Electrical Stimulation publications

Specific behavioral associative memory induced by stimulation of the cortically-projecting cholinergic nucleus basalis (NB) is dependent on intrinsic acetylcholine and shares with natural memory such features as associativity, specificity, rapid formation, consolidation and long-term retention. Herein, we examined extinction and the effects of stimulus pre-exposure. Two groups of adult male rats (n=4 each) were first tested for behavioral responses (disruption of ongoing respiration) to tones (1-15 kHz), constituting a pre-training behavioral frequency generalization gradient (BFGG). They next received a first session of training, 200 trials of a tone (8.00 kHz, 70 dB, 2 s) either paired with electrical stimulation of the NB (100 Hz, 0.2 s, approximately 67 microA, NBstm) (group IP) or unpaired (group IU). Twenty-four hours later, they were tested for behavioral memory by obtaining post-training BFGGs. Then the contingencies were reversed yet another 24 h later; the IP group received tone and NBstm unpaired and the IU group received them paired. A final set of generalization gradients was obtained the next day. All stimuli were presented with subjects under state control indexed by regular respiration. Tested 24 h post-initial training, the IP group developed specific associative behavioral memory indicated by increased responses only to CS-band frequencies, while the IU group did not. After subsequent training with unpaired stimuli, the IP group exhibited experimental extinction. Furthermore, after initial exposure to the CS and NBstm unpaired, the IU group exhibited a tendency toward reduced conditioning to CS/NBstm pairing and a significant increase in latency of conditioned responses. The present findings provide additional support for the hypothesis that engagement of the NB is sufficient to induce natural associative memory and suggest that activation of the NB may be a normal component in the formation of natural associative memory.

Commercially available data acquisition systems for multielectrode recording from freely moving animals are expensive, often rely on proprietary software, and do not provide detailed, modifiable circuit schematics. When used in conjunction with electrical stimulation, they are prone to prolonged, saturating stimulation artifacts that prevent the recording of short-latency evoked responses. Yet electrical stimulation is integral to many experimental designs, and critical for emerging brain-computer interfacing and neuroprosthetic applications. To address these issues, we developed an easy-to-use, modifiable, and inexpensive system for multielectrode neural recording and stimulation. Setup costs are less than US$10,000 for 64 channels, an order of magnitude lower than comparable commercial systems. Unlike commercial equipment, the system recovers rapidly from stimulation and allows short-latency action potentials (<1 ms post-stimulus) to be detected, facilitating closed-loop applications and exposing neural activity that would otherwise remain hidden. To illustrate this capability, evoked activity from microstimulation of the rodent hippocampus is presented. System noise levels are similar to existing platforms, and extracellular action potentials and local field potentials can be recorded simultaneously. The system is modular, in banks of 16 channels, and flexible in usage: while primarily designed for in vivo use, it can be combined with commercial preamplifiers to record from in vitro multielectrode arrays. The system's open-source control software, NeuroRighter, is implemented in C#, with an easy-to-use graphical interface. As C# functions in a managed code environment, which may impact performance, analysis was conducted to ensure comparable speed to C++ for this application. Hardware schematics, layout files, and software are freely available. Since maintaining wired headstage connections with freely moving animals is difficult, we describe a new method of electrode-headstage coupling using neodymium magnets.

Chronic microstimulation-based devices are being investigated to treat conditions such as blindness, deafness, pain, paralysis, and epilepsy. Small-area electrodes are desired to achieve high selectivity. However, a major trade-off with electrode miniaturization is an increase in impedance and charge density requirements. Thus, the development of novel materials with lower interfacial impedance and enhanced charge storage capacity is essential for the development of micro-neural interface-based neuroprostheses. In this report, we study the use of conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) as a neural interface material for microstimulation of small-area iridium electrodes on silicon-substrate arrays. Characterized by electrochemical impedance spectroscopy, electrodeposition of PEDOT results in lower interfacial impedance at physiologically relevant frequencies, with the 1 kHz impedance magnitude being 23.3 +/- 0.7 kOmega, compared to 113.6 +/- 3.5 kOmega for iridium oxide (IrOx) on 177 mum(2) sites. Further, PEDOT exhibits enhanced charge storage capacity at 75.6 +/- 5.4 mC/cm(2) compared to 28.8 +/- 0.3 mC/cm(2) for IrOx, characterized by cyclic voltammetry (50 mV/s). These improvements at the electrode interface were corroborated by observation of the voltage excursions that result from constant current pulsing. The PEDOT coatings provide both a lower amplitude voltage and a more ohmic representation of the applied current compared to IrOx. During repetitive pulsing, PEDOT-coated electrodes show stable performance and little change in electrical properties, even at relatively high current densities which cause IrOx instability. These findings support the potential of PEDOT coatings as a micro-neural interface material for electrostimulation.

Cochlear hair cells use SK2 currents to shape responses to cholinergic efferent feedback from the brain. Using SK2(-/-) mice, we demonstrate that, in addition to their previously defined role in modulating hair cell membrane potentials, SK2 channels are necessary for long-term survival of olivocochlear fibers and synapses. Loss of the SK2 gene also results in loss of electrically driven olivocochlear effects in vivo, and down regulation of ryanodine receptors involved in calcium-induced calcium release, the main inducer of nAChR evoked SK2 activity. Generation of double-null mice lacking both the alpha10 nAChR gene, loss of which results in hypertrophied olivocochlear terminals, and the SK2 gene, recapitulates the SK2(-/-) synaptic phenotype and gene expression, and also leads to down regulation of alpha9 nAChR gene expression. The data suggest a hierarchy of activity necessary to maintain early olivocochlear synapses at their targets, with SK2 serving an epistatic, upstream, role to the nAChRs.

We demonstrate that distinct mechanisms of top-down control regulate, respectively, the sensitivity and gain of sensory responses in the owl's optic tectum (OT). Electrical microstimulation in the forebrain gaze control area, the arcopallial gaze field (AGF), results in a space-specific regulation of sensory responses in the OT. AGF microstimulation increases the responsiveness of OT neurons representing stimuli at the same location as that represented at the AGF site. We show that the mechanism that underlies this effect operates focally to enhance neuronal sensitivity and improve tuning consistency and spatial resolution. At the same time, AGF microstimulation decreases the responsiveness of OT neurons representing stimuli at all other locations. The mechanism that underlies this effect operates globally to modulate neuronal gain. The coordinated action of these different mechanisms can account for many of the reported effects of spatial attention on neural responses in monkeys and on behavioral performance in humans.

The survival of the auditory nerve in cases of sensorineural hearing loss is believed to be a major factor in effective cochlear implant function. The current study assesses two measures of cochlear implant thresholds following a post-deafening treatment intended to halt auditory nerve degeneration. We used an adenoviral construct containing a gene insert for brain-derived neurotrophic factor (BDNF), a construct that has previously been shown to promote neuronal survival in a number of biological systems. We implanted ototoxically deafened guinea pigs with a multichannel cochlear implant and delivered a single inoculation of an adenovirus suspension coding for BDNF (Ad.BDNF) into the scala tympani at the time of implantation. Thresholds to electrical stimulation were assessed both psychophysically and electrophysiologically over a period of 80 days. Spiral ganglion cell survival was analyzed at the 80 days time point. Compared to the control group, the Ad.BDNF treated group had lower psychophysical and electrophysiological thresholds as well as higher survival of spiral ganglion cells. Electrophysiological, but not psychophysical, thresholds correlated well with the density of spiral ganglion cells. These results indicate that the changes in the anatomy of the auditory nerve induced by the combination of Ad.BDNF inoculation and the electrical stimulation used for testing improved functional measures of CI performance.

Implantable microfabricated microelectrode arrays represent a versatile and powerful tool to record electrophysiological activity across multiple spatial locations in the brain. Spikes and field potentials, however, correspond to only a fraction of the physiological information available at the neural interface. In urethane-anesthetized rats, microfabricated microelectrode arrays were implanted acutely for simultaneous recording of striatal local field potentials, spikes, and electrically evoked dopamine overflow on the same spatiotemporal scale. During these multi-modal recordings we observed (1) that the amperometric method used to detect dopamine did not significantly influence electrophysiological activity, (2) that electrical stimulation in the medial forebrain bundle (MFB) region resulted in electrochemically transduced dopamine transients in the striatum that were spatially heterogeneous within at least 200 microm, and (3) following MFB stimulation, dopamine levels and electrophysiological activity within the striatum exhibited similar temporal profiles. These neural probes are capable of incorporating customized microelectrode geometries and configurations, which may be useful for examining specific spatiotemporal relationships between electrical and chemical signaling in the brain.

Although the cholinergic system has long been implicated in the formation of memory, there had been no direct demonstration that activation of this system can actually induce specific behavioral memory. We have evaluated the "cholinergic-memory" hypothesis by pairing a tone with stimulation of the nucleus basalis (NB), which provides acetylcholine to the cerebral cortex. We found that such pairing induces behaviorally-validated auditory memory. NB-induced memory has the key features of natural memory: it is associative, highly-specific and rapidly induced. Moreover, the level of NB stimulation controls the amount of detail in memory about the tonal conditioned stimulus. While consistent with the hypothesis that properly-timed release of acetylcholine (ACh) during natural learning is sufficient to induce memory, pharmacological evidence has been lacking. This study asked whether scopolamine, a muscarinic antagonist, impairs or prevents the formation of NB-induced memory. Adult male rats were first tested for responses (disruption of ongoing respiration) to tones (1-15 kHz), constituting a pre-training behavioral frequency generalization gradient (BFGG). Then, they received a single session of 200 trials of a tone (8.00 kHz, 70 dB, 2 s) paired with electrical stimulation of the NB (100 Hz, 0.2 s). Immediately after training, they received either scopolamine (1.0 mg/kg, i.p.) or saline. Twenty-four hours later, they were tested for specific memory by obtaining post-training BFGGs. The saline group developed CS-specific memory, manifested by maximum increase in response specific to the CS frequency band. In contrast, the scopolamine group exhibited no such memory. These findings indicate that NB-induced specific associative behavioral memory requires the action of intrinsic acetylcholine at muscarinic receptors, and supports the hypothesis that natural memory formation engages the nucleus basalis and muscarinic receptors.

The central auditory system creates various types of neurons tuned to different acoustic parameters other than a specific frequency. The response latency of auditory neurons typically shortens with an increase in stimulus intensity. However, ∼10% of collicular neurons of the little brown bat show a “paradoxical latency-shift (PLS)”: long latencies to intense sounds but short latencies to weak sounds. These neurons presumably are involved in the processing of target distance information carried by a pair of an intense biosonar pulse and its weak echo. Our current studies show that collicular PLS neurons of the big brown bat are modulated by the corticofugal (descending) system. Electric stimulation of cortical auditory neurons evoked two types of changes in the PLS neurons, depending on the relationship in the best frequency (BF) between the stimulated cortical and recorded collicular neurons. When the BF was matched between them, the cortical stimulation did not shift the BFs of the collicular neurons and shortened their response latencies at intense sounds so that the PLS became smaller. When the BF was unmatched, however, the cortical stimulation shifted the BFs of the collicular neurons and lengthened their response latencies at intense sounds, so that the PLS became larger. Cortical electric stimulation also modulated the response latencies of non-PLS neurons. It produced an inhibitory frequency tuning curve or curves. Our findings indicate that corticofugal feedback is involved in shaping the spectrotemporal patterns of responses of subcortical auditory neurons presumably through inhibition.

Cochlear implant speech processors transmit temporal features of sound as amplitude modulation of constant-rate electrical pulse trains. This study evaluated the central representation of amplitude modulation in the form of phase-locked firing of neurons in the auditory cortex. Anesthetized pigmented guinea pigs were implanted with cochlear electrode arrays. Stimuli were 254 pulse/s (pps) trains of biphasic electrical pulses, sinusoidally modulated with frequencies of 10–64 Hz and modulation depths of −40 to −5 dB re 100% (i.e., 1–56.2% modulation). Single- and multiunit activity was recorded from multi-site silicon-substrate probes. The maximum frequency for significant phase locking (limiting modulation frequency) was ≥60 Hz for 42% of recording sites, whereas phase locking to pulses of unmodulated pulse trains rarely exceeded 30 pps. The strength of phase locking to frequencies ≥40 Hz often varied nonmonotonically with modulation depth, commonly peaking at modulation depths around −15 to −10 dB. Cortical phase locking coded modulation frequency reliably, whereas a putative rate code for frequency was confounded by rate changes with modulation depth. Group delay computed from the slope of mean phase versus modulation frequency tended to increase with decreasing limiting modulation frequency. Neurons in cortical extragranular layers had lower limiting modulation frequencies than did neurons in thalamic afferent layers. Those observations suggest that the low-pass characteristic of cortical phase locking results from intracortical filtering mechanisms. The results show that cortical neurons can phase lock to modulated electrical pulse trains across the range of modulation frequencies and depths presented by cochlear implant speech processors.

Previous studies have shown large decreases in cochlear implant psychophysical detection thresholds during the weeks following the onset of electrical testing. The current study sought to determine the variables underlying these threshold decreases by examining the effects of four deafening and implantation procedures on detection thresholds and implant impedances. Thirty-two guinea pigs were divided into four matched groups. Group I was deafened and implanted Day 0 and began electrical testing Day 1. Group II was deafened and implanted Day 0 and began electrical testing Day 45. Group III was deafened Day 0, implanted Day 45 and began electrical testing Day 46. Group IV was not predeafened but was implanted Day 0 and began electrical testing Day 1. All groups showed threshold decreases over time but the magnitude of change, time course and final stable threshold levels depended on the type and time course of treatment. Impedances increased over the first two weeks following the onset of electrical testing except in Group II. Results suggest that multiple mechanisms underlie the observed threshold shifts including (1) recovery of the cochlea from a temporary pathology caused by the deafening and/or implantation procedures, (2) effects of electrical stimulation on the auditory pathway, and (3) tissue growth in the implanted cochlea. They also suggest that surviving hair cells influence electrical threshold levels.

Recent measurements of three-dimensional stapes motion in gerbil indicated that the piston component of stapes motion was the primary contributor to intracochlear pressure. In order to make a detailed correlation between stapes piston motion and intracochlear pressure behind the stapes, simultaneous pressure and motion measurements were undertaken. We found that the scala vestibuli pressure followed the piston component of the stapes velocity with high fidelity, reinforcing our previous finding that the piston motion of the stapes was the main stimulus to the cochlea. The present data allowed us to calculate cochlear input impedance and power flow into the cochlea. Both the amplitude and phase of the impedance were quite flat with frequency from 3 kHz to at least 30 kHz, with a phase that was primarily resistive. With constant stimulus pressure in the ear canal the intracochlear pressure at the stapes has been previously shown to be approximately flat with frequency through a wide range, and coupling that result with the present findings indicates that the power that flows into the cochlea is quite flat from about 3 to 30 kHz. The observed wide-band intracochlear pressure and power flow are consistent with the wide-band audiogram of the gerbil.

A growing number of brain-machine interfaces have now been developed that allow movements of an external device to be controlled using recordings from the brain. This work has been undertaken with a number of different animal models, as well as several human patients with quadriplegia. The resulting movements, whether of computer cursors or robotic limbs, remain quite slow and unstable compared to normal limb movements. It is an open question, how much of this instability is the result of the limited forward control path, and how much has to do with the total lack of normal proprioceptive feedback. We have begun preliminary studies of the effectiveness of electrical stimulation in the proprioceptive area of the primary somatosensory cortex (area 3a) as a potential means to deliver an artificial sense of proprioception to a monkey. We have demonstrated that it is possible for the monkey to detect brief stimulus trains at relatively low current levels, and to discriminate between trains of different frequencies. These observations need to be expanded to include more complex, time-varying waveforms that could potentially convey information about the state of the limb.

In the “4–6” condition of experiment 1, normal-hearing (NH) listeners compared the pitch of a bandpass-filtered pulse train, whose inter-pulse intervals (IPIs) alternated between 4 and 6ms, to that of isochronous pulse trains. Consistent with previous results obtained at a lower signal level, the pitch of the 4–6 stimulus corresponded to that of an isochronous pulse train having a period of 5.7ms—longer than the mean IPI of 5ms. In other conditions the IPI alternated between 3.5–5.5 and 4.5–6.5ms. Experiment 2 was similar but presented electric pulse trains to one channel of a cochlear implant. In both cases, as overall IPI increased, the pitch of the alternating-interval stimulus approached that of an isochronous train having a period equal to the mean IPI. Experiment 3 measured compound action potentials (CAPs) to alternating-interval stimuli in guinea pigs and in NH listeners. The CAPs to pulses occurring after 4-ms intervals were smaller than responses to pulses occurring after 6-ms intervals, resulting in a modulated pattern that was independent of overall level. The results are compared to the predictions of a simple model incorporating auditory-nerve (AN) refractoriness, and where pitch is estimated from first-order intervals in the AN response.

This article reports on a retinal stimulation system for long‐term use in animal electrical stimulation experiments. The presented system consisted of an implantable stimulator which provided continuous electrical stimulation, and an external component which provided preset stimulation patterns and power to the implanted stimulator via a paired radio frequency (RF) coil. A rechargeable internal battery and a parameter memory component were introduced to the implanted retinal stimulator. As a result, the external component was not necessary during the stimulation mode. The inductive coil pair was used to pass the parameter data and to recharge the battery. A switch circuit was used to separate the stimulation mode from the battery recharging mode. The implantable stimulator was implemented with IC chips and the electronics, except for the stimulation electrodes, were hermetically packaged in a biocompatible metal case. A polyimide‐based gold electrode array was used. Surgical implantation into rabbits was performed to verify the functionality and safety of this newly designed system. The electrodes were implanted in the suprachoroidal space. Evoked cortical potentials were recorded during electrical stimulation of the retina. Long‐term follow‐up using OCT showed no chorioretinal abnormality after implantation of the electrodes.

Electrical microstimulation can establish causal links between the activity of groups of neurons and perceptual and cognitive functions. However, the number and identities of neurons microstimulated, as well as the number of action potentials evoked, are difficult to ascertain. To address these issues we introduced the light-gated algal channel channelrhodopsin-2 (ChR2) specifically into a small fraction of layer 2/3 neurons of the mouse primary somatosensory cortex. ChR2 photostimulation in vivo reliably generated stimulus-locked action potentials at frequencies up to 50 Hz. Here we show that naive mice readily learned to detect brief trains of action potentials (five light pulses, 1 ms, 20 Hz). After training, mice could detect a photostimulus firing a single action potential in approximately 300 neurons. Even fewer neurons (approximately 60) were required for longer stimuli (five action potentials, 250 ms). Our results show that perceptual decisions and learning can be driven by extremely brief epochs of cortical activity in a sparse subset of supragranular cortical pyramidal neurons.

The multichannel design of contemporary cochlear implants (CIs) is predicated on the assumption that each channel activates a relatively restricted and independent sector of the deaf auditory nerve array, just as a sound within a restricted frequency band activates a restricted region of the normal cochlea The independence of CI channels, however, is limited; and the factors that determine their independence, the relative overlap of the activity patterns that they evoke, are poorly understood. In this study, we evaluate the spread of activity evoked by cochlear implant channels by monitoring activity at 16 sites along the tonotopic axis of the guinea pig inferior colliculus (IC). "Spatial tuning curves" (STCs) measured in this way serve as an estimate of activation spread within the cochlea and the ascending auditory pathways. We contrast natural stimulation using acoustic tones with two kinds of electrical stimulation either (1) a loose fitting banded array consisting of a cylindrical silicone elastomer carrier with a linear series of ring contacts; or (2) a space-filling array consisting of a tapered silicone elastomer carrier that is designed to fit snugly into the guinea pig scala tympani with a linear series of ball contacts positioned along it Spatial tuning curves evoked by individual acoustic tones, and by activation of each contact of each array as a monopole, bipole or tripole were recorded. Several channel configurations and a wide range of electrode separations were tested for each array, and their thresholds and selectivity were estimated. The results indicate that the tapered space-filling arrays evoked more restricted activity patterns at lower thresholds than did the banded arrays. Monopolar stimulation (one intracochlear contact activated with an extracochlear return) using either array evoked broad activation patterns that involved the entire recording array at current levels <6dBSL, but at relatively low thresholds. Bi- and tri-polar configurations of both array types evoked more restricted activity patterns, but their thresholds were higher than those of monopolar configurations. Bipolar and tripolar configurations with closely spaced contacts evoked activity patterns that were comparable to those evoked by pure tones. As the spacing of bipolar electrodes was increased (separations >1mm), the activity patterns became broader and evoked patterns with two distinct threshold minima, one associated with each contact.

Cochlear implant surgery is currently the therapy of choice for profoundly deaf patients. However, the functionality of cochlear implants depends on the integrity of the auditory spiral ganglion neurons. This study assesses the combined efficacy of two classes of agents found effective in preventing degeneration of the auditory nerve following deafness, neurotrophic factors, and antioxidants. Guinea pigs were deafened and treated for 4 weeks with either local administration of GDNF or a combination of GDNF and systemic injections of the antioxidants ascorbic acid and Trolox. The density of surviving spiral ganglion cells was significantly enhanced and the thresholds for eliciting an electrically evoked brain stem response were significantly reduced in GDNF treated animals compared to deafened-untreated. The addition of antioxidants significantly enhanced the evoked responsiveness over that observed with GDNF alone. The results suggest multiple sites of intervention in the rescue of these cells from deafferentation-induced cell death.

Multisensory neurons in the dorsal cochlear nucleus (DCN) achieve their bimodal response properties [Shore (2005) Eur. J. Neurosci. , 21 , 3334–3348] by integrating auditory input via VIIIth nerve fibers with somatosensory input via the axons of cochlear nucleus granule cells [Shore et al. (2000) J. Comp. Neurol. , 419 , 271–285; Zhou & Shore (2004) J. Neurosci. Res. , 78 , 901–907]. A unique feature of multisensory neurons is their propensity for receiving cross‐modal compensation following sensory deprivation. Thus, we investigated the possibility that reduction of VIIIth nerve input to the cochlear nucleus results in trigeminal system compensation for the loss of auditory inputs. Responses of DCN neurons to trigeminal and bimodal (trigeminal plus acoustic) stimulation were compared in normal and noise‐damaged guinea pigs. The guinea pigs with noise‐induced hearing loss had significantly lower thresholds, shorter latencies and durations, and increased amplitudes of response to trigeminal stimulation than normal animals. Noise‐damaged animals also showed a greater proportion of inhibitory and a smaller proportion of excitatory responses compared with normal. The number of cells exhibiting bimodal integration, as well as the degree of integration, was enhanced after noise damage. In accordance with the greater proportion of inhibitory responses, bimodal integration was entirely suppressive in the noise‐damaged animals with no indication of the bimodal enhancement observed in a sub‐set of normal DCN neurons. These results suggest that projections from the trigeminal system to the cochlear nucleus are increased and/or redistributed after hearing loss. Furthermore, the finding that only neurons activated by trigeminal stimulation showed increased spontaneous rates after cochlear damage suggests that somatosensory neurons may play a role in the pathogenesis of tinnitus.

We studied the effects of electrically microstimulating a gaze-control area in the owl's forebrain, the arcopallial gaze fields (AGFs), on the responsiveness of neurons in the optic tectum (OT) to visual and auditory stimuli. Microstimulation of the AGF enhanced the visual and auditory responsiveness and stimulus discriminability of OT neurons representing the same location in space as that represented at the microstimulation site in the AGF. At such OT sites, AGF microstimulation also sharpened auditory receptive fields and shifted them toward the location represented at the AGF stimulation site. At the same time, AGF microstimulation suppressed the responsiveness of OT neurons that represented visual or auditory stimuli at other locations in space. The top-down influences of this forebrain gaze-control area on sensory responsiveness in the owl OT are strikingly similar to the space-specific regulation of visual responsiveness in the monkey visual cortex produced by voluntary attention as well as by microstimulation of the frontal eye fields. This experimental approach provides a means for discovering mechanisms that underlie the top-down regulation of sensory responses.