Subthalamic Nucleus Cells Research Articles

Mathematical model of subthalamic nucleus neuron: Characteristic activity patterns and bifurcation analysis.

The subthalamic nucleus (STN) has an important role in the pathophysiology of the basal ganglia in Parkinson's disease. The ability of STN cells to generate bursting rhythms under either transient or sustained hyperpolarization may underlie the excessively synchronous beta rhythms observed in Parkinson's disease. In this study, we developed a conductance-based single compartment model of an STN neuron, which is able to generate characteristic activity patterns observed in experiments including hyperpolarization-induced bursts and post-inhibitory rebound bursts. This study focused on the role of three currents in rhythm generation: T-type calcium (CaT) current, L-type calcium (CaL) current, and hyperpolarization-activated cyclic nucleotide-gated (HCN) current. To investigate the effects of these currents in rhythm generation, we performed a bifurcation analysis using slow variables in these currents. Bifurcation analysis showed that the HCN current promotes single-spike activity patterns rather than bursting in agreement with experimental results. It also showed that the CaT current is necessary for characteristic bursting activity patterns. In particular, the CaT current enables STN neurons to generate these activity patterns under hyperpolarizing stimuli. The CaL current enriches and reinforces these characteristic activity patterns. In hyperpolarization-induced bursts or post-inhibitory rebound bursts, the CaL current allows STN neurons to generate long bursting patterns. Thus, the bifurcation analysis explained the synergistic interaction of the CaT and CaL currents, which enables STN neurons to respond to hyperpolarizing stimuli in a salient way. The results of this study implicate the importance of CaT and CaL currents in the pathophysiology of the basal ganglia in Parkinson's disease.

Avoiding Internal Capsule Stimulation With a New Eight-Channel Steering Deep Brain Stimulation Lead

Novel deep brain stimulation (DBS) lead designs are currently entering the market, which are hypothesized to provide a way to steer the stimulation field away from neural populations responsible for side effects and towards populations responsible for beneficial effects. The objective of this study is to assess the performances of a new eight channel steering-DBS lead and compare this with a conventional cylindrical contact (CC) lead. The two leads were evaluated in a finite element electric field model combined with multicompartment neuron and axon models, representing the internal capsule (IC) fibers and subthalamic nucleus (STN) cells. We defined the optimal stimulation setting as the configuration that activated the highest percentage of STN cells, without activating any IC fibers. With this criterion, we compared monopolar stimulation using a single contact of the steering-DBS lead and CC lead, on three locations and four orientations of the lead. In addition, we performed a current steering test case by dividing the current over two contacts with the steering-DBS lead in its worst-case orientation. In most cases, the steering-DBS lead is able to stimulate a significantly higher percentage of STN cells compared to the CC lead using single contact stimulation or using a two contact current steering protocol when there is approximately a 1 mm displacement of the CC lead. The results also show that correct placement and orientation of the lead in the target remains an important aspect in achieving the optimal stimulation outcome. Currently, clinical trials are set up in Europe with a similar design as the steering-DBS lead. Our results illustrate the importance of the orientation of the new steering-DBS lead in avoiding side effects induced by stimulation of IC fibers. Therefore, in clinical trials sufficient attention should be paid to implanting the steering DBS-lead in the most effective orientation.

Efficient hardware implementation of the subthalamic nucleus–external globus pallidus oscillation system and its dynamics investigation

Modeling and implementation of the nonlinear neural system with physiologically plausible dynamic behaviors are considerably meaningful in the field of computational neuroscience. This study introduces a novel hardware platform to investigate the dynamical behaviors within the nonlinear subthalamic nucleus–external globus pallidus system. In order to reduce the implementation complexities, a hardware-oriented conductance-based subthalamic nucleus (STN) model is presented, which can reproduce accurately the dynamical characteristics of biological conductance-based STN cells. The accuracy of the presented design is ensured by the investigation of the dynamical properties including bifurcation analysis and phase portraits. Hardware implementation on a field-programmable gate array (FPGA) demonstrates that the proposed digital system can mimic the relevant biological characteristics with higher performance, which means the resource cost is cut down and the computational efficiency is improved by introducing the multiplier-less techniques including novel “shift MUL” approach and piecewise linear approximation. The central pattern generator (CPG) coupled by the presented system is also investigated, which can be applied as an embedded intelligent system in the field of neuro-robotic engineering.

Hyperbolic Modeling of Subthalamic Nucleus Cells to Investigate the Effect of Dopamine Depletion.

To investigate how different types of neurons can produce well-known spiking patterns, a new computationally efficient model is proposed in this paper. This model can help realize the neuronal interconnection issues. The model can demonstrate various neuronal behaviors observed in vivo through simple parameter modification. The behaviors include tonic and phasic spiking, tonic and phasic bursting, class 1 and class 2 excitability, rebound spike, rebound burst, subthreshold oscillation, and accommodated spiking along with inhibition neuron responses. Here, we investigate the neuronal spiking patterns in Parkinson's disease through our proposed model. Abnormal pattern of subthalamic nucleus in Parkinson's disease can be studied through variations in the shape and frequency of firing patterns. Our proposed model introduces mathematical equations, where these patterns can be derived and clearly differentiated from one another. The irregular and arrhythmic behaviors of subthalamic nucleus firing pattern under normal conditions can easily be transformed to those caused by Parkinson's disease through simple parameter modifications in the proposed model. This model can explicitly show the change of neuronal activity patterns in Parkinson's disease, which may eventually lead to effective treatment with deep brain stimulation devices.

Subthalamic nucleus volumes are highly consistent but decrease age-dependently-a combined magnetic resonance imaging and stereology approach in humans.

The subthalamic nucleus (STN) is a main target structure of deep brain stimulation (DBS) in idiopathic Parkinson's disease. Nevertheless, there is an ongoing discussion regarding human STN volumes and neuron count, which could potentially have an impact on STN-DBS. Moreover, a suspected functional subdivision forms the basis of the tripartite hypothesis, which has not yet been morphologically substantiated. In this study, it was aimed to investigate the human STN by means of combined magnetic resonance imaging (MRI) and stereology. STN volumes were obtained from 14 individuals (ranging from 65 to 96 years, 25 hemispheres) in 3 T MRI and in luxol-stained histology slices. Neuron number and cell densities were investigated stereologically over the entire STN and in pre-defined subregions in anti-human neuronal protein HuC/D-stained slices. STN volumes measured with MRI were smaller than in stereology but appeared to be highly consistent, measuring on average 99 ± 6 mm3 (MRI) and 132 ± 20 mm3 (stereology). The neuron count was 431,088 ± 72,172. Both STN volumes and cell count decreased age-dependently. Neuron density was different for the dorsal, medial and ventral subregion with significantly higher values ventrally than dorsally. Small variations in STN volumes in both MRI and stereology contradict previous findings of large variations in STN size. Age-dependent decreases in STN volumes and neuron numbers might influence the efficacy of STN-DBS in a geriatric population. Though the study is limited in sample size, site-dependent differences for the STN subregions form a morphological basis for the tripartite theory. Hum Brain Mapp 38:909-922, 2017. © 2016 Wiley Periodicals, Inc.

Phase-amplitude coupling, an indication of bursting in parkinsonism, is masked by periodic pulses.

Interactions between neural oscillations in the brain have been observed in many structures including the hippocampus, amygdala, motor cortex, and basal ganglia. In this study, one popular approach for quantifying oscillation interactions was considered: phase-amplitude coupling. The goals of the study were to use simulations to examine potential causes of elevated phase-amplitude coupling in parkinsonism, to compare simulated parkinsonian signals with recorded local field potentials from animal models of parkinsonism, to investigate possible relationships between increased bursting in parkinsonian single cells and elevated phase-amplitude coupling, and to uncover potential noise and artifact effects. First, a cell model that integrates incremental input currents and fires at realistic voltage thresholds was modified to allow control of stochastic parameters related to firing and burst rates. Next, the input currents and distribution of integration times were set to reproduce firing patterns consistent with those from parkinsonian subthalamic nucleus cells. Then, local field potentials were synthesized from the output of multiple simulated cells with varying degrees of synchronization and compared with subthalamic nucleus recordings from animal models of parkinsonism. The results showed that phase-amplitude coupling can provide important information about underlying neural activity. In particular, signals synthesized from synchronized bursting neurons showed increased oscillatory interactions similar to those observed in parkinsonian animals. Additionally, changes in bursting parameters such as the intraburst rate, the mean interburst period, and the amount of synchronization between neurons influenced the phase-amplitude coupling in predictable ways. Finally, simulation results revealed that small periodic signals can have a surprisingly large masking effect on phase-amplitude coupling.

Fidelity of frequency and phase entrainment of circuit-level spike activity during DBS.

High-frequency stimulation is known to entrain spike activity downstream and upstream of several clinical deep brain stimulation (DBS) targets, including the cerebellar-receiving area of thalamus (VPLo), subthalamic nucleus (STN), and globus pallidus (GP). Less understood are the fidelity of entrainment to each stimulus pulse, whether entrainment patterns are stationary over time, and how responses differ among DBS targets. In this study, three rhesus macaques were implanted with a single DBS lead in VPLo, STN, or GP. Single-unit spike activity was recorded in the resting state in motor cortex during VPLo DBS, in GP during STN DBS, and in STN and pallidal-receiving area of motor thalamus (VLo) during GP DBS. VPLo DBS induced time-locked spike activity in 25% (n = 15/61) of motor cortex cells, with entrained cells following 7.5 ± 7.4% of delivered pulses. STN DBS entrained spike activity in 26% (n = 8/27) of GP cells, which yielded time-locked spike activity for 8.7 ± 8.4% of stimulus pulses. GP DBS entrained 67% (n = 14/21) of STN cells and 32% (n = 19/59) of VLo cells, which showed a higher fraction of pulses effectively inhibiting spike activity (82.0 ± 9.6% and 86.1 ± 16.6%, respectively). Latency of phase-locked spike activity increased over time in motor cortex (58%, VPLo DBS) and to a lesser extent in GP (25%, STN DBS). In contrast, the initial inhibitory phase observed in VLo and STN during GP DBS remained stable following stimulation onset. Together, these data suggest that circuit-level entrainment is low-pass filtered during high-frequency stimulation, most notably for glutamatergic pathways. Moreover, phase entrainment is not stationary or consistent at the circuit level for all DBS targets.

Potential mechanisms for imperfect synchronization in parkinsonian basal ganglia.

Neural activity in the brain of parkinsonian patients is characterized by the intermittently synchronized oscillatory dynamics. This imperfect synchronization, observed in the beta frequency band, is believed to be related to the hypokinetic motor symptoms of the disorder. Our study explores potential mechanisms behind this intermittent synchrony. We study the response of a bursting pallidal neuron to different patterns of synaptic input from subthalamic nucleus (STN) neuron. We show how external globus pallidus (GPe) neuron is sensitive to the phase of the input from the STN cell and can exhibit intermittent phase-locking with the input in the beta band. The temporal properties of this intermittent phase-locking show similarities to the intermittent synchronization observed in experiments. We also study the synchronization of GPe cells to synaptic input from the STN cell with dependence on the dopamine-modulated parameters. Earlier studies showed how the strengthening of dopamine-modulated coupling may lead to transitions from non-synchronized to partially synchronized dynamics, typical in Parkinson's disease. However, dopamine also affects the cellular properties of neurons. We show how the changes in firing patterns of STN neuron due to the lack of dopamine may lead to transition from a lower to a higher coherent state, roughly matching the synchrony levels observed in basal ganglia in normal and parkinsonian states. The intermittent nature of the neural beta band synchrony in Parkinson's disease is achieved in the model due to the interplay of the timing of STN input to pallidum and pallidal neuronal dynamics, resulting in sensitivity of pallidal output to the phase of the arriving STN input. Thus the mechanism considered here (the change in firing pattern of subthalamic neurons through the dopamine-induced change of membrane properties) may be one of the potential mechanisms responsible for the generation of the intermittent synchronization observed in Parkinson's disease.

Phase response curves of subthalamic neurons measured with synaptic input and current injection

Infinitesimal phase response curves (iPRCs) provide a simple description of the response of repetitively firing neurons and may be used to predict responses to any pattern of synaptic input. Their simplicity makes them useful for understanding the dynamics of neurons when certain conditions are met. For example, the sizes of evoked phase shifts should scale linearly with stimulus strength, and the form of the iPRC should remain relatively constant as firing rate varies. We measured the PRCs of rat subthalamic neurons in brain slices using corticosubthalamic excitatory postsynaptic potentials (EPSPs; mediated by both AMPA- and NMDA-type receptors) and injected current pulses and used them to calculate the iPRC. These were relatively insensitive to both the size of the stimulus and the cell's firing rate, suggesting that the iPRC can predict the response of subthalamic nucleus cells to extrinsic inputs. However, the iPRC calculated using EPSPs differed from that obtained using current pulses. EPSPs (normalized for charge) were much more effective at altering the phase of subthalamic neurons than current pulses. The difference was not attributable to the extended time course of NMDA receptor-mediated currents, being unaffected by blockade of NMDA receptors. The iPRC provides a good description of subthalamic neurons' response to input, but iPRCs are best estimated using synaptic inputs rather than somatic current injection.

Modeling effect of GABAergic current in a basal ganglia computational model.

Electrical high frequency stimulation (HFS) of deep brain regions is a method shown to be clinically effective in different types of movement and neurological disorders. In order to shed light on its mode of action a computational model of the basal ganglia network coupled the HFS as injection current into the cells of the subthalamic nucleus (STN). Its overall increased activity rendered a faithful transmission of sensorimotor input through thalamo-cortical relay cells possible. Our contribution uses this model by Rubin and Terman (J Comput Neurosci, 16, 211-223, 2004) as a starting point and integrates recent findings on the importance of the extracellular concentrations of the inhibiting neurotransmitter GABA. We are able to show in this computational study that besides electrical stimulation a high concentration of GABA and its resulting conductivity in STN cells is able to re-establish faithful thalamocortical relaying, which otherwise broke down in the simulated parkinsonian state.

Dopamine deficiency increases synchronized activity in the rat subthalamic nucleus

Abnormal neuronal activity in the subthalamic nucleus (STN) plays a crucial role in the pathophysiology of Parkinson's disease (PD). In this study we investigated changes in rat STN neuronal activity after 28days following the injection of 6-OHDA in the substantia nigra pars compacta (SNc). This drug provoked a lesion of SNc that induced a dopamine (DA) depletion assessed by changes in rotating capacity in response to apomorphine injection and by histological analysis. By means of extracellular recordings and waveshape spike sorting it was possible to analyze simultaneous spike trains and compute the crosscorrelations. Based on the analysis of the autocorrelograms we classified four types of firing patterns: regular (Poissonian-like), oscillatory (in the range 4–12Hz), bursty and cells characterized by a long refractoriness. The distribution of unit types in the control (n=61) and lesioned (n=83) groups was similar, as well as the firing rate. In 6-OHDA treated rats we observed a significant increase (from 26% to 48%) in the number of pairs with synchronous firing. These data suggest that the synchronous activity of STN cells, provoked by loss of DA cells in SNc, is likely to be among the most significant dysfunctions in the basal ganglia of Parkinsonian patients. We raise the hypothesis that in normal conditions, DA maintains a balance between funneling information via the hyperdirect cortico-subthalamic pathway and parallel processing through the parallel cortico-basal ganglia-subthalamic pathways, both of which are necessary for selected motor behaviors.This article is part of a Special Issue entitled ‘Neural Coding’.

The effect of spike time dependent plasticity on activity patterns in the basal ganglia

Background Pathophysiology of Parkinson’s disease (PD) is characterized by increased firing rates of cells in the basal ganglia, a tendency toward bursting and abnormal synchronization in cells of subthalamic nucleus (STN) and globus pallidus pars externa (GPe) [1]. In advanced PD, deep brain stimulation (DBS) can be used to disrupt this pathological activity. The standard protocol for DBS is continuous high frequency stimulation of target cells, such as STN. It has been proposed that short-duration stimulation protocols may also disrupt the pathological activity [2]. The mechanism underlying this protocol is supposedly synaptic plasticity. The goal of this study is to investigate, with a biophysically plausible model, the role of synaptic plasticity in stabilizing firing patterns in the basal ganglia.

Phase response curves of subthalamic neurons: experimental measurement and theoretical prediction

The subthalamic nucleus (STN) is an autonomously active population of glutamatergic neurons that occupies a pivotal location within the basal ganglia, receiving direct cortical input and innervating the globus pallidus and substantia nigra. As intrinsically oscillating neurons, STN cells may be suitable candidates for reduction to phase models, where the state of each neuron is represented by a single number (phase) and their response to synaptic input is given by infinitesimal phase response curves (iPRCs). Phase models are analytically tractable and assist the study of large neural populations, but whether they can describe the behavior of STN cells with sufficient accuracy is an open question. We addressed this issue by measuring the iPRCs of STN cells in brain slices, using both glutamatergic synaptic input and brief current injection. We found that iPRCs measured synaptically were relatively insensitive to the size of the EPSP used to measure them, and that iPRCs measured with current pulses were the same regardless of the polarity of the current, at least during the first 60% of the oscillation cycle; both observations suggest that iPRCs might accurately describe the response of STN cells to finite inputs. However, we also found that iPRCs measured synaptically and by current injection were dramatically different, with current pulse iPRCs giving much less phase shift for a given stimulus amplitude. We developed and analyzed a biophysical model of STN cells, to better understand the nature of subthalamic iPRCs. This model produced an iPRC that closely resembled those we measured experimentally. Observing that this model consisted mainly of kinetically fast voltagedependent currents and AHP currents that can be treated as a function of time since the last spike, we explored the iPRCs of cells whose conductances are direct functions of voltage. Ignoring the spike itself by assuming that it is triggered at a certain threshold potential followed by return (2 ms later) to resetting potential, we found that the iPRC of such cells is a simple function of their IV curves and that their iPRC is valid for arbitrarily large currents. The contribution of AHP currents could therefore be covered by treating them as applied currents acting through this IV curve-based iPRC. Following this approach, we developed a method for deriving the iPRC of any cell well described by a combination of fast voltage-dependent currents and time-dependent AHP currents, covering a wide range of cell types. We were also able to estimate experimentally the IV curves and AHP currents of STN cells in which we had empirically determined the synaptic and current pulse iPRCs, allowing us to compare theoretically predicted iPRCs to experimentally measured iPRCs. We found that the theoretically predicted PRC approximated the synaptic–but not the current pulse–iPRC. We hypothesize that somatically injected charge slowly trickles into distal dendrites, reducing its effectiveness at advancing the phase, whereas synaptically delivered charge comes from precharged dendrites. We conclude that current injection is not an effective method for measuring iPRCs in dendritic neurons.

Dynamic Spike Threshold and Zero Membrane Slope Conductance Shape the Response of Subthalamic Neurons to Cortical Input

The subthalamic nucleus (STN) provides a second entry point for cortical input to the basal ganglia, supplementing the corticostriatal pathway. We examined the way intrinsic properties shape the response of the STN to cortical excitation, recording from rat STN in vivo and in brain slices. STN cells exhibited a near-zero slope conductance-and hence an effectively infinite membrane time constant-at subthreshold potentials. This makes STN cells exceptional temporal integrators, consistent with the common view that basal ganglia nuclei use rate coding. However, STN cells also exhibited a drop in spike threshold triggered by larger EPSPs, allowing them to fire time-locked spikes in response to coincident input. In addition to promoting coincidence detection, the threshold dynamics associated with larger EPSPs reduced the probability of firing spikes outside of a narrow window immediately after the stimulus, even on trials in which the EPSP did not directly trigger a spike. This shift in stimulus-evoked firing pattern would allow downstream structures to distinguish coincidence-triggered spikes from other spikes and thereby permit coincidence detection and rate coding to operate in parallel in the same cell. Thus, STN cells can combine two functions-integration and coincidence detection-that are normally considered mutually exclusive. This could support rapid communication between cortex and basal ganglia targets that bypasses the striatum without disrupting slower rate coding pathways.

Slow Spike Frequency Adaptation in Neurons of the Rat Subthalamic Nucleus

Neurons of the subthalamic nucleus (STN) are very sensitive to applied currents, firing at 10-20/s during spontaneous activity, but increasing to peak firing rates of 200/s with applied currents <0.5 nA. They receive a powerful tonic excitatory input from neurons in the cerebral cortex, yet in vivo maintain an irregular firing rate only slightly higher than the autonomous firing rate seen in slices. Spike frequency adaptation acts to normalize background firing rate by removing slow trends in firing due to changes in average input. Subthalamic neurons have been previously described as showing little spike frequency adaptation, but this was based on tests using brief stimuli. We applied long-duration depolarizing current steps to STN neurons in slices and observed a very strong spike frequency adaptation with a time constant of 20 s and that recovered at a similar rate. This adaptation could return firing to near-baseline levels during prolonged current pulses that transiently drove the cells at high rates. The current responsible for adaptation was studied in voltage clamp during and after high-frequency driving of the cell and was determined to be a slowly accumulating K(+) current. This current was independent of calcium or sodium entry and could be induced with long-duration voltage steps after blockade of action potentials. In addition to the adaptation current, driven firing produced slow inactivation of the persistent Na(+) current, which also contributed to the reduced excitability of STN cells during and after driven firing.

Dynamics of the Subthalamo-pallidal Complex in Parkinson’s Disease During Deep Brain Stimulation

The dynamics of the subthalamo-pallidal complex in Parkinson's disease during deep brain stimulation (DBS) were studied using two models, a simple firing-rate model and a population-based model. We extended the simple firing-rate model of the complex formed by the subthalamic nucleus (STN) and the external segment of the Globus Pallidus (GPe) to explore its dynamical regime during DBS. More specifically, the modulation of neuronal activity (i.e., pattern and amplitude) during DBS was studied. A similar approach was used with the population-based model. Simulation results revealed a gradual decrease in bursting activity in STN cells when the DBS frequency increased. In addition, the contribution of the stimulation current type (mono- or biphasic) to the results was also examined. A comparison of the two models indicated that the population-based model was more biologically realistic and more appropriate for exploring DBS mechanisms. Understanding the underlying mechanisms of DBS is a prerequisite for developing new stimulation protocols.

A computational modelling approach to investigate different targets in deep brain stimulation for Parkinson’s disease

We investigated by a computational model of the basal ganglia the different network effects of deep brain stimulation (DBS) for Parkinson's disease (PD) in different target sites in the subthalamic nucleus (STN), the globus pallidus pars interna (GPi), and the globus pallidus pars externa (GPe). A cellular-based model of the basal ganglia system (BGS), based on the model proposed by Rubin and Terman (J Comput Neurosci 16:211-235, 2004), was developed. The original Rubin and Terman model was able to reproduce both the physiological and pathological activities of STN, GPi, GPe and thalamo-cortical (TC) relay cells. In the present study, we introduced a representation of the direct pathway of the BGS, allowing a more complete framework to simulate DBS and to interpret its network effects in the BGS. Our results suggest that DBS in the STN could functionally restore the TC relay activity, while DBS in the GPe and in the GPi could functionally over-activate and inhibit it, respectively. Our results are consistent with the experimental and the clinical evidences on the network effects of DBS.

Depolarisation and suppression of burst firing activity in the mouse subthalamic nucleus by dopamine D1/D5 receptor activation of a cyclic-nucleotide gated non-specific cation conductance

Neuronal burst firing in the subthalamic nucleus (STN) is one of the hallmarks of dopamine depletion in Parkinson's disease. Here, we have determined the postsynaptic effects of dopamine in the STN and the functional consequences of dopamine receptor modulation on burst firing in vitro. STN cells displayed regular spiking activity at a rate of 7.9 ± 0.5 Hz. Application of dopamine (30 μM) induced membrane depolarisations accompanied by an increase in firing rate of mean 12.0 ± 0.6 Hz in all 69 cells. The dopamine effect was mimicked by the dopamine D1/D5 receptor agonist SKF38393 (10 μM, 17 cells) and the dopamine D2-like receptor agonist quinpirole (10 μM, 35 cells), partly reduced by D1/D5 antagonist SCH23390 (2 μM, seven cells), but unaffected by the D2 antagonists sulpiride (10 μM, seven cells) or eticlopride (10 μM, six cells). Using voltage ramps, dopamine induced an inward current of 69 ± 9.4 pA at a holding potential of −60 mV ( n = 17). This current was accompanied by an increase in input conductance of 1.55 ± 0.35 nS which reversed at −30.6 ± 2.3 mV, an effect mimicked by SKF38393 (10 μM, nine cells). Similar responses were observed when measuring instantaneous current evoked by voltage steps and in the presence of the I h blocker, ZD7288, indicating effects independent of I h. The increase in conductance was blocked by SCH23390 (2 μM, n = 4), mimicked by the activator of adenylyl cyclase forskolin (10 μM, n = 7) and blocked by H-89, an inhibitor of cyclic AMP dependent protein kinase A (10 μM, n = 6). These results indicate that the dopamine depolarisation is in part mediated by D1/D5 receptor mediated activation of a cyclic-nucleotide gated (CNG) non-specific cation conductance. This conductance contributes to the membrane depolarisation that changes STN neuronal bursting to more regular activity by significantly increasing burst duration and number of spikes per burst.

Deep brain stimulation promotes excitation and inhibition in subthalamic nucleus in Parkinson's disease

Subthalamic nucleus single-unit recordings were undertaken before and during pedunculopontine [corrected] nucleus-stimulation at clinically relevant frequency (25 Hz) in six patients with Parkinson's disease. Pedunculopontine [corrected] nucleus stimulation changed the firing activity of almost every subthalamic nucleus cell (44/48) by decreasing the ongoing discharge in bursting subthalamic nucleus neurons (-62.1%) and exciting irregular (+63.2%) and tonic/regular discharges (+20.1%). These conflicting data challenge the definition of pedunculopontine [corrected] nucleus as a new target area for Parkinson's disease. If the modulation of subthalamic nucleus bursting units may corroborate the pedunculopontine [corrected] nucleus therapeutic role, the simultaneous excitatory influence during nonbursty patterns might interfere with a favorable outcome on motor signs. As a result, the implantation of pedunculopontine [corrected] nucleus alone may be hazardous while the association of subthalamic nucleus plus pedunculopontine [corrected] nucleus seems to be reasonable.

Accumulation of cytoplasmic calcium, but not apamin‐sensitive afterhyperpolarization current, during high frequency firing in rat subthalamic nucleus cells

The autonomous firing pattern of neurons in the rat subthalamic nucleus (STN) is shaped by action potential afterhyperpolarization currents. One of these is an apamin-sensitive calcium-dependent potassium current (SK). The duration of SK current is usually considered to be limited by the clearance of calcium from the vicinity of the channel. When the cell is driven to fire faster, calcium is expected to accumulate, and this is expected to result in accumulation of calcium-dependent AHP current. We measured the time course of calcium transients in the soma and proximal dendrites of STN neurons during spontaneous firing and their accumulation during driven firing. We compared these to the time course and accumulation of AHP currents using whole-cell and perforated patch recordings. During spontaneous firing, a rise in free cytoplasmic calcium was seen after each action potential, and decayed with a time constant of about 200 ms in the soma, and 80 ms in the dendrites. At rates higher than 10 Hz, calcium transients accumulated as predicted. In addition, there was a slow calcium transient not predicted by summation of action potentials that became more pronounced at high firing frequency. Spike AHP currents were measured in voltage clamp as tail currents after 2 ms voltage pulses that triggered action currents. Apamin-sensitive AHP (SK) current was measured by subtraction of tail currents obtained before and after treatment with apamin. SK current peaked between 10 and 15 ms after an action potential, had a decay time constant of about 30 ms, and showed no accumulation. At frequencies between 5 and 200 spikes s(-1), the maximal SK current remained the same as that evoked by a single action potential. AHP current did not have time to decay between action potentials, so at frequencies above 50 spikes s(-1) the apamin-sensitive current was effectively constant. These results are inconsistent with the view that the decay of SK current is governed by calcium dynamics. They suggest that the calcium is present at the SK channel for a very short time after each action potential, and the current decays at a rate set by the deactivation kinetics of the SK channel. At high rates, repetitive firing was governed by a fast apamin-insensitive AHP current that did not accumulate, but rather showed depression with increases in activation frequency. A slowly accumulating AHP current, also insensitive to apamin, was extremely small at low rates but became significant with higher firing rates.