Range Of Stimulus Frequencies Research Articles

Local cochlear mechanical responses revealed through outer hair cell receptor potential measurements

Sensory hair cells, including the sensorimotor outer hair cells, which enable the sensitive, sharply tuned responses of the mammalian cochlea, are excited by radial shear between the organ of Corti and the overlying tectorial membrane. It is not currently possible to measure directly in vivo mechanical responses in the narrow cleft between the tectorial membrane and organ of Corti over a wide range of stimulus frequencies and intensities. The mechanical responses can, however, be derived by measuring hair cell receptor potentials. We demonstrate that the seemingly complex frequency- and intensity-dependent behavior of outer hair cell receptor potentials could be qualitatively explained by a two degrees of freedom system with local cochlear partition and tectorial membrane resonances strongly coupled by the outer hair cell stereocilia. A local minimum in the receptor potential below the characteristic frequency should always be observed at a frequency where the tectorial membrane mechanical impedance is minimal, i.e., at the presumed tectorial membrane resonance frequency. The tectorial membrane resonance frequency might, however, shift with stimulus intensity in accordance with a shift in the maximum of the tectorial membrane radial mechanical responses to lower frequencies, as observed in experiments.

The functional operation of the vestibulo-ocular reflex.

The biophysical properties of the labyrinthine semicircular canals, and the electrophysiological properties of peripheral vestibular afferent neurons over a range of stimulus frequencies, are reviewed. Resting discharge activity and adaptive properties of vestibular neurons are discussed. Central processing of vestibular signals is then examined, including push-pull organization and the velocity storage mechanism. A detailed treatment of the final common neural integrator for oculomotor signals follows with consideration of its neural substrate and how distributed networks of neurons can overcome several problems posed by conventional control-systems models, such as why neural signals, but not background discharge, are integrated. Next, the behavior of the vestibulo-ocular reflex in darkness is compared with how it satisfies visual demands during natural activities. Finally, the reflex's performance at high frequencies of head rotation is discussed.

Establishing Reproducibility and Correlation of Cochlear Microphonic Amplitude to Implant Electrode Position Using Intraoperative Electrocochleography and Postoperative Cone Beam Computed Tomography.

The primary objective of this study was to establish the reproducibility of cochlear microphonic (CM) recordings obtained from a cochlear implant (CI) electrode contact during and immediately after insertion. This was achieved by evaluating the insertion angle and calculating the position of the apical electrode contact during insertion, using postoperative cone beam computed tomography (CBCT). The secondary objective was to create individualized patient maps of electrode contacts located within acoustically sensitive regions by correlating the CM amplitude to the electrode position determined using CBCT. CMs were recorded from a CI electrode contact during and immediately after insertion in 12 patients (n = 14 ears). Intraoperative recordings were made for a 0.5 kHz tone burst stimulus and were recorded from the apical electrode contact. Postinsertion recordings were made from the odd-numbered electrode contacts (1-15) along the array, using a range of stimulus frequencies (from 0.125 to 2 kHz). The time point at which each electrode contact passed through the round window was noted throughout the insertion, and the CM amplitude at this point was correlated to postoperative CBCT. This correlation was then used to estimate the CM amplitude at particular points within the cochlea, which was in turn compared with the amplitudes recorded from each electrode postoperatively to assess the reproducibility of the recordings. Significant correlation was shown between intraoperative insertion and postinsertion angles at two amplitude events (maximum amplitude: 29° mean absolute error, r = 0.77, p = 0.006; 10% of maximum amplitude: 52° mean absolute error, r = 0.85, p = 0.002). We have developed a novel method to demonstrate the reproducibility of the CM responses recorded from a CI electrode during insertion. By correlating the CM amplitude with the postoperative CBCT, we have also been able to create individualized maps of CM responses, categorizing the cochlea into acoustically responsive and unresponsive regions. If the electrode contacts within the acoustically sensitive regions are shown to be associated with improved loudness discrimination, it could have implications for optimal electrode mapping and placement.

Transferring Subject-Specific Knowledge Across Stimulus Frequencies in SSVEP-Based BCIs

Learning from subject's calibration data can significantly improve the performance of a steady-state visually evoked potential (SSVEP)-based brain-computer interface (BCI), for example, the state-of-the-art target recognition methods utilize the learned subject-specific and stimulus-specific model parameters. Unfortunately, when dealing with new stimuli or new subjects, new calibration data must be acquired, thus requiring laborious calibration sessions, which becomes a major challenge in developing high-performance BCIs for real-life applications. This study investigates the feasibility of transferring the model parameters (i.e., the spatial filters and the SSVEP templates) across two different groups of visual stimuli in SSVEP-based BCIs. According to our exploration, we can extract a common spatial filter from the spatial filters across different stimulus frequencies and a common impulse response from the SSVEP templates across different neighboring stimulus frequencies, in which the common spatial filter is considered as the transferred spatial filter and the common impulse response is utilized to reconstruct the transferred SSVEP template according to the theory that an SSVEP is a superposition of the impulse responses. Then, we develop a transfer learning canonical correlation analysis (tlCCA) incorporating the transferred model parameters. For evaluation, we compare the recognition performance of the calibration-free, the calibration-based, and the proposed tlCCA on an SSVEP data set with 60 subjects. Experiment results prove that the spatial filters share commonality across different frequencies and the impulse responses share commonality across neighboring frequencies. More importantly, the tlCCA performs significantly better than the calibration-free algorithms, comparably to the calibration-based algorithm. Note to Practitioners-This work is motivated by the long calibration time problem in using an steady-state visually evoked potential (SSVEP)-based brain-computer interface (BCI) because most state-of-the-art frequency recognition methods consider merely the situation that the calibration data and the test data are from the same subject and the same visual stimulus. This article assumes that the model parameters share the stimulus-nonspecific knowledge in a limited stimulus frequency range, and thus, the subject's old calibration data can be reused to learn new model parameters for new visual stimuli. First, the model parameters can be decomposed into the stimulus-nonspecific knowledge (or subject-specific knowledge) and stimulus-specific knowledge. Second, the new model parameters can be generated via transferring the knowledge across stimulus frequencies. Then, a new recognition algorithm is developed using the transferred model parameters. Experiment results validate the assumptions, and moreover, the proposed scheme could be extended to other scenarios, such as when facing new subjects, or adopting new signal acquisition equipment, which would be helpful to the future development of zero-calibration SSVEP-based BCIs for real-life healthcare applications.

Opioid modulation of cochlear auditory responses in the rat inner ear.

The auditory system has an extensive efferent innervation, which contributes to processes of control and regulation of the afferent input. The expression of receptors to various neurotransmitters and neuropeptides in the inner ear has been described, among which endogenous opioid receptors are found. The role of opioid receptors in the cochlea is not yet fully defined, it has been reported that opioid agonists and antagonists modulate the response to auditory stimuli and in clinical practice, multiple cases have been reported in which the consumption of opioid derivatives induce sensorineural hearing loss. In this work, we evaluated the effects of acute treatment with morphine, fentanyl, tramadol, and naloxone, in the auditory brain stem potentials (ABR), the compound action potential (CAP), and distortion products otacoustic emissions (DPOAE), across a wide range of stimulus frequencies and amplitudes. Adult Long-Evans rats of the strain CII/ZV weighing 180-220g were used. For the ABR recording drugs were administered intraperitoneally or intravenously. For the CAP and DPOAE drugs were applied by direct perfusion in the middle ear. The opioid agonists produced a consistent increase in the amplitude of the PI component of the ABR and of the N1-P1 amplitude of the CAP. Naloxone produced no significant changes in the ABR and a reduction of the CAP N1-P1 amplitude. Also, opioid agonists induced a decrease in the amplitude of the DPOAE. These results show that the opioid receptor activation modulates both the afferent response at both the afferent response to acoustic stimuli, and also at the cochlear mechanics as revealed by DPOAE changes. These results present a significant step in understanding how opioid modulation of auditory responses may contribute to the auditory processing and to sensorineural hearing loss produced by opioids.

Nonlinearities in the flicker electroretinogram: A tool for studying retinal dysfunction applied to early-stage diabetic retinopathy

The flicker electroretinogram (ERG) is typically analyzed in terms of peak-to-trough amplitude and implicit time. However, additional important information may be captured by spectral-domain analysis of the ERG harmonics (responses that occur at multiples of the stimulus frequency). This study describes an approach to analyze the harmonic components of the flicker ERG and its application to patients who have early-stage non-proliferative diabetic retinopathy (NPDR). Of particular interest were the sub-harmonic components occurring at 1.5x and 2.5x the stimulus frequency that produce cycle-to-cycle variation in amplitude termed “period doubling.” Twenty visually-normal subjects, 20 diabetic subjects who have no clinically-apparent retinopathy (NDR), and 20 diabetic subjects who have mild NPDR participated. ERGs were recorded in response to sinusoidal flicker (27–63 Hz) and Fourier analysis was performed to extract fundamental and harmonic response amplitudes. Linear quantile mixed models (LQMMs) were used to compare the amplitude of the response components among the three subject groups. Results indicated that the maximum sub-harmonic amplitude occurred in the stimulus frequency range of 33–38 Hz for all subjects. The LQMMs showed a significant sub-harmonic amplitude reduction for the mild NPDR subjects compared to the controls; sub-harmonic amplitude for the NDR subjects did not differ significantly from the controls. In contrast, the fundamental response did not differ among the groups for stimulus frequencies between 33 and 38 Hz. Modeling these results indicated that subharmonic amplitude loss in mild NPDR subjects may be attributed to attenuated feedback occurring early in the retina, possibly at the synapse of cone photoreceptors and OFF bipolar cells.

Period doubling behavior in human steady state visual evoked potentials

Objective. Previous human steady state visual evoked potential (SSVEP) experiments have yielded different results regarding the range of stimulus frequencies in which period doubling (PD) behavior is observed. This study aims at obtaining experimental and statistical data regarding the frequency range of PD generation and also investigates other characteristics of PD. Approach. In two sets of experiments, seven subjects were presented a sinusoidal flickering light stimulus with frequencies varying from 15 to 42 Hz. To observe the short term variations in PD generation, another set of 5 successive experiments were performed on five subjects with 10 min breaks in between. To obtain the SSVEP responses, filtering, signal averaging and power spectral density (PSD) estimation were applied to the recorded electroencephalogram. From the PSD estimates, subharmonic occurrence rates were calculated for each experiment and were used along with ANOVA for interpreting the outcomes of the short term repeatability experiments. Main results. Although fundamental (excitation frequency) and second harmonic components appear in almost all SSVEP spectra, there is considerable inter-subject and intra-subject variability regarding PD occurrence. PD occurs for all stimulus frequencies from 15 to 42 Hz when all subjects are considered together. Furthermore, the statistical analyses of short term repeatability experiments suggest that in the short term, PD generation is consistent when all frequencies are considered together but for a single frequency significant short term differences occur. There also is considerable variation in the ratio of subharmonic amplitude to fundamental amplitude across different frequencies for a given subject. Significance. Important results and statistical data are obtained regarding PD generation. Our results indicate that modeling studies should attempt to generate PD for a broader range of stimulus frequencies. It is argued that SSVEP based brain–computer interface applications would likely benefit from the utilization of subharmonics in classification.

Probing Apical-Basal Differences in the Human Cochlea Using Distortion-Product Otoacoustic Emission Phase.

Distortion-product otoacoustic emission (DPOAE) phase is shaped by interaction between the evoking stimulus waves. Near-invariant at high frequencies, DPOAE phase-vs-frequency functions measured at fixed ratios bend into sloping functions at low frequencies. The different phase behaviors observed suggest that the mechanics underlying the generation of OAEs differ in the halves of the cochlea. To map out the phenomenological extent of low-to-mid frequency phase bends, this study recorded DPOAE responses from 20 normal-hearing human adult ears for a wide range of stimulus frequencies, f1 and f2, where f2 frequency sweeps from 0.25 to 8 kHz, and the f2/ f1 ratio varies from 1.05 to 1.49. Our preliminary results show two transitions in the phase slopes. One near 2.6 kHz in agreement with the literature, and another of opposite polarity near 0.75 kHz which has not been reported before. We find that the f2 frequencies marking these defining phase features are invariant with stimulus ratio. Even as the underlying mechanics remain unknown, the invariance opens the door for DPOAE phase to reliably characterize apical-basal differences across age groups and species.

No effect of prolonged pulsed high frequency ultrasound imaging of the basilar membrane on cochlear function or hair cell survival found in an initial study

Miniature high frequency ultrasound devices show promise as tools for clinical middle ear and basal cochlea imaging and vibrometry. However, before clinical use it is important to verify that the ultrasound exposure does not damage the cochlea. In this initial study, electrophysiological responses of the cochlea were measured for a range of stimulus frequencies in both ears of anesthetized chinchillas, before and after exposing the organ of Corti region of one ear to pulsed focused ultrasound for 30 min. Measurements were again taken after an 11 day survival period. Cochlear tissue was examined with a confocal microscope for signs of damage to the cochlear hair cells. No significant change in response thresholds due to exposure was found, and no signs of ultrasound-induced tissue damage were observed, although one animal (out of ten) did have a region of extensive tissue damage in the exposed cochlea. However, after further analysis this was concluded to be not likely a result of the ultrasound exposure.

Predicting the response of striatal spiny neurons to sinusoidal input.

Spike-timing effects of small-amplitude sinusoidal currents were measured in mouse striatal spiny neurons firing repetitively. Spike-timing reliability varied with the stimulus frequency. For frequencies near the cell's firing rate, the cells altered firing rate to match the stimulus and became phase locked to it. The stimulus phase of firing during lock depended on the stimulus frequency relative to the cell's unperturbed firing rate. Interspike intervals during sinusoidal stimulation were predicted using an iterative map constructed from the cells' phase-resetting curve. Variability of interspike intervals was reduced by stimulation at all frequencies higher than about half the cell's unperturbed rate, and interspike intervals were accurately predicted by the map. Long sequences of spike times were predicted by iterating on the map. The accuracy of that prediction varied with frequency. Spike time predictability was highest near and during phase lock. The map predicted the phase of firing on the input and its dependence on stimulus frequency. Prediction errors, when they occurred, were of two kinds: unpredicted variation in interspike interval from intrinsic cell noise and accumulation of prediction errors from previous interspike intervals. Each type of prediction error arose from a different mechanism, and their impact was also predicted from the phase model. When two oscillatory input currents were presented simultaneously, striatal neurons responded selectively to only one of them, the one closest in frequency to the cell's unperturbed firing rate. Their spike times encoded the frequency and phase of that single oscillatory input.NEW & NOTEWORTHY During repetitive firing, the timing of action potentials is determined by the interaction between the input and voltage-sensitive currents throughout the interspike interval. This interaction is encapsulated in the neuron's phase-resetting curve. The phase-resetting curve predicted spike timing to small sinusoidal currents over a wide range of stimulus frequencies. Firing patterns were most sensitive to oscillatory components near the cell's own firing rate, even in the presence of noise and other inputs.

High-order synchronization of hair cell bundles.

Auditory and vestibular hair cell bundles exhibit active mechanical oscillations at natural frequencies that are typically lower than the detection range of the corresponding end organs. We explore how these noisy nonlinear oscillators mode-lock to frequencies higher than their internal clocks. A nanomagnetic technique is used to stimulate the bundles without an imposed mechanical load. The evoked response shows regimes of high-order mode-locking. Exploring a broad range of stimulus frequencies and intensities, we observe regions of high-order synchronization, analogous to Arnold Tongues in dynamical systems literature. Significant areas of overlap occur between synchronization regimes, with the bundle intermittently flickering between different winding numbers. We demonstrate how an ensemble of these noisy spontaneous oscillators could be entrained to efficiently detect signals significantly above the characteristic frequencies of the individual cells.

Differential Modulation of Excitatory and Inhibitory Neurons during Periodic Stimulation.

Non-invasive transcranial neuronal stimulation, in addition to deep brain stimulation, is seen as a promising therapeutic and diagnostic approach for an increasing number of neurological diseases such as epilepsy, cluster headaches, depression, specific type of blindness, and other central nervous system disfunctions. Improving its effectiveness and widening its range of use may strongly rely on development of proper stimulation protocols that are tailored to specific brain circuits and that are based on a deep knowledge of different neuron types response to stimulation. To this aim, we have performed a simulation study on the behavior of excitatory and inhibitory neurons subject to sinusoidal stimulation. Due to the intrinsic difference in membrane conductance properties of excitatory and inhibitory neurons, we show that their firing is differentially modulated by the wave parameters. We analyzed the behavior of the two neuronal types for a broad range of stimulus frequency and amplitude and demonstrated that, within a small-world network prototype, parameters tuning allow for a selective enhancement or suppression of the excitation/inhibition ratio.

Modulation of auditory brainstem responses by serotonin and specific serotonin receptors

The neuromodulator serotonin is found throughout the auditory system from the cochlea to the cortex. Although effects of serotonin have been reported at the level of single neurons in many brainstem nuclei, how these effects correspond to more integrated measures of auditory processing has not been well-explored. In the present study, we aimed to characterize the effects of serotonin on far-field auditory brainstem responses (ABR) across a wide range of stimulus frequencies and intensities. Using a mouse model, we investigated the consequences of systemic serotonin depletion, as well as the selective stimulation and suppression of the 5-HT1 and 5-HT2 receptors, on ABR latency and amplitude. Stimuli included tone pips spanning four octaves presented over a forty dB range. Depletion of serotonin reduced the ABR latencies in Wave II and later waves, suggesting that serotonergic effects occur as early as the cochlear nucleus. Further, agonists and antagonists of specific serotonergic receptors had different profiles of effects on ABR latencies and amplitudes across waves and frequencies, suggestive of distinct effects of these agents on auditory processing. Finally, most serotonergic effects were more pronounced at lower ABR frequencies, suggesting larger or more directional modulation of low-frequency processing. This is the first study to describe the effects of serotonin on ABR responses across a wide range of stimulus frequencies and amplitudes, and it presents an important step in understanding how serotonergic modulation of auditory brainstem processing may contribute to modulation of auditory perception.

Differential inhibition onto developing and mature granule cells generates high-frequency filters with variable gain.

Adult hippocampal neurogenesis provides the dentate gyrus with heterogeneous populations of granule cells (GC) originated at different times. The contribution of these cells to information encoding is under current investigation. Here, we show that incoming spike trains activate different populations of GC determined by the stimulation frequency and GC age. Immature GC respond to a wider range of stimulus frequencies, whereas mature GC are less responsive at high frequencies. This difference is dictated by feedforward inhibition, which restricts mature GC activation. Yet, the stronger inhibition of mature GC results in a higher temporal fidelity compared to that of immature GC. Thus, hippocampal inputs activate two populations of neurons with variable frequency filters: immature cells, with wide-range responses, that are reliable transmitters of the incoming frequency, and mature neurons, with narrow frequency response, that are precise at informing the beginning of the stimulus, but with a sparse activity.

Myosin phosphorylation and force potentiation in skeletal muscle: evidence from animal models

The contractile performance of mammalian fast twitch skeletal muscle is history dependent. The effect of previous or ongoing contractile activity to potentiate force, i.e. increase isometric twitch force, is a fundamental property of fast skeletal muscle. The precise manifestation of force potentiation is dependent upon a variety of factors with two general types being identified; staircase potentiation referring to the progressive increase in isometric twitch force observed during low frequency stimulation while posttetanic potentiation refers to the step-like increase in isometric twitch force observed following a brief higher frequency (i.e. tetanic) stimulation. Classic studies established that the magnitude and duration of potentiation depends on a number of factors including muscle fiber type, species, temperature, sarcomere length and stimulation paradigm. In addition to isometric twitch force, more recent work has shown that potentiation also influences dynamic (i.e. concentric and/or isotonic) force, work and power at a range of stimulus frequencies in situ or in vitro, an effect that may translate to enhanced physiological function in vivo. Early studies performed on both intact and permeabilized models established that the primary mechanism for this modulation of performance was phosphorylation of myosin, a modification that increased the Ca(2+) sensitivity of contraction. More recent work from a variety of muscle models indicates, however, the presence of a secondary mechanism for potentiation that may involve altered Ca(2+) handling. The primary purpose of this review is to highlight these recent findings relative to the physiological utility of force potentiation in vivo.

TNF signals via neuronal-type nitric oxide synthase and reactive oxygen species to depress specific force of skeletal muscle

TNF promotes skeletal muscle weakness, in part, by depressing specific force of muscle fibers. This is a rapid, receptor-mediated response, in which TNF stimulates cellular oxidant production, causing myofilament dysfunction. The oxidants appear to include nitric oxide (NO); otherwise, the redox mechanisms that underlie this response remain undefined. The current study tested the hypotheses that 1) TNF signals via neuronal-type NO synthase (nNOS) to depress specific force, and 2) muscle-derived reactive oxygen species (ROS) are essential co-mediators of this response. Mouse diaphragm fiber bundles were studied using live cell assays. TNF exposure increased general oxidant activity (P < 0.05; 2',7'-dichlorodihydrofluorescein diacetate assay) and NO activity (P < 0.05; 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate assay) and depressed specific force across the full range of stimulus frequencies (1-300 Hz; P < 0.05). These responses were abolished by pretreatment with N(ω)-nitro-L-arginine methyl ester (L-NAME; a nonspecific inhibitor of NOS activity), confirming NO involvement. Genetic nNOS deficiency replicated L-NAME effects on TNF-treated muscle, diminishing NO activity (-80%; P < 0.05) and preventing the decrement in specific force (P < 0.05). Comparable protection was achieved by selective depletion of muscle-derived ROS. Pretreatment with either SOD (degrades superoxide anion) or catalase (degrades hydrogen peroxide) depressed oxidant activity in TNF-treated muscle and abolished the decrement in specific force. These findings indicate that TNF signals via nNOS to depress contractile function, a response that requires ROS and NO as obligate co-mediators.

GABAA receptor mediated inhibition contributes to corticostriatal frequency filtering

The striatum plays an important role in the initiation and learning of skilled motor behavior [6] and receives topographic input from most areas of the cortex. Cortical afferents make divergent contact with many striatal medium spiny neurons while individual medium spiny neurons receive tens of thousands of these glutamatergic synapses [13]. Temporal filtering of frequency information within synaptic fields plays an important role in the processing of neuronal signals. We have previously shown differential filtering characteristics within CA1, CA3, and the dentate gyrus of the hippocampus [26] and have now extended these studies to the cortical input to the dorsal striatum in order to address the network filtering characteristics in this important synaptic field. We measured field potentials of striatal medium spiny neurons in response to layer V cortical input over a range of stimulus frequencies from 2Hz to 100Hz. The average population spike amplitude in response to these stimulus trains exhibited a non-linear relationship to frequency, with characteristics of a low pass filter. In order to assess potential modulation of these filter properties, we examined the frequency response in the presence of antagonists to CB1, D2, nACh, and GABAA receptors, which are all known to be expressed at these synapses [13]. Of these, only GABAA receptor antagonists significantly modulated the frequency filtering characteristics over the examined frequency range. High frequency stimulation induces long term plasticity at corticostriatal synapses [4] and this process is strengthened when GABAA receptors are blocked [7,20,29]. Our results suggest a model whereby a temporary decrease in GABA level would modulate the filtering parameters of the corticostriatal circuit, allowing a more robust induction of high frequency-dependent plasticity.

Modulation by pregnenolone sulfate of filtering properties in the hippocampal trisynaptic circuit

Short-term synaptic plasticity alters synaptic efficacy on a timescale that is relevant to encoding information in spike trains. The dynamics of this plasticity, combined with that of the feedback and feedforward contributions of local interneurons, impose frequency-dependent properties on neuronal networks with implications for nervous system function. The trisynaptic network of the hippocampus is especially well suited to selectively filter components of frequency-dependent signals that are transmitted from the entorhinal cortex. We measured presynaptic [Ca(2+)](i) in perforant path, mossy fiber, or Schaffer collateral terminals while simultaneously measuring field potentials of principal cells of the dentate, CA3, or CA1 synaptic fields over a range of stimulus frequencies of 2 to 77 Hz. In all three synaptic fields, the average [Ca(2+)](i) during a 500 ms stimulus train rose monotonically with stimulus frequency. The average population spike amplitude during this stimulus train, however, exhibited a non-linear relationship to frequency that was distinct for each of the three synaptic fields. The dentate synaptic field exhibited the characteristics of a low pass filter, while both CA synaptic fields had bandpass filter characteristics with a gain that was greater than 1 in the passband frequencies. Importantly, alteration of the dynamic properties of this network could significantly impact information processing performed by the hippocampus. Pregnenolone sulfate (PregS), has frequency-dependent effects on paired- and multipulse plasticity in the dentate and CA1 synaptic fields of the hippocampal formation. We investigated the PregS-dependent modulation of the dynamic properties of transmission by the principal cells of the three hippocampal synaptic fields. Importantly, PregS is capable of altering the pattern separation capabilities that may underlie hippocampal information processing.

Chaotic decorrelation of Globus Pallidus by periodic forcing: a possible mechanism for the therapeutic effects of deep brain stimulation

High frequency (~100 Hz) stimulation of the subthalamic nucleus is an effective therapy for the symptoms of Parkinson's disease. Presumably, stimulation partly normalizes a pathological change in rate or pattern of neuronal activity in the output neurons of the globus pallidus. The rate effects of subthalamic stimulation are paradoxical, because firing rate in the globus pallidus is increased in Parkinson's disease, and subthalamic input is excitatory. Parkinson's disease is also accompanied by changes in globus pallidus cell firing pattern. Pallidal neurons are autonomous single-spiking oscillators that fire continuously and usually show no periodic bursting. They fire independently of each other, having flat cross-correlations. In Parkinson's disease the cells burst at 5-10/s and are highly correlated [1]. Rubin and Terman [2] have proposed that subthalamic stimulation entrains globus pallidus cells interfering with the low frequency bursting. In their model, the synchrony of globus pallidus cells should be high, because all cells are entrained by the same stimulus. The periodic nature of deep brain stimulation is inconsequential in their model. A recent clinical study has shown that the periodicity of deep brain stimulation is critical to its effectiveness [3]. Poisson stimulation at the same rate was much less beneficial. This observation, coupled with the frequency dependence of DBS effectiveness, suggests that disruption of low frequency bursting may not be the only mechanism of action. Globus pallidus cells are oscillators, so it is possible that periodic stimulation may not only suppress low frequency bursting, but also disrupt synchrony by driving the cells into chaotic firing patterns. We examined the range of stimulus frequencies and amplitudes required to chaotically desynchronize pallidal neurons. Oscillating pallidal cells were represented by their phase resetting curves. We used a type 1 phase resetting curve similar to that measured from model pallidal neurons [4]. The variance of the phase resetting curve was estimated as in Ermentrout et al [5] and used to form a stochastic phase map. The stationary distribution of latencies and the phase resetting curve were used to calculate Lyapunov exponents for both hyperpolarizing and depolarizing stimulation, and compared to the synchronizing or desynchronizing effect of stimulation on a population of simulated pallidal neurons that were weakly synchronized by common noisy input. Powerful synchronization and desynchronization were evoked at different frequencies as predicted by the sign of the Lyapunov exponents. Chaotic decorrelation in response to depolarizing stimulation occurred at frequencies similar to those known to be most effective for deep brain stimulation clinically. We suggest that in addition to its effects on low frequency oscillations in the pallido-thalamic projection, deep brain stimulation decorrelates the activity of pallidal neurons by driving them into a chaotic firing pattern. When the stimulus is randomized the chaotic response is destroyed, explaining why it is less effective. This chaotic effect may be essential to the clinical benefit of stimulation, being responsible for its frequency sensitivity and the requirement for periodicity in the stimulus pattern.

Calcium channel dynamics limit synaptic release in response to prosthetic stimulation with sinusoidal waveforms

Extracellular electric stimulation with sinusoidal waveforms has been shown to allow preferential activation of individual types of retinal neurons by varying stimulus frequency. It is important to understand the mechanisms underlying this frequency dependence as a step toward improving methods of preferential activation. In order to elucidate these mechanisms, we implemented a morphologically realistic model of a retinal bipolar cell and measured the response to extracellular stimulation with sinusoidal waveforms. We compared the frequency response of a passive membrane model to the kinetics of voltage-gated calcium channels that mediate synaptic release. The passive electrical properties of the membrane exhibited lowpass filtering with a relatively high cutoff frequency (nominal value = 717 Hz). This cutoff frequency was dependent on intra-axonal resistance, with shorter and wider axons yielding higher cutoff frequencies. However, we found that the cutoff frequency of bipolar cell synaptic release was primarily limited by the relatively slow opening kinetics of L- and T-type calcium channels. The cutoff frequency of calcium currents depended nonlinearly on stimulus amplitude, but remained lower than the cutoff frequency of the passive membrane model for a large range of membrane potential fluctuations. These results suggest that while it may be possible to modulate the membrane potential of bipolar cells over a wide range of stimulus frequencies, synaptic release will only be initiated at the lower end of this range.