Electrical Stimulation publications

Fast-scan cyclic voltammetry (FSCV) is often used to measure real-time dopamine (DA) concentrations in awake, behaving rodents. Extending this technique to work in monkeys would provide a platform for advanced behavioral studies and a primate model for preclinical research. The present study demonstrates the feasibility of DA recordings in two awake monkeys (Macaca mulatta) using a mixture of techniques adapted from rodent, primate and brain slice work. We developed a long carbon fiber electrode to operate in the larger primate brain. This electrode was lowered into the striatum each day using a recording chamber and a detachable micromanipulator system. A manipulator also moved one or more tungsten stimulating electrodes into either the nearby striatum or the ventral tegmental area/substantia nigra pars compacta (VTA/SNc). We developed an electrical stimulation controller to reduce artifacts during electrical stimulation. We also introduce a stimulation-based methodology for estimating distances between electrodes in the brain. Dopamine responses within the striatum were evoked by either stimulation of the striatum near the FSCV electrode, or stimulation within the VTA/SNc. Unexpected juice rewards also evoked dopamine responses in the ventral striatum. Thus, we demonstrate that robust dopamine responses can be recorded from awake, behaving primates with FSCV. In addition, we describe how a stimulation technique borrowed from the neuroprosthetics field can activate the distributed monkey midbrain dopamine system in a way that mimics rodent VTA stimulation.

Objective: Cochlear implants (CIs) have provided some auditory function to hundreds of thousands of people around the world. Although traditionally carried out only in profoundly deaf patients, the eligibility criteria for implantation have recently been relaxed to include many partially-deaf patients with useful levels of hearing. These patients receive both electrical stimulation from their implant and acoustic stimulation via their residual hearing (electro-acoustic stimulation; EAS) and perform very well. It is unclear how EAS improves speech perception over electrical stimulation alone, and little evidence exists about the nature of the interactions between electric and acoustic stimuli. Furthermore, clinical results suggest that some patients that undergo cochlear implantation lose some, if not all, of their residual hearing, reducing the advantages of EAS over electrical stimulation alone. A reliable animal model with clinically-relevant partial deafness combined with clinical CIs is important to enable these issues to be studied. This paper outlines such a model that has been successfully used in our laboratory. Approach: This paper outlines a battery of techniques used in our laboratory to generate, validate and examine an animal model of partial deafness and chronic CI use. Main results: Ototoxic deafening produced bilaterally symmetrical hearing thresholds in neonatal and adult animals. Electrical activation of the auditory system was confirmed, and all animals were chronically stimulated via adapted clinical CIs. Acoustic compound action potentials (CAPs) were obtained from partially-hearing cochleae, using the CI amplifier. Immunohistochemical analysis allows the effects of deafness and electrical stimulation on cell survival to be studied. Significance: This animal model has applications in EAS research, including investigating the functional interactions between electric and acoustic stimulation, and the development of techniques to maintain residual hearing following cochlear implantation. The ability to record CAPs via the CI has clinical direct relevance for obtaining objective measures of residual hearing.

Aim: Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB) is a new drug candidate for ischemic stroke. The aim of this study was to investigate the effects of dl-PHPB on memory deficits and long-term potentiation (LTP) impairment in animal models of Alzheimer's disease. Methods: The expression of NMDA receptor subunits GluN1 and GluN2B in the hippocampus and cortex of APP/PS1 transgenic mice were detected using Western blot analysis. Memory deficits of the mice were evaluated with the passive avoidance test. LTP impairment was studied in the dentate region of Aβ1-42-injected rats and APP/PS1 transgenic mice. Results: APP/PS1 transgenic mice showed significantly lower levels of GluN1 and p-GluN2B in hippocampus, and chronic administration of dl-PHPB (100 mg · kg(-1) · d(-1), po) reversed the downregulation of p-GluN2B, but did not change GluN1 level in the hippocampus. Furthermore, chronic administration of dl-PHPB reversed the memory deficits in APP/PS1 transgenic mice. In the dentate region of normal rats, injection of dl-PHPB (100 μmol/L, icv) did not change the basal synaptic transmission, but significantly enhanced the high-frequency stimulation (HFS)-induced LTP, which was completely prevented by pre-injection of APV (150 μmol/L, icv). Chronic administration of dl-PHPB (100 mg · kg(-1) · d(-1), po) reversed LTP impairment in Aβ1-42-injected normal rats and APP/PS1 transgenic mice. Conclusion: Chronic administration of dl-PHPB improves learning and memory and promotes LTP in the animal models of Alzheimer's disease, possibly via increasing p-GluN2B expression in the hippocampus.

Cochlear trauma causes increased spontaneous activity (hyperactivity) to develop in central auditory structures, and this has been suggested as a neural substrate for tinnitus. Using a guinea pig model we have previously demonstrated that for some time after cochlear trauma, central hyperactivity is dependent on peripheral afferent drive and only later becomes generated intrinsically within central structures. Furosemide, a loop diuretic, reduces spontaneous firing of auditory afferents. We investigated in our guinea pig model the efficacy of furosemide in reducing 1) spontaneous firing of auditory afferents, using the spectrum of neural noise (SNN) from round window recording, 2) hyperactivity in inferior colliculus, using extracellular single neuron recordings and 3) tinnitus at early time-points after cochlear trauma. Tinnitus was assessed using gap prepulse inhibition of acoustic startle (GPIAS). Intraperitoneal furosemide, but not saline, caused a marked decrease in both SNN and central hyperactivity. Intracochlear perfusion with furosemide similarly reversed central hyperactivity. In animals in which GPIAS measurements suggested the presence of tinnitus (reduced GPIAS), this could be reversed with an intraperitoneal injection with furosemide but not saline. The results are consistent with furosemide reducing central hyperactivity and behavioural signs of tinnitus by acting peripherally to decrease spontaneous firing of auditory afferents. The data support the notion that hyperactivity may be involved in the generation of tinnitus and further suggest that there may be a therapeutic window after cochlear trauma using drug treatments that target peripheral spontaneous activity.

The response of neurons in the Red Nucleus pars magnocellularis (RNm) to both tone bursts and electrical stimulation were observed in three cynomolgus monkeys (Macaca fascicularis), in a series of studies primarily designed to characterize the influence of the dopaminergic ventral midbrain on auditory processing. Compared to its role in motor behavior, little is known about the sensory response properties of neurons in the red nucleus (RN); particularly those concerning the auditory modality. Sites in the RN were recognized by observing electrically evoked body movements characteristic for this deep brain structure. In this study we applied brief monopolar electrical stimulation to 118 deep brain sites at a maximum intensity of 200 μA, thus evoking minimal body movements. Auditory sensitivity of RN neurons was analyzed more thoroughly at 15 sites, with the majority exhibiting broad tuning curves and phase locking up to 1.03 kHz. Since the RN appears to receive inputs from a very early stage of the ascending auditory system, our results suggest that sounds can modify the motor control exerted by this brain nucleus. At selected locations, we also tested for the presence of functional connections between the RN and the auditory cortex by inserting additional microelectrodes into the auditory cortex and investigating how action potentials and local field potentials (LFPs) were affected by electrical stimulation of the RN.

Rodents show robust behavioral responses to odors, including strong preferences or aversions for certain odors. The neural mechanisms underlying the effects of odors on these behaviors in animals are not well understood. Here, we provide an initial proof-of-concept study into the role of the olfactory tubercle (OT), a structure with known anatomical connectivity with both brain reward and olfactory structures, in regulating odor-motivated behaviors. We implanted c57bl/6 male mice with an ipsilateral bipolar electrode into the OT to administer electric current and thereby yield gross activation of the OT. We confirmed that electrical stimulation of the OT was rewarding, with mice frequently self-administering stimulation on a fixed ratio schedule. In a separate experiment, mice were presented with either fox urine or peanut odors in a three-chamber preference test. In absence of OT stimulation, significant preference for the peanut odor chamber was observed which was abolished in the presence of OT stimulation. Perhaps providing a foundation for this modulation in behavior, we found that OT stimulation significantly increased the number of c-Fos positive neurons in not only the OT, but also in forebrain structures essential to motivated behaviors, including the nucleus accumbens and lateral septum. The present results support the notion that the OT is integral to the display of motivated behavior and possesses the capacity to modulate odor hedonics either by directly altering odor processing or perhaps by indirect actions on brain reward and motivation structures.

Objective: There is great interest in closed-loop neurostimulators that sense and respond to a patient's brain state. Such systems may have value for neurological and psychiatric illnesses where symptoms have high intraday variability. Animal models of closed-loop stimulators would aid preclinical testing. We therefore sought to demonstrate that rodents can directly control a closed-loop limbic neurostimulator via a brain-computer interface (BCI). Approach: We trained rats to use an auditory BCI controlled by single units in prefrontal cortex (PFC). The BCI controlled electrical stimulation in the medial forebrain bundle, a limbic structure involved in reward-seeking. Rigorous offline analyses were performed to confirm volitional control of the neurostimulator. Main results: All animals successfully learned to use the BCI and neurostimulator, with closed-loop control of this challenging task demonstrated at 80% of PFC recording locations. Analysis across sessions and animals confirmed statistically robust BCI control and specific, rapid modulation of PFC activity. Significance: Our results provide a preliminary demonstration of a method for emotion-regulating closed-loop neurostimulation. They further suggest that activity in PFC can be used to control a BCI without pre-training on a predicate task. This offers the potential for BCI-based treatments in refractory neurological and mental illness.

The neural substrate for the perception of vocalizations is relatively well described, but how their timing and specificity are tightly coupled with accompanying physiological changes and context-appropriate behaviors remains unresolved. We hypothesized that temporally integrated vocal and emotive responses, especially the expression of fear, vigilance and aggression, originate within the amygdala. To test this hypothesis, we performed electrical microstimulation at 461 highly restricted loci within the basal and central amygdala in awake mustached bats. At a subset of these sites, high frequency stimulation with weak constant current pulses presented at near-threshold levels triggered vocalization of either echolocation pulses or social calls. At the vast majority of locations, microstimulation produced a constellation of changes in autonomic and somatomotor outputs. These changes included widespread co-activation of significant tachycardia and hyperventilation and/or rhythmic ear pinna movements (PMs). In a few locations, responses were constrained to vocalization and/or PMs despite increases in the intensity of stimulation. The probability of eliciting echolocation pulses vs. social calls decreased in a medial-posterior to anterolateral direction within the centrobasal amygdala. Microinjections of kainic acid (KA) at stimulation sites confirmed the contribution of cellular activity rather than fibers-of-passage in the control of multimodal outputs. The results suggest that localized clusters of neurons may simultaneously modulate the activity of multiple central pattern generators (CPGs) present within the brainstem.

Purpose The use of bilateral stimulation is becoming common for cochlear implant (CI) recipients with either (a) a CI in one ear and a hearing aid (HA) in the nonimplanted ear (CI&HA—bimodal) or (b) CIs in both ears (CI&CI—bilateral). The objective of this study was to evaluate 4 individuals who transitioned from bimodal to bilateral stimulation. Method Participants had completed a larger study of bimodal hearing and subsequently received a second CI. Test procedures from the bimodal study, including roaming speech recognition, localization, and a questionnaire (the Speech, Spatial, and Qualities of Hearing Scale; Gatehouse & Noble, 2004) were repeated after 6–7 months of bilateral CI experience. Results Speech recognition and localization were not significantly different between bimodal and unilateral CI. In contrast, performance was significantly better with CI&CI compared with unilateral CI. Speech recognition with CI&CI was significantly better than with CI&HA for 2 of 4 participants. Localization was significantly better for all participants with CI&CI compared with CI&HA. CI&CI performance was rated as significantly better on the Speech, Spatial, and Qualities of Hearing Scale compared with CI&HA. Conclusions There was a strong preference for CI&CI for all participants. The variability in speech recognition and localization, however, suggests that performance under these stimulus conditions is individualized. Differences in hearing and/or HA history may explain performance differences.

Purpose In this study, the authors examined the effects of aging and residual hearing on the identification of acoustically similar and dissimilar vowels in adults with postlingual deafness who use hearing aids (HAs) and/or cochlear implants (CIs). Method The authors used two groups of acoustically similar and dissimilar vowels to assess vowel identification. Also, the Consonant–Nucleus–Consonant Word Recognition Test (Peterson & Lehiste, 1962) and sentences from the Hearing in Noise Test (Nilsson, Soli, & Sullivan, 1994) were administered. Forty CI recipients with postlingual deafness (ages 31–81 years) participated in the study. Results Acoustically similar vowels were more difficult to identify than acoustically dissimilar vowels. With increasing age, performance deteriorated when identifying acoustically similar vowels. Vowel identification was also affected by the use of a contralateral HA and the degree of residual hearing prior to implantation. Moderate correlations were found between speech perception and vowel identification performance. Conclusions Identification performance was affected by the acoustic similarity of the vowels. Older adults experienced more difficulty identifying acoustically similar confusable vowels than did younger adults. The findings might lend support to the ease of language understanding model (Ronnberg, Rudner, Foo, & Lunner, 2008), which proposes that the quality and perceptual robustness of acoustic input affects speech perception. Supplemental Material https://doi.org/10.23641/asha.6170174

Mutations in the connexin 26 gene (GJB2) are the most common genetic cause of deafness, leading to congenital bilateral non-syndromic sensorineural hearing loss. Here we report the generation of a mouse model for a connexin 26 (Cx26) mutation, in which cre-Sox10 drives excision of the Cx26 gene from non-sensory cells flanking the auditory epithelium. We determined that these conditional knockout mice, designated Gjb2-CKO, have a severe hearing loss. Immunocytochemistry of the auditory epithelium confirmed absence of Cx26 in the non-sensory cells. Histology of the organ of Corti and the spiral ganglion neurons (SGNs) performed at ages 1, 3, or 6 months revealed that in Gjb2-CKO mice, the organ of Corti began to degenerate in the basal cochlear turn at an early stage, and the degeneration rapidly spread to the apex. In addition, the density of SGNs in Rosenthal's canal decreased rapidly along a gradient from the base of the cochlea to the apex, where some SGNs survived until at least 6 months of age. Surviving neurons often clustered together and formed clumps of cells in the canal. We then assessed the influence of brain derived neurotrophic factor (BDNF) gene therapy on the SGNs of Gjb2-CKO mice by inoculating Adenovirus with the BDNF gene insert (Ad.BDNF) into the base of the cochlea via the scala tympani or scala media. We determined that over-expression of BDNF beginning around 1 month of age resulted in a significant rescue of neurons in Rosenthal's canal of the cochlear basal turn but not in the middle or apical portions. This data may be used to design therapies for enhancing the SGN physiological status in all GJB2 patients and especially in a sub-group of GJB2 patients where the hearing loss progresses due to ongoing degeneration of the auditory nerve, thereby improving the outcome of cochlear implant therapy in these ears.

Cochlear implant electrical stimulation of the auditory system to rehabilitate deafness has been remarkably successful. Its deployment requires both an intact auditory nerve and a suitably patent cochlear lumen. When disease renders prerequisite conditions impassable, such as in neurofibromatosis type II and cochlear obliterans, alternative treatment targets are considered. Electrical stimulation of the cochlear nucleus and midbrain in humans has delivered encouraging clinical outcomes, buttressing the promise of central auditory prostheses to mitigate deafness in those who are not candidates for cochlear implantation. In this study we explored another possible implant target: the auditory thalamus. In anesthetized cats, we first presented pure tones to determine frequency preferences of thalamic and cortical sites. We then electrically stimulated tonotopically organized thalamic sites while recording from primary auditory cortical sites using a multichannel recording probe. Cathode-leading biphasic thalamic stimulation thresholds that evoked cortical responses were much lower than published accounts of cochlear and midbrain stimulation. Cortical activation dynamic ranges were similar to those reported for cochlear stimulation, but they were narrower than those found through midbrain stimulation. Our results imply that thalamic stimulation can activate auditory cortex at low electrical current levels and suggest an auditory thalamic implant may be a viable central auditory prosthesis.

Auditory prostheses can partially restore speech comprehension when hearing fails. Sound coding with current prostheses is based on electrical stimulation of auditory neurons and has limited frequency resolution due to broad current spread within the cochlea. In contrast, optical stimulation can be spatially confined, which may improve frequency resolution. Here, we used animal models to characterize optogenetic stimulation, which is the optical stimulation of neurons genetically engineered to express the light-gated ion channel channelrhodopsin-2 (ChR2). Optogenetic stimulation of spiral ganglion neurons (SGNs) activated the auditory pathway, as demonstrated by recordings of single neuron and neuronal population responses. Furthermore, optogenetic stimulation of SGNs restored auditory activity in deaf mice. Approximation of the spatial spread of cochlear excitation by recording local field potentials (LFPs) in the inferior colliculus in response to suprathreshold optical, acoustic, and electrical stimuli indicated that optogenetic stimulation achieves better frequency resolution than monopolar electrical stimulation. Virus-mediated expression of a ChR2 variant with greater light sensitivity in SGNs reduced the amount of light required for responses and allowed neuronal spiking following stimulation up to 60 Hz. Our study demonstrates a strategy for optogenetic stimulation of the auditory pathway in rodents and lays the groundwork for future applications of cochlear optogenetics in auditory research and prosthetics.

High frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used treatment for Parkinson's disease, but its effects on neural activity in basal ganglia circuits are not fully understood. DBS increases the excitation of STN efferents yet decouples STN spiking patterns from the spiking patterns of STN synaptic targets. We propose that this apparent paradox is resolved by recent studies showing an increased rate of axonal and synaptic failures in STN projections during DBS. To investigate this hypothesis, we combine in vitro and in vivo recordings to derive a computational model of axonal and synaptic failure during DBS. Our model shows that these failures induce a short term depression that suppresses the synaptic transfer of firing rate oscillations, synchrony and rate-coded information from STN to its synaptic targets. In particular, our computational model reproduces the widely reported suppression of parkinsonian β oscillations and synchrony during DBS. Our results support the idea that short term depression is a therapeutic mechanism of STN DBS that works as a functional lesion by decoupling the somatic spiking patterns of STN neurons from spiking activity in basal ganglia output nuclei.

Brain-machine interface (BMI) systems give users direct neural control of robotic, communication, or functional electrical stimulation systems. As BMI systems begin transitioning from laboratory settings into activities of daily living, an important goal is to develop neural decoding algorithms that can be calibrated with a minimal burden on the user, provide stable control for long periods of time, and can be responsive to fluctuations in the decoder's neural input space (e.g. neurons appearing or being lost amongst electrode recordings). These are significant challenges for static neural decoding algorithms that assume stationary input/output relationships. Here we use an actor-critic reinforcement learning architecture to provide an adaptive BMI controller that can successfully adapt to dramatic neural reorganizations, can maintain its performance over long time periods, and which does not require the user to produce specific kinetic or kinematic activities to calibrate the BMI. Two marmoset monkeys used the Reinforcement Learning BMI (RLBMI) to successfully control a robotic arm during a two-target reaching task. The RLBMI was initialized using random initial conditions, and it quickly learned to control the robot from brain states using only a binary evaluative feedback regarding whether previously chosen robot actions were good or bad. The RLBMI was able to maintain control over the system throughout sessions spanning multiple weeks. Furthermore, the RLBMI was able to quickly adapt and maintain control of the robot despite dramatic perturbations to the neural inputs, including a series of tests in which the neuron input space was deliberately halved or doubled.

After severe hair cell loss, secondary degeneration of spiral ganglion cells (SGCs) is observed-a gradual process that spans years in humans but only takes weeks in guinea pigs. Being the target for cochlear implants (CIs), the physiological state of the SGCs is important for the effectiveness of a CI. For assessment of the nerve's state, focus has generally been on its response threshold. Our goal was to add a more detailed characterization of SGC functionality. To this end, the electrically evoked compound action potential (eCAP) was recorded in normal-hearing guinea pigs and guinea pigs that were deafened 2 or 6 weeks prior to the experiments. We evaluated changes in eCAP characteristics when the phase duration (PD) and inter-phase gap (IPG) of a biphasic current pulse were varied. We correlated the magnitude of these changes to quantified histological measures of neurodegeneration (SGC packing density and SGC size). The maximum eCAP amplitude, derived from the input-output function, decreased after deafening, and increased with both PD and IPG. The eCAP threshold did not change after deafening, and decreased with increasing PD and IPG. The dynamic range was wider for the 6-weeks-deaf animals than for the other two groups. Excitability increased with IPG (steeper slope of the input-output function and lower stimulation level at the half-maximum eCAP amplitude), but to a lesser extent for the deafened animals than for normal-hearing controls. The latency was shorter for the 6-weeks-deaf animals than for the other two groups. For several of these eCAP characteristics, the effect size of IPG correlated well with histological measures of degeneration, whereas effect size of PD did not. These correlations depend on the use of high current levels, which could limit clinical application. Nevertheless, their potential of these correlations towards assessment of the condition of the auditory nerve may be of great benefit to clinical diagnostics and prognosis in cochlear implant recipients.

Aims: Pudendal afferent fibers can be excited using electrical stimulation to evoke reflex bladder activity. While this approach shows promise for restoring bladder function, stimulation of desired pathways, and integration of afferent signals for sensory feedback remains challenging. At sacral dorsal root ganglia (DRG), the convergence of pelvic and pudendal afferent fibers provides a unique location for access to lower urinary tract neurons. Our goal in this study was to demonstrate the potential of microstimulation in sacral DRG for evoking reflex bladder responses. Methods: Penetrating microelectrode arrays were inserted in the left S1 and S2 DRG of six anesthetized adult male cats. While the bladder volume was held at a level below the leak volume, single and multiple channel stimulation was performed using various stimulation patterns. Results: Reflex bladder excitation was observed in five cats, for stimulation in either S1 or S2 DRG at 1 Hz and 30-33 Hz with a pulse amplitude of 10-50 µA. Bladder relaxation was observed during a few trials. Adjacent electrodes frequently elicited very different responses. Conclusions: These results demonstrate the potential of low-current microstimulation to recruit reflexive bladder responses. An approach such as this could be integrated with DRG recordings of bladder afferents to provide a closed-loop bladder neuroprosthesis.

Delivery of therapeutic compounds to the inner ear via absorption through the round window membrane (RWM) has advantages over direct intracochlear infusions; specifically, minimizing impact upon functional hearing measures. However, previous reports show that significant basal-to-apical concentration gradients occur, with the potential to impact treatment efficacy. Here we present a new approach to inner ear drug delivery with induced advection aiding distribution of compounds throughout the inner ear in the murine cochlea. Polyimide microtubing was placed near the RWM niche through a bullaostomy into the middle ear cavity allowing directed delivery of compounds to the RWM. We hypothesized that a posterior semicircular canalostomy would induce apical flow from the patent cochlear aqueduct to the canalostomy due to influx of cerebral spinal fluid. To test this hypothesis, young adult CBA/CaJ mice were divided into two groups: bullaostomy approach only (BA) and bullaostomy+canalostomy (B+C). Cochlear function was evaluated by distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) thresholds during and after middle ear infusion of salicylate in artificial perilymph (AP), applied near the RWM. The mice recovered for 1week, and were re-tested. The results demonstrate there was no significant impact on auditory function utilizing the RWM surgical procedure with or without the canalostomy, and DPOAE thresholds were elevated reversibly during the salicylate infusion. Comparing the threshold shifts for both methods, the B+C approach had more of a physiological effect than the BA approach, including at lower frequencies representing more apical cochlear locations. Unlike mouse cochleostomies, there was no deleterious auditory functional impact after 1week recovery from surgery. The B+C approach had more drug efficacy at lower frequencies, underscoring potential benefits for more precise control of delivery of inner ear therapeutic compounds.

Brain machine interfaces (BMIs) have attracted intense attention as a promising technology for directly interfacing computers or prostheses with the brain’s motor and sensory areas, thereby bypassing the body. The availability of multiscale neural recordings including spike trains and local field potentials (LFPs) brings potential opportunities to enhance computational modeling by enriching the characterization of the neural system state. However, heterogeneity on data type (spike timing versus continuous amplitude signals) and spatiotemporal scale complicates the model integration of multiscale neural activity. In this paper, we propose a tensor-product-kernel-based framework to integrate the multiscale activity and exploit the complementary information available in multiscale neural activity. This provides a common mathematical framework for incorporating signals from different domains. The approach is applied to the problem of neural decoding and control. For neural decoding, the framework is able to identify the nonlinear functional relationship between the multiscale neural responses and the stimuli using general purpose kernel adaptive filtering. In a sensory stimulation experiment, the tensor-product-kernel decoder outperforms decoders that use only a single neural data type. In addition, an adaptive inverse controller for delivering electrical microstimulation patterns that utilizes the tensor-product kernel achieves promising results in emulating the responses to natural stimulation.