Norepinephrine regulates long-term potentiation of both the population spike and dendritic EPSP in hippocampal dentate gyrus

Hippocampal slices from norepinephrine (NE)-depleted rats exhibited marked reductions in long-term potentiation (LTP) of both the population spike and dendritic EPSP in the dentate gyrus. In contrast, depletion of serotonin (5-hydroxytryptamine, 5-HT) had no effect on either population spike or EPSP-LTP. In addition, superfusion of slices with NE produced potentiation of both the granule cell population spike and dendritic EPSP which persisted long after NE washout. These data support a role for NE in regulating long-term plasticity of both granule cell action potential firing and dendritic EPSPs.     

Mechanisms of long-term potentiation: EPSP/spike dissociation, intradendritic recordings, and glutamate sensitivity

Synaptic efficacy is modified following a brief train of high-frequency stimulation (HFS) to a cell's afferent fibers (long-term potentiation; LTP). An alteration in the postsynaptic response to endogenous neurotransmitter, as a result of an increase in the number of postsynaptic receptors, has been proposed (Baudry and Lynch, 1980). We tested this hypothesis in the CA1 hippocampus by intracellularly recording the postsynaptic response to localized application of glutamate before and after induction of LTP. When LTP was produced, there was no corresponding change in neuronal sensitivity to glutamate application. These findings are not consistent with the hypothesis that HFS of fibers in CA1 stratum radiatum induces an increase in the number of postsynaptic glutamate receptors in CA1 pyramidal cells. Previous reports concerning LTP have indicated a dissociation between the degree of potentiation in the population EPSP and population spike. Simultaneous recordings of the CA 1 population EPSP and population spike in hippocampal slices confirmed that the degree of potentiation of the population spike was not predicted by the degree of potentiation in the population EPSP. Intradendritic impalements were obtained to more accurately assess changes in the intracellular EPSP following HFS. When the population EPSP was potentiated, there was also a potentiated intradendritic EPSP. When the population spike was potentiated following HFS, however, the intradendritic EPSP was often unchanged; in the same cell, there was an increased probability of action potential discharge to stimulation which was originally (i.e., pre-HFS) subthreshold for spike initiation. These results indicate that the EPSP (intracellular or extracellular) may be potentiated following HFS, but this potentiation is not a prerequisite for, or a correlation of, potentiation in the population spike. Furthermore, these findings suggest that LTP is composed of 2 independent components--a synaptic component and an EPSP-to-spike coupling component.     

Local field potential recordings from the pedunculopontine nucleus in a Parkinsonian patient

The pedunculopontine nucleus has recently been introduced as a new therapeutic target for deep brain stimulation in patients suffering from Parkinson's disease, particularly those with severe gait and postural impairment. Stimulation at this site is typically delivered at low frequencies in contrast to the high frequency stimulation required for therapeutic benefit in the subthalamic nucleus. Therefore, we looked for and demonstrated evidence of low frequency synchronization of activity in the pedunculopontine nucleus of a patient with Parkinson's disease that increased after treatment with dopamine and which might be mimicked by local deep brain stimulation at low frequency.     

An electronic device for artefact suppression in human local field potential recordings during deep brain stimulation

The clinical efficacy of high-frequency deep brain stimulation (DBS) for Parkinson's disease and other neuropsychiatric disorders likely depends on the modulation of neuronal rhythms in the target nuclei. This modulation could be effectively measured with local field potential (LFP) recordings during DBS. However, a technical drawback that prevents LFPs from being recorded from the DBS target nuclei during stimulation is the stimulus artefact. To solve this problem, we designed and developed 'FilterDBS', an electronic amplification system for artefact-free LFP recordings (in the frequency range 2-40 Hz) during DBS. After defining the estimated system requirements for LFP amplification and DBS artefact suppression, we tested the FilterDBS system by conducting experiments in vitro and in vivo in patients with advanced Parkinson's disease undergoing DBS of the subthalamic nucleus (STN). Under both experimental conditions, in vitro and in vivo, the FilterDBS system completely suppressed the DBS artefact without inducing significant spectral distortion. The FilterDBS device pioneers the development of an adaptive DBS system retroacted by LFPs and can be used in novel closed-loop brain-machine interface applications in patients with neurological disorders.     

Biophysical characterization of local field potential recordings from directional deep brain stimulation electrodes

ObjectiveTwo major advances in clinical deep brain stimulation (DBS) technology have been the introduction of local field potential (LFP) recording capabilities, and the deployment of directional DBS electrodes. However, these two technologies are not operationally integrated within current clinical DBS devices. Therefore, we evaluated the theoretical advantages of using directional DBS electrodes for LFP recordings, with a focus on measuring beta-band activity in the subthalamic nucleus (STN).MethodsWe used a computational model of human STN neural activity to simulate LFP recordings. The model consisted of 235,280 anatomically and electrically detailed STN neurons surrounding the DBS electrode, which was previously optimized to mimic beta-band synchrony in the dorsolateral STN. We then used that model system to compare LFP recordings from cylindrical and directional DBS contacts, and evaluate how the selection of different contacts for bipolar recording affected the LFP measurements.ResultsThe model predicted two advantages of directional DBS electrodes over cylindrical DBS electrodes for STN LFP recording. First, recording from directional contacts could provide additional insight on the location of a synchronous volume of neurons within the STN. Second, directional contacts could detect a smaller volume of synchronous neurons than cylindrical contacts, which our simulations predicted to be a ~0.5 mm minimum radius.ConclusionsSTN LFP recordings from 8-contact directional DBS electrodes (28 possible bipolar pairs) can provide more information than 4-contact cylindrical DBS electrodes (6 possible bipolar pairs), but they also introduce additional complexity in analyzing the signals.SignificanceIntegration of directional electrodes with DBS systems that are capable of LFP recordings could improve localization of targeted volumes of synchronous neurons in PD patients.     

An on-line spike form discriminator for extracellular recordings based on an analog correlation technique

The discrimination of single unit activity in extracellular recordings presents a serious problem when the signal-to-noise ratio is low or when the amplitudes of interspersed spikes are similar. By exploiting spike form, the system described here performs discrimination using on-line hardware template matching. Using analog delay lines, the combined deviation of 8 input signal values from 8 stored template values is calculated simultaneously. The 8 template values are selected by adjusting 8 cursors to the desired spike trace on a CRT; the spike form discriminator (SPIFODIS) then generates a deviation function which steeply drops to zero whenever form similarity occurs, allowing for easy triggering. The performance of SPIFODIS was compared quantitatively with that of a conventional amplitude trigger in two cases: when detecting a single unit with varied signal-to-noise ratios and when separating double units of equal amplitude. At signal-to-noise ratios between 2 and 1 the error rate for SPIFODIS was only 15-50% of that of an amplitude trigger. In double-unit recordings showing only form differences, spikes are discriminated with very low error rate, while an amplitude trigger fails completely.     

Performance comparison of extracellular spike sorting algorithms for single-channel recordings

Proper classification of action potentials from extracellular recordings is essential for making an accurate study of neuronal behavior. Many spike sorting algorithms have been presented in the technical literature. However, no comparative analysis has hitherto been performed. In our study, three widely-used publicly-available spike sorting algorithms (WaveClus, KlustaKwik, OSort) were compared with regard to their parameter settings. The algorithms were evaluated using 112 artificial signals (publicly available online) with 2-9 different neurons and varying noise levels between 0.00 and 0.60. An optimization technique based on Adjusted Mutual Information was employed to find near-optimal parameter settings for a given artificial signal and algorithm. All three algorithms performed significantly better (p < 0.01) with optimized parameters than with the default ones. WaveClus was the most accurate spike sorting algorithm, receiving the best evaluation score for 60% of all signals. OSort operated at almost five times the speed of the other algorithms. In terms of accuracy, OSort performed significantly less well (p < 0.01) than WaveClus for signals with a noise level in the range 0.15-0.30. KlustaKwik achieved similar scores to WaveClus for signals with low noise level 0.00-0.15 and was worse otherwise. In conclusion, none of the three compared algorithms was optimal in general. The accuracy of the algorithms depended on proper choice of the algorithm parameters and also on specific properties of the examined signal.     

Cellular and field potential properties of epileptogenic hippocampal slices

Epileptogenic activity was induced in hippocampal slices by addition of penicillin (2.0 mM) to the binding medium. Field potential epileptiform events were recorded and single cell bursts studied with intracellular electrodes. Epileptogenic activity was seen in areas CA1 and CA3 of the slice, with bursts in CA3 always leading CA1 bursts; a cut between CA1 and CA3 abolished spontaneous bursting in CA1 but not in CA3. Increased [Mg²⁺] and decreased [Ca²⁺] abolished epileptiform discharge, thus demonstrating its dependence on synaptic activity; burst occurrence was also sensitive to [K⁺]. Measurements of single cell resting potentials, resistance, and time constant in CA1 cells revealed no difference between cells in normal medium and cells made epileptogenic by penicillin. Depolarization shifts in CA1 neurons during epileptogenesis did not behave like ‘giant EPSPs’ but rather were complexes to which depolarizing spike after-potentials, fast prepotentials, and underlying slow depolarizing events all contributed.     

An efficient algorithm for continuous time cross correlogram of spike trains

We propose an efficient algorithm to compute the smoothed correlogram for the detection of temporal relationship between two spike trains. Unlike the conventional histogram-based correlogram estimations, the proposed algorithm operates on continuous time and does not bin either the spike train nor the correlogram. Hence it can be more precise in detecting the effective delay between two recording sites. Moreover, it can take advantage of the higher temporal resolution of the spike times provided by the current recording methods. The Laplacian kernel for smoothing enables efficient computation of the algorithm. We also provide the basic statistics of the estimator and a guideline for choosing the kernel size. This new technique is demonstrated by estimating the effective delays in a neuronal network from synthetic data and recordings of dissociated cortical tissue.     

Optimizing a linear algorithm for real-time robotic control using chronic cortical ensemble recordings in monkeys

Previous work in our laboratory has demonstrated that a simple linear model can be used to translate cortical neuronal activity into real-time motor control commands that allow a robot arm to mimic the intended hand movements of trained primates. Here, we describe the results of a comprehensive analysis of the contribution of single cortical neurons to this linear model. Key to the operation of this model was the observation that a large percentage of cortical neurons located in both frontal and parietal cortical areas are tuned for hand position. In most neurons, hand position tuning was time-dependent, varying continuously during a 1-sec period before hand movement onset. The relevance of this physiological finding was demonstrated by showing that maximum contribution of individual neurons to the linear model was only achieved when optimal parameters for the impulse response functions describing time-varying neuronal position tuning were selected. Optimal parameters included impulse response functions with 1.0- to 1.4-sec time length and 50- to 100-msec bins. Although reliable generalization and long-term predictions (60-90 min) could be achieved after 10-min training sessions, we noticed that the model performance degraded over long periods. Part of this degradation was accounted by the observation that neuronal position tuning varied significantly throughout the duration (60-90 min) of a recording session. Altogether, these results indicate that the experimental paradigm described here may be useful not only to investigate aspects of neural population coding, but it may also provide a test bed for the development of clinically useful cortical prosthetic devices aimed at restoring motor functions in severely paralyzed patients.     

Separation of synaptic and spike activity in intracellular recordings for selective analysis.

A software spike filter has been developed which allows the separation of synaptic activity and action potentials in intracellular recordings. The algorithm uses the different velocities of the membrane potential during synaptic and spike activity and a time window to identify action potentials. When spikes are recognized, they are removed and the membrane potential is substituted by interpolated values. The spike filter makes possible a separate quantitative evaluation of postsynaptic potentials and spike activity. Thus a comprehensive characterization of neuron activity can be obtained. The spike filter is part of a modular software package designed for the evaluation of neurobiological data.     

Idazoxan increases perforant path-evoked EPSP slope paired pulse inhibition and reduces perforant path-evoked population spike paired pulse facilitation in rat dentate gyrus

Norepinephrine, acting via beta-adrenoceptors, enhances the perforant path-evoked potential in dentate gyrus. Using systemic idazoxan to increase norepinephrine, and paired perforant path pulses to probe early inhibition, previous investigators reported that idazoxan increased initial spike amplitude and increased somatic feedback inhibition. Here, feedback inhibition was re-examined in idazoxan-treated (5 mg/kg) rats under urethane anesthesia. To control for initial increased spike amplitude after idazoxan, evoked potentials were matched, pre- and post-idazoxan, on initial population spike. Input-output current profiles were also compared pre- and post-idazoxan. Saline- and timolol-filled micropipettes permitted evaluation of a contribution of local beta-adrenoceptors. As previously observed, initial spike amplitude was potentiated by idazoxan. Comparable spike potentiation was not seen on the timolol micropipette. Paired pulse inhibition of spike amplitude apparently increased, but input-output curve comparisons revealed a loss of feedback facilitation rather than an increase in feedback inhibition. Initial EPSP slopes were depressed after idazoxan in input-output curve data. EPSP slope feedback ratios were significantly reduced following idazoxan.These data suggest idazoxan has multiple effects on perforant path input to the dentate gyrus. Spike potentiation following idazoxan has previously been shown to depend on intact norepinephrine input. Here, the reduction in spike potentiation on the timolol pipette is consistent with other evidence that norepinephrine-mediated potentiation of the perforant path-evoked potential is dependent on local beta-adrenoceptor activation. The input-output data suggest a decrease in feedback facilitation after idazoxan is likely to account for the apparent increase in feedback inhibition previously reported. Decreased EPSP slope ratios with similar paired pulse intervals have been reported in novel environments. Since exposure to novel environments activates locus coeruleus neurons, norepinephrine may mediate the change in EPSP slope inhibition reported in awake rats.In summary, these results are consistent with the hypothesis that idazoxan potentiates granule cell responses to perforant path input in the dentate gyrus via increases in norepinephrine that lead to beta-adrenoceptor activation, and, further, that idazoxan reduces paired pulse feedback spike facilitation and enhances EPSP slope, but not spike, feedback inhibition.     

Central oscillators in a patient with neuropathic tremor: Evidence from intraoperative local field potential recordings

Present pathophysiological concepts of neuropathic tremor assume mistimed and defective afferent input resulting in deregulation of cerebello‐thalamo‐cortical motor networks. Here, we provide direct evidence of central tremor processing in a 76‐year‐old female who underwent bilateral deep brain stimulation of the ventral intermedial nucleus of the thalamus (Vim‐DBS) because of neuropathic tremor associated with IgM paraproteinemia. Electrophysiological recordings of EEG and EMG were performed in three perioperative sessions: (1) preoperatively, (2) intraoperatively, and (3) 4 days after surgery in both rest and postural tremor conditions. Tremor‐related synchronization (coherence) between motor cortex (M1) and muscles (M. extensor digitorum, M. flexor digitorum) was assessed, and additional intraoperative local field potential (LFP) recordings from Vim allowed comprehensive coherence mapping in thalamo‐cortico‐muscular networks. Directionality of information flow was determined by directed transfer function (DTF) and phase analyses. Stimulation effects on tremor and corticomuscular coherence were assessed and the patient was followed for 12 months on clinical outcome measures (Tremor Rating Scale, CADET‐Score). Vim‐DBS reduced tremor (59%) and improved motor functionality in daily activities (31%, CADET‐A) after 12 months. Intraoperative recordings demonstrated significant coherence in the tremor frequency (4 Hz) between M1 and contralateral muscle, Vim and ipsilateral M1, Vim and contralateral muscle, but not between Vim and contralateral M1. Information flow was directed from M1 to Vim and bidirectional between M1 and muscle and between Vim and muscle, respectively. Corticomuscular coherence at tremor frequency was completely suppressed by Vim‐DBS. Our case study demonstrates central oscillators underlying neuropathic tremor and implies a strong pathophysiological rationale for Vim‐DBS. © 2010 Movement Disorder Society     

Studies on long-term potentiation of the population spike component of hippocampal field potential by the tetanic stimulation of the perforant path in rats: effects of a dopamine agonist, SKF-38393

Long-term potentiation of the field potentials recorded in the dentate gyrus of the hippocampus was observed in freely-moving rats by delivering a brief tetanic stimulation to the perforant path, and the effects of the D₁ agonist, SKF-38393, on it was investigated. The field potential was divided into two components; excitatory postsynaptic potential (EPSP) and population spike. In Expt. I, synaptic stimulus-response (S-R) relationship, spike S-R relationship, and EPSP-spike (E-S) relationship were plotted. The estimated slope of the regression line in the spike S-R relationship was enhanced after delivery of the tetanic stimulation (10 pulse at 400 Hz), where that in synaptic S-R relationship was not enhanced. The estimated slope of the regression line in the E-S relationship was also enhanced by the tetanic stimulation. In Expt. II, time-dependent change of the field potential after tetanic stimulation was investigated. The population spike was enhanced significantly for about 2 h following tetanic stimulation, while pEPSP did not change sigficantly. The changes following tetanic stimulation in Expt. I and II were significantly inhibited by previous administration of SKF-38393 (10 mg/kg, i.p.), and the effect of this drug was dose-dependently antagonized by the D₁ antagonist, SCH-23390 (0.1, 0.2 and 0.5 mg/kg, i.p.). These results suggest that a brief tetanic stimulation of the perforant path induces long-term potentiation of the population spike without potentiating the synaptic input in the perforant path-dentate synapses, and that potentiation of the population spike is inhibited by the dopaminergic D₁ mechanism.     

An algorithm for real-time detection of spike-wave discharges in rodents

The automatic real-time detection of spike-wave discharges (SWDs), the electroencephalographic hallmark of absence seizures, would provide a complementary tool for rapid interference with electrical deep brain stimulation in both patients and animal models. This paper describes a real-time detection algorithm for SWDs based on continuous wavelet analyses in rodents. It has been implemented in a commercially available data acquisition system and its performance experimentally verified. ECoG recordings lasting 5-8h from rats (n=8) of the WAG/Rij strain were analyzed using the real-time SWD detection system. The results indicate that the algorithm is able to detect SWDs within 1s with 100% sensitivity and with a precision of 96.6% for the number of SWDs. Similar results are achieved for 24-h ECoG recordings of two rats. The dependence of accuracy and speed of detection on program settings and attributes of ECoG are discussed. It is concluded that the wavelet based real-time detecting algorithm is well suited for automatic, real-time detection of SWDs in rodents.     

A simple and effective process for noise reduction of multichannel cortical field potential recordings in freely moving rats

Simple and useful steps, i.e. placing a grounded plate under the recording chamber as well as using multiple reference electrodes, are introduced here for obtaining reliable low-noise recordings of brain activity in freely moving rats. A general circuit model was built to analyze the electrical interference of both single-grounded and two-reference ground-free recording configurations. In both simulated and realistic conditions under two recording states, 60-Hz magnitude was in the microvolt range. Moreover, the noise was significantly reduced by shortening the distance between the subject and the grounded plate under the recording chamber. Furthermore, in chronically implanted rats, average 60-Hz interference of multichannel electroencephalograms of two-reference ground-free recordings (3.74 +/- 0.18 microV) was significantly smaller than that of the single-grounded condition (9.03 +/- 1.98 microV). Thus, we demonstrated that a lower-noise recording can be achieved by a two-reference configuration and a closely-placed metal grounded plate in an open-field circumstance. As compared to the use of a Faraday cage, this simple procedure is of benefit for long-term behavioral tracking with a video camera and for pharmacological experiments.     

A pattern grouping algorithm for analysis of spatiotemporal patterns in neuronal spike trains. 2. Application to simultaneous single unit recordings

This study demonstrates the practical application of the pattern grouping algorithm (PGA), presented in the companion paper (Tetko IV, Villa AEP. A pattern grouping algorithm for analysis of spatiotemporal patterns in neuronal spike trains. 1. Detection of repeated patterns. J. Neurosci. Methods 2000; accompanying article), to data sets including up to 30 simultaneously recorded spike trains. The analysis of a large network of simulated neurons shows that the incidence of patterns cannot be simply related to an increase in firing rates obtained after Hebbian learning. Patterns that disappeared and reappeared in the thalamus of anesthetized rats when the cerebral cortex was reversibly inactivated suggest that widespread cell assemblies contribute to the generation and propagation of precisely timed activity. In an another experiment multiple spike trains were recorded from the temporal cortex of freely moving rats performing a complex two-choice discrimination task. The presence or absence of particular patterns in the period preceding the cue was associated with changes in reaction time. In conclusion, neuronal network interactions may generate spatiotemporal firing patterns detectable by PGA. We provide evidence of such patterned activity associated with specific animal's behavior, thus suggesting the existence of complex temporal coding schemes in the higher nervous centers of the brain.