapeutic stimulation in Parkinson’s disease

Communications Biology ◽

10.1038/s42003-021-01915-7 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Musa Ozturk ◽

Ashwin Viswanathan ◽

Sameer A. Sheth ◽

Nuri F. Ince

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Pharmacological Treatment ◽

High Frequency ◽

High Frequency Stimulation ◽

High Frequency Oscillations ◽

Stimulation Pulse ◽

Main Challenge ◽

Frequency Stimulation ◽

Underlying Mechanisms

AbstractDespite having remarkable utility in treating movement disorders, the lack of understanding of the underlying mechanisms of high-frequency deep brain stimulation (DBS) is a main challenge in choosing personalized stimulation parameters. Here we investigate the modulations in local field potentials induced by electrical stimulation of the subthalamic nucleus (STN) at therapeutic and non-therapeutic frequencies in Parkinson’s disease patients undergoing DBS surgery. We find that therapeutic high-frequency stimulation (130–180 Hz) induces high-frequency oscillations (~300 Hz, HFO) similar to those observed with pharmacological treatment. Along with HFOs, we also observed evoked compound activity (ECA) after each stimulation pulse. While ECA was observed in both therapeutic and non-therapeutic (20 Hz) stimulation, the HFOs were induced only with therapeutic frequencies, and the associated ECA were significantly more resonant. The relative degree of enhancement in the HFO power was related to the interaction of stimulation pulse with the phase of ECA. We propose that high-frequency STN-DBS tunes the neural oscillations to their healthy/treated state, similar to pharmacological treatment, and the stimulation frequency to maximize these oscillations can be inferred from the phase of ECA waveforms of individual subjects. The induced HFOs can, therefore, be utilized as a marker of successful re-calibration of the dysfunctional circuit generating PD symptoms.

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Enhanced Ih Depresses Rat Entopeduncular Nucleus Neuronal Activity From High-Frequency Stimulation or Raised Ke+

Journal of Neurophysiology ◽

10.1152/jn.01065.2007 ◽

2008 ◽

Vol 99 (5) ◽

pp. 2203-2219 ◽

Cited By ~ 13

Author(s):

D. S. Shin ◽

P. L. Carlen

Keyword(s):

Neuronal Activity ◽

High Frequency ◽

Neurological Diseases ◽

Input Resistance ◽

High Frequency Stimulation ◽

Channel Activity ◽

Entopeduncular Nucleus ◽

Inhibitory Effects ◽

Frequency Stimulation ◽

Spontaneous Action

High-frequency stimulation (HFS) is used to treat a variety of neurological diseases, yet its underlying therapeutic action is not fully elucidated. Previously, we reported that HFS-induced elevation in [K+]e or bath perfusion of raised Ke+ depressed rat entopeduncular nucleus (EP) neuronal activity via an enhancement of an ionic conductance leading to marked depolarization. Herein, we show that the hyperpolarization-activated ( Ih) channel mediates the HFS- or K+-induced depression of EP neuronal activity. The perfusion of an Ih channel inhibitor, 50 μM ZD7288 or 2 mM CsCl, increased input resistance by 23.5 ± 7% (ZD7288) or 35 ± 10% (CsCl), hyperpolarized cells by 3.4 ± 1.7 mV (ZD7288) or 2.3 ± 0.9 mV (CsCl), and decreased spontaneous action potential (AP) frequency by 51.5 ± 12.5% (ZD7288) or 80 ± 13.5% (CsCl). The Ih sag was absent with either treatment, suggesting a block of Ih channel activity. Inhibition of the Ih channel prior to HFS or 6 mM K+ perfusion not only prevented the previously observed decrease in AP frequency, but increased neuronal activity. Under voltage-clamp conditions, Ih currents were enhanced in the presence of 6 mM K+. Calcium is also involved in the depression of EP neuronal activity, since its removal during raised Ke+ application prevented this attenuation and blocked the Ih sag. We conclude that the enhancement of Ih channel activity initiates the HFS- and K+-induced depression of EP neuronal activity. This mechanism could underlie the inhibitory effects of HFS used in deep brain stimulation in output basal ganglia nuclei.

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Electroceutically induced subthalamic high frequency oscillations and evoked compound activity may explain the mechanism of therapeutic stimulation in Parkinson's Disease

10.21203/rs.3.rs-63781/v1 ◽

2020 ◽

Author(s):

Musa Ozturk ◽

Ashwin Viswanathan ◽

Sameer Sheth ◽

Nuri Ince

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Pharmacological Treatment ◽

High Frequency ◽

High Frequency Stimulation ◽

High Frequency Oscillations ◽

Stimulation Pulse ◽

Main Challenge ◽

Frequency Stimulation ◽

Underlying Mechanisms

Abstract Despite having remarkable utility in treating movement disorders, the lack of understanding of the underlying mechanisms of high-frequency deep brain stimulation (DBS) is a main challenge in choosing personalized stimulation parameters. Here we investigate the modulations in local field potentials induced by therapeutic and non-therapeutic electrical stimulation of the subthalamic nucleus (STN) in Parkinson’s disease patients undergoing DBS surgery. We find that therapeutic high-frequency stimulation (130-180 Hz) induces high-frequency oscillations (~300 Hz, HFO) similar to those observed with pharmacological treatment. Along with HFOs, we also observed evoked compound activity (ECA) after each stimulation pulse. While ECA was observed in both therapeutic and non-therapeutic (20Hz) stimulation, the HFOs were induced only with therapeutic frequencies and the associated ECA were significantly more resonant. The relative degree of enhancement in the HFO power was related to the interaction of stimulation pulse with the phase of ECA.We propose that high-frequency STN-DBS tunes the neural oscillations to their healthy/treated state, similar to pharmacological treatment, and the stimulation frequency to maximize these oscillations can be inferred from the phase of ECA waveforms of individual subjects. The induced HFOs can, therefore, be utilized as a marker of successful re-calibration of the dysfunctional circuit generating PD symptoms.

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High-Frequency Stimulation Together with Adrenoceptor Activation Facilitates the Maintenance of Long-Term Potentiation at Visual Cortical Inhibitory Synapses

Cerebral Cortex ◽

10.1093/cercor/bhj065 ◽

2005 ◽

Vol 16 (9) ◽

pp. 1239-1248 ◽

Cited By ~ 8

Author(s):

Kazumasa Yamada ◽

Tsuyoshi Inagaki ◽

Rie Funahashi ◽

Yumiko Yoshimura ◽

Yukio Komatsu

Keyword(s):

High Frequency ◽

Long Term Potentiation ◽

Inhibitory Synapses ◽

High Frequency Stimulation ◽

Term Potentiation ◽

Frequency Stimulation ◽

Visual Cortical

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High-frequency stimulation of the entopeduncular nucleus improves dystonia in dtsz hamsters

Neuroreport ◽

10.1097/01.wnr.0000130435.75715.64 ◽

2004 ◽

Vol 15 (9) ◽

pp. 1391-1393 ◽

Cited By ~ 16

Author(s):

Daniel Harnack ◽

Melanie Hamann ◽

Wassilios Meissner ◽

Rudolf Morgenstern ◽

Andreas Kupsch ◽

...

Keyword(s):

High Frequency ◽

High Frequency Stimulation ◽

Entopeduncular Nucleus ◽

Frequency Stimulation ◽

Stimulation Of

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Faculty Opinions recommendation of Cellular mechanisms preventing sustained activation of cortex during subcortical high-frequency stimulation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1033216.375182 ◽

2006 ◽

Author(s):

Michele A Basso

Keyword(s):

High Frequency ◽

High Frequency Stimulation ◽

Cellular Mechanisms ◽

Frequency Stimulation ◽

Sustained Activation

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Cellular Mechanisms Preventing Sustained Activation of Cortex During Subcortical High-Frequency Stimulation

Journal of Neurophysiology ◽

10.1152/jn.00105.2006 ◽

2006 ◽

Vol 96 (2) ◽

pp. 613-621 ◽

Cited By ~ 58

Author(s):

Karl J. Iremonger ◽

Trent R. Anderson ◽

Bin Hu ◽

Zelma H. T. Kiss

Keyword(s):

Motor Cortex ◽

High Frequency ◽

Cortical Neurons ◽

Primary Motor Cortex ◽

Brain Slices ◽

Subcortical White Matter ◽

High Frequency Stimulation ◽

Cellular Mechanisms ◽

Ventral Thalamus ◽

Frequency Stimulation

Axonal excitation has been proposed as a key mechanism in therapeutic brain stimulation. In this study we examined how high-frequency stimulation (HFS) of subcortical white matter tracts projecting to motor cortex affects downstream postsynaptic responses in cortical neurons. Whole cell recordings were performed in the primary motor cortex (M1) and ventral thalamus of rat brain slices. In M1, neurons showed only an initial depolarization in response to HFS, after which the membrane potential returned to prestimulation levels. The prolonged suppression of excitation during stimulation was neither associated with GABAergic inhibition nor complete action potential failure in stimulated axons. Instead we found that HFS caused a depression of excitatory synaptic currents in postsynaptic neurons that was specific to the stimulated subcortical input. These data are consistent with the hypothesis that axonal HFS produces a functional deafferentation of postsynaptic targets likely from depletion of neurotransmitter.

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Cellular Mechanisms Underlying Antiepileptic Effects of Low- and High-Frequency Electrical Stimulation in Acute Epilepsy in Neocortical Brain Slices In Vitro

Journal of Neurophysiology ◽

10.1152/jn.00514.2006 ◽

2007 ◽

Vol 97 (3) ◽

pp. 1887-1902 ◽

Cited By ~ 77

Author(s):

Yitzhak Schiller ◽

Yael Bankirer

Keyword(s):

Electrical Stimulation ◽

High Frequency ◽

Brain Slices ◽

Low Frequency ◽

High Frequency Stimulation ◽

Dependent Manner ◽

Cellular Mechanisms ◽

Epileptiform Discharges ◽

Frequency Stimulation

Approximately 30% of epilepsy patients suffer from drug-resistant epilepsy. Direct electrical stimulation of the epileptogenic zone is a potential new treatment modality for this devastating disease. In this study, we investigated the effect of two electrical stimulation paradigms, sustained low-frequency stimulation and short trains of high-frequency stimulation, on epileptiform discharges in neocortical brain slices treated with either bicuculline or magnesium-free extracellular solution. Sustained low-frequency stimulation (5–30 min of 0.1- to 5-Hz stimulation) prevented both interictal-like discharges and seizure-like events in an intensity-, frequency-, and distance-dependent manner. Short trains of high-frequency stimulation (1–5 s of 25- to 200-Hz stimulation) prematurely terminated seizure-like events in a frequency-, intensity-, and duration-dependent manner. Roughly one half the seizures terminated within the 100-Hz stimulation train ( P < 0.01 compared with control), whereas the remaining seizures were significantly shortened by 53 ± 21% ( P < 0.01). Regarding the cellular mechanisms underlying the antiepileptic effects of electrical stimulation, both low- and high-frequency stimulation markedly depressed excitatory postsynaptic potentials (EPSPs). The EPSP amplitude decreased by 75 ± 3% after 10-min, 1-Hz stimulation and by 86 ± 6% after 1-s, 100-Hz stimulation. Moreover, partial pharmacological blockade of ionotropic glutamate receptors was sufficient to suppress epileptiform discharges and enhance the antiepileptic effects of stimulation. In conclusion, this study showed that both low- and high-frequency electrical stimulation possessed antiepileptic effects in the neocortex in vitro, established the parameters determining the antiepileptic efficacy of both stimulation paradigms, and suggested that the antiepileptic effects of stimulation were mediated mostly by short-term synaptic depression of excitatory neurotransmission.

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