Electrical Stimulation publications

Assessing the instantaneous effect of dorsal root ganglia (DRG) stimulation on the transmission of electrically evoked action potentials from the spinal nerve via the ex vivo preparation with mouse L6 spinal nerve (SN), DRG, and dorsal root (DR) in continuity, i.e., the SN-DRG-DR preparation. Synchronized spinal nerve and DRG stimulation reveal a progressive increase in conduction delay by DRG stimulation, suggesting an activity-dependent slowing in blocked fibers. Midrange frequencies (50-500 Hz) are more efficient at blocking transmission than lower or higher frequencies.

Animals can capitalize on invariance in the environment by learning and automating highly consistent actions; however, they must also remain flexible and adapt to environmental changes. It remains unclear how primary motor cortex (M1) can drive precise movements, yet also support behavioral exploration when faced with consistent errors. Using a reach-to-grasp task in rats, along with simultaneous electrophysiological monitoring in M1 and dorsolateral striatum (DLS), we find that behavioral exploration to overcome consistent task errors is closely associated with tandem increases in M1 and DLS neural variability; subsequently, consistent ensemble patterning returns with convergence to a new successful strategy. We also show that compared to reliably patterned intracranial microstimulation in M1, variable stimulation patterns result in significantly greater movement variability. Our results thus indicate that motor and striatal areas can flexibly transition between two modes, reliable neural pattern generation for automatic and precise movements versus variable neural patterning for behavioral exploration.

Electrically evoked compound action potentials (ECAPs) generated in the subthalamic nucleus (STN) contain features that may be useful for titrating deep brain stimulation (DBS) therapy for Parkinson’s disease. Delivering a strong therapeutic effect with DBS therapies, however, relies on selectively targeting neural pathways to avoid inducing side effects. In this study, we investigated the spatiotemporal features of ECAPs in and around the STN across parameter sweeps of stimulation current amplitude, pulse width, and electrode configuration, and used a linear classifier of ECAP responses to predict electrode location. Four non-human primates were implanted unilaterally with either a directional (n=3) or non-directional (n=1) DBS lead targeting the sensorimotor STN. ECAP responses were characterized by primary features (within 1.6 ms after a stimulus pulse) and secondary features (between 1.6-7.4 ms after a stimulus pulse). Using these ECAP features, a linear classifier was able to accurately differentiate electrodes within the STN versus dorsal to the STN in all four subjects. ECAP responses varied systematically with recording and stimulating electrode locations, which provides a subject-specific neuroanatomical basis for selecting electrode configurations in the treatment of Parkinson’s disease with DBS therapy.

Objective To assess whether multiple injections of a powerful antioxidant can improve established sensorineural hearing loss in guinea pigs. Study Design Animal study. Setting Animal science laboratory, University of Manitoba. Methods A total of 16 guinea pigs were used in our study: 8 underwent unilateral intracochlear neomycin injection, and 8 underwent unilateral saline to serve as controls. After a period of 3 weeks for hearing loss to stabilize, 4 guinea pigs from each group received weekly intraperitoneal injections of N‐acetylcysteine (NAC) for 4 weeks. Click auditory brainstem response (ABR) testing was conducted at baseline, weekly after the start of NAC injections, and after the last injection. Pure tone ABR tests were conducted prior to intracochlear injections and at completion of the study. Results Click ABR thresholds were significantly worse in ears treated with neomycin ( P <. 001), as expected, but not significantly different when treated with NAC ( P =. 664). Thresholds for pure tone ABR were also not statistically different in neomycin‐treated ears with or without NAC ( P >. 99). Conclusions The aggressive antioxidant therapy performed in this study was not successful in improving established hearing loss via an antioxidant regimen that is known to change the oxidation‐reduction potential in the cochlea.

Objective . Neural prosthetics often use intracortical microstimulation (ICMS) for sensory restoration. To restore natural and functional feedback, we must first understand how stimulation parameters influence the recruitment of neural populations. ICMS waveform asymmetry modulates the spatial activation of neurons around an electrode at 10 Hz; however, it is unclear how asymmetry may differentially modulate population activity at frequencies typically employed in the clinic (e.g. 100 Hz). We hypothesized that stimulation waveform asymmetry would differentially modulate preferential activation of certain neural populations, and the differential population activity would be frequency-dependent. Approach . We quantified how asymmetric stimulation waveforms delivered at 10 or 100 Hz for 30 s modulated spatiotemporal activity of cortical layer II/III pyramidal neurons using in vivo two-photon and mesoscale calcium imaging in anesthetized mice. Asymmetry is defined in terms of the ratio of the duration of the leading phase to the duration of the return phase of charge-balanced cathodal- and anodal-first waveforms (i.e. longer leading phase relative to return has larger asymmetry). Main results . Neurons within 40–60 µ m of the electrode display stable stimulation-induced activity indicative of direct activation, which was independent of waveform asymmetry. The stability of 72% of activated neurons and the preferential activation of 20%–90% of neurons depended on waveform asymmetry. Additionally, this asymmetry-dependent activation of different neural populations was associated with differential progression of population activity. Specifically, neural activity tended to increase over time during 10 Hz stimulation for some waveforms, whereas activity remained at the same level throughout stimulation for other waveforms. During 100 Hz stimulation, neural activity decreased over time for all waveforms, but decreased more for the waveforms that resulted in increasing neural activity during 10 Hz stimulation. Significance. These data demonstrate that at frequencies commonly used for sensory restoration, stimulation waveform alters the pattern of activation of different but overlapping populations of excitatory neurons. The impact of these waveform specific responses on the activation of different subtypes of neurons as well as sensory perception merits further investigation.

Speech perception in noise is a challenging everyday task with which many listeners have difficulty. Here, we report a case in which electrical brain stimulation of implanted intracranial electrodes in the left planum temporale (PT) of a neurosurgical patient significantly and reliably improved subjective quality (up to 50%) and objective intelligibility (up to 97%) of speech in noise perception. Stimulation resulted in a selective enhancement of speech sounds compared with the background noises. The receptive fields of the PT sites whose stimulation improved speech perception were tuned to spectrally broad and rapidly changing sounds. Corticocortical evoked potential analysis revealed that the PT sites were located between the sites in Heschl's gyrus and the superior temporal gyrus. Moreover, the discriminability of speech from nonspeech sounds increased in population neural responses from Heschl's gyrus to the PT to the superior temporal gyrus sites. These findings causally implicate the PT in background noise suppression and may point to a novel potential neuroprosthetic solution to assist in the challenging task of speech perception in noise. SIGNIFICANCE STATEMENT Speech perception in noise remains a challenging task for many individuals. Here, we present a case in which the electrical brain stimulation of intracranially implanted electrodes in the planum temporale of a neurosurgical patient significantly improved both the subjective quality (up to 50%) and objective intelligibility (up to 97%) of speech perception in noise. Stimulation resulted in a selective enhancement of speech sounds compared with the background noises. Our local and network-level functional analyses placed the planum temporale sites in between the sites in the primary auditory areas in Heschl's gyrus and nonprimary auditory areas in the superior temporal gyrus. These findings causally implicate planum temporale in acoustic scene analysis and suggest potential neuroprosthetic applications to assist hearing in noise.

Objective: Intraneural nerve interfaces often operate in a monopolar configuration with a common and distant ground electrode. This configuration leads to a wide spreading of the electric field. Therefore, this approach is suboptimal for intraneural nerve interfaces when selective stimulation is required. Approach: We designed a multilayer electrode array embedding three-dimensional concentric bipolar electrodes. First, we validated the higher stimulation selectivity of this new electrode array compared to classical monopolar stimulation using simulations. Next, we compared them in-vivo by intraneural stimulation of the rabbit optic nerve and recording evoked potentials in the primary visual cortex. Main results: Simulations showed that three-dimensional concentric bipolar electrodes provide a high localisation of the electric field in the tissue so that electrodes are electrically independent even for high electrode density. Experiments in-vivo highlighted that this configuration leads to evoked responses with lower amplitude and more localised cortical patterns due to the fewer fibres activated by the electric stimulus in the nerve. Significance: Highly focused electric stimulation is crucial to achieving high selectivity in fibre activation. The multilayer array embedding three-dimensional concentric bipolar electrodes improves selectivity in optic nerve stimulation. This approach is suitable for other neural applications, including bioelectronic medicine.

Higher vertebrates are capable not only of forward but also backward and sideways locomotion. Also, single steps in different directions are generated for postural corrections. While the networks responsible for the control of forward walking (FW) have been studied in considerable detail, the networks controlling steps in other directions are mostly unknown. Here, to characterize the operation of the spinal locomotor network during FW and backward walking (BW), we recorded the activity of individual spinal interneurons from L4 to L6 during both FW and BW evoked by epidural stimulation (ES) of the spinal cord at L5–L6 in decerebrate cats of either sex. Three groups of neurons were revealed. Group 1 (45%) had a similar phase of modulation during both FW and BW. Group 2 (27%) changed the phase of modulation in the locomotor cycle depending on the direction of locomotion. Group 3 neurons were modulated during FW only (Group 3a, 21%) or during BW only (Group 3b, 7%). We suggest that Group 1 neurons belong to the network generating the vertical component of steps (the limb elevation and lowering) because it should operate similarly during locomotion in any direction, while Groups 2 and 3 neurons belong to the networks controlling the direction of stepping. Results of this study provide new insights into the organization of the spinal locomotor circuits, advance our understanding of ES therapeutic effects, and can potentially be used for the development of novel strategies for recuperation of impaired balance control, which requires the generation of corrective steps in different directions. SIGNIFICANCE STATEMENT Animals and humans can perform locomotion in different directions in relation to the body axis (forward, backward, sideways). While the networks that control forward walking have been studied in considerable detail, the networks controlling steps in other directions are unknown. Here, by recording the activity of the same spinal neurons during forward and backward walking, we revealed three groups of neurons forming, respectively, the network operating similarly during stepping in different directions, the network changing its operation with a change in the direction of stepping, and the network operating only during locomotion in a specific direction. These networks presumably control different aspects of the step. The obtained results provide new insights into the organization of the spinal locomotor networks.

Mechanosensation – by which mechanical stimuli are converted into a neuronal signal – is the basis for the sensory systems of hearing, balance, and touch. Mechanosensation is unmatched in speed and its diverse range of sensitivities, reaching its highest temporal limits with the sense of hearing; however, hair cells (HCs) and the auditory nerve (AN) serve as obligatory bottlenecks for sounds to engage the brain. Like other sensory neurons, auditory neurons use the canonical pathway for neurotransmission and millisecond-duration action potentials (APs). How the auditory system utilizes the relatively slow transmission mechanisms to achieve ultrafast speed, and high audio-frequency hearing remains an enigma. Here, we address this paradox and report that the mouse, and chinchilla, AN are mechanically sensitive, and minute mechanical displacement profoundly affects its response properties. Sound-mimicking sinusoidal mechanical and electrical current stimuli affect phase-locked responses. In a phase-dependent manner, the two stimuli can also evoke suppressive responses. We propose that mechanical sensitivity interacts with synaptic responses to shape responses in the AN, including frequency tuning and temporal phase locking. Combining neurotransmission and mechanical sensation to control spike patterns gives the mammalian AN a secondary receptor role, an emerging theme in primary neuronal functions.

Spinal interneurons play a critical role in motor output. A given interneuron may receive convergent input from several different sensory modalities and descending centers and relay this information to just as many targets. Therefore, there is a critical need to quantify populations of spinal interneurons simultaneously. Here, we quantify the functional connectivity of spinal neurons through the concurrent recording of populations of lumbar interneurons and hindlimb motor units in the in vivo cat model during activation of either the ipsilateral sural nerve or contralateral tibial nerve. Two microelectrode arrays were placed into lamina VII, one at L3 and a second at L6/7, while an electrode array was placed on the surface of the exposed muscle. Stimulation of tibial and sural nerves elicited similar changes in the discharge rate of both interneurons and motor units. However, these same neurons showed highly significant differences in prevalence and magnitude of correlated activity underlying these two forms of afferent drive. Activation of the ipsilateral sural nerve resulted in highly correlated activity, particularly at the caudal array. In contrast, the contralateral tibial nerve resulted in less, but more widespread correlated activity at both arrays. These data suggest that the ipsilateral sural nerve has dense projections onto caudal lumbar spinal neurons, while contralateral tibial nerve has a sparse pattern of projections.

The investigation of neuronal activity in non-human primate models is of critical importance due to their genetic similarity to human brains. In this study, we tested the feasibility of using photoacoustic imaging for the detection of cortical and subcortical responses due to peripheral electrical stimulation in a squirrel monkey model. Photoacoustic computed tomography and photoacoustic microscopy were applied on squirrel monkeys for real-time deep subcortical imaging and optical-resolution cortical imaging, respectively. The electrically evoked hemodynamic changes in primary somatosensory cortex, premotor cortices, primary motor cortex, and underlying subcortical areas were measured. Hemodynamic responses were observed in both cortical and subcortical brain areas at the cortices during external stimulation, demonstrating the feasibility of photoacoustic technique for functional imaging of non-human primate brain.

Aminoglycosides (AGs) are commonly used antibiotics that cause deafness through the irreversible loss of cochlear sensory hair cells (HCs). How AGs enter the cochlea and then target HCs remains unresolved. Here, we performed time-lapse multicellular imaging of cochlea in live adult hearing mice via a chemo-mechanical cochleostomy. The in vivo tracking revealed that systemically administered Texas Red–labeled gentamicin (GTTR) enters the cochlea via the stria vascularis and then HCs selectively. GTTR uptake into HCs was completely abolished in transmembrane channel-like protein 1 (TMC1) knockout mice, indicating mechanotransducer channel-dependent AG uptake. Blockage of megalin, the candidate AG transporter in the stria vascularis, by binding competitor cilastatin prevented GTTR accumulation in HCs. Furthermore, cilastatin treatment markedly reduced AG-induced HC degeneration and hearing loss in vivo. Together, our in vivo real-time tracking of megalin-dependent AG transport across the blood–labyrinth barrier identifies new therapeutic targets for preventing AG-induced ototoxicity.

Background: Closed-loop neuromodulation systems have received increased attention in recent years as potential therapeutic approaches for treating neurological injury and disease. Objective: The purpose of this study was to assess the ability of intraspinal microstimulation (ISMS), triggered by action potentials (spikes) recorded in motor cortex, to alter synaptic efficacy in descending motor pathways in an anesthetized rat model of spinal cord injury (SCI). Methods: Experiments were carried out in adult, male, Sprague Dawley rats with a moderate contusion injury at T8. For activity-dependent stimulation (ADS) sessions, a recording microelectrode was used to detect neuronal spikes in motor cortex that triggered ISMS in the spinal cord grey matter. SCI rats were randomly assigned to one of four experimental groups differing by: a) cortical spike-ISMS stimulus delay (10 or 25 ms) and b) number of ISMS pulses (1 or 3). Four weeks after SCI, ADS sessions were conducted in three consecutive 1-hour conditioning bouts for a total of 3 hours. At the end of each conditioning bout, changes in synaptic efficacy were assessed using intracortical microstimulation (ICMS) to examine the number of spikes evoked in spinal cord neurons during 5-minute test bouts. A multichannel microelectrode recording array was used to record cortically-evoked spike activity from multiple layers of the spinal cord. Results: The results showed that ADS resulted in an increase in cortically-evoked spikes in spinal cord neurons at specific combinations of spike-ISMS delays and numbers of pulses. Efficacy in descending motor pathways was increased throughout all dorsoventral depths of the hindlimb spinal cord. Conclusions: These results show that after an SCI, ADS can increase synaptic efficacy in spared pathways between motor cortex and spinal cord. This study provides further support for the potential of ADS therapy as an effective method for enhancing descending motor control after SCI.

Alcohol use disorder (AUD) is a chronic relapsing brain disorder characterized by an impaired ability to stop or control alcohol consumption despite adverse social, occupational, or health consequences. AUD affects nearly one-third of adults at some point during their lives, with an associated cost of approximately $249 billion annually in the U.S. alone. The effects of alcohol consumption are expected to increase significantly during the COVID-19 pandemic, with alcohol sales increased by approximately 54%, potentially exacerbating health concerns and risk-taking behaviors. Unfortunately, existing pharmacological and behavioral therapies for AUD have historically been associated with poor success rates, with approximately 40% of individuals relapsing within three years of treatment. Pre-clinical studies have shown that chronic alcohol consumption leads to significant changes in synaptic function within the dorsal medial striatum (DMS), one of the brain regions associated with AUD and responsible for mediating goal-directed behavior. Specifically, chronic alcohol consumption has been associated with hyperactivity of dopamine receptor 1 (D1) medium spiny neurons (MSN) and hypoactivity of dopamine receptor 2 (D1) MSNs within the DMS. Optogenetic, chemogenetic, and transgenic approaches have demonstrated that reducing the D1/D2 MSN signaling imbalance decreases alcohol self-administration in rodent models of AUD. Here, we present an electrical stimulation approach that uses ultra-low (≤ 1Hz) frequency (ULF) spike-timing dependent plasticity (STDP) in mouse models of AUD to reduce DMS D1/D2 MSN signaling imbalances by stimulating D1-MSN afferents into the GPi and ACC glutamatergic projections to the DMS in a time-locked stimulation sequence. Our data suggest that GPi/ACC ULF-STDP selectively decreases DMS D1-MSN hyperactivity leading to reduced alcohol consumption without evoking undesired affective behaviors using electrical stimulation rather than approaches requiring genetic modification. This work represents a step towards fulfilling the unmet need for a reliable method of treating severe AUD through cell-type specific control with clinically available neuromodulation tools.

Ultrasound (US) has been shown to stimulate brain circuits, however, the ability to excite peripheral nerves with US remains controversial. To the best of our knowledge, there is still no in vivo neural recording study that has applied US stimulation to a nerve isolated from surrounding tissue to confirm direct activation effects. Here, we show that US cannot excite an isolated mammalian sciatic nerve in an in vivo preparation, even at high pressures (relative to levels recommended in the FDA guidance for diagnostic ultrasound) and for a wide range of parameters, including different pulse patterns and center frequencies. US can, however, reliably inhibit nerve activity whereby greater suppression is correlated with increases in nerve temperature. By prohibiting the nerve temperature from increasing during US application, we did not observe suppressive effects. Overall, these findings demonstrate that US can reliably inhibit nerve activity through a thermal mechanism that has potential for various health disorders, though future studies are needed to evaluate the long-term safety of therapeutic ultrasound applications.

The ability to determine a sound’s location is critical in everyday life. However, sound source localization is severely compromised for patients with hearing loss who receive bilateral cochlear implants (BiCIs). Several patient factors relate to poorer performance in listeners with BiCIs, associated with auditory deprivation, experience, and age. Critically, characteristic errors are made by patients with BiCIs (e.g., medial responses at lateral target locations), and the relationship between patient factors and the type of errors made by patients has seldom been investigated across individuals. In the present study, several different types of analysis were used to understand localization errors and their relationship with patient-dependent factors (selected based on their robustness of prediction). Binaural hearing experience is required for developing accurate localization skills, auditory deprivation is associated with degradation of the auditory periphery, and aging leads to poorer temporal resolution. Therefore, it was hypothesized that earlier onsets of deafness would be associated with poorer localization acuity and longer periods without BiCI stimulation or older age would lead to greater amounts of variability in localization responses. A novel machine learning approach was introduced to characterize the types of errors made by listeners with BiCIs, making them simple to interpret and generalizable to everyday experience. Sound localization performance was measured in 48 listeners with BiCIs using pink noise trains presented in free-field. Our results suggest that older age at testing and earlier onset of deafness are associated with greater average error, particularly for sound sources near the center of the head, consistent with previous research. The machine learning analysis revealed that variability of localization responses tended to be greater for individuals with earlier compared to later onsets of deafness. These results suggest that early bilateral hearing is essential for best sound source localization outcomes in listeners with BiCIs.

We report on the ensemble organization of interneuronal activity in the spinal cord during locomotor movements and show that lumbar intermediate zone interneurons organize in two groups related to the two major phases of walking: stance and swing. Ensemble organization is also shown to better correlate with muscular output than single-cell activity, although ensemble membership does not appear to be somatotopically organized within the spinal cord.

Novelty detection is a primitive subcomponent of cognitive control that can be deficient in Parkinson's disease (PD) patients. Here, we studied the corticostriatal mechanisms underlying novelty-response deficits. In participants with PD, we recorded from cortical circuits with scalp-based electroencephalography (EEG) and from subcortical circuits using intraoperative neurophysiology during surgeries for implantation of deep brain stimulation (DBS) electrodes. We report three major results. First, novel auditory stimuli triggered midfrontal low-frequency rhythms; of these, 1-4 Hz "delta" rhythms were linked to novelty-associated slowing, whereas 4-7 Hz "theta" rhythms were specifically attenuated in PD. Second, 32% of subthalamic nucleus (STN) neurons were response-modulated; nearly all (94%) of these were also modulated by novel stimuli. Third, response-modulated STN neurons were coherent with midfrontal 1-4 Hz activity. These findings link scalp-based measurements of neural activity with neuronal activity in the STN. Our results provide insight into midfrontal cognitive control mechanisms and how purported hyperdirect frontobasal ganglia circuits evaluate new information.

We tested whether sensitivity to acoustic spectrotemporal modulations can be observed from reaction times for normal-hearing and impaired-hearing conditions. In a manual reaction-time task, normal-hearing listeners had to detect the onset of a ripple (with density between 0–8 cycles/octave and a fixed modulation depth of 50%), that moved up or down the log-frequency axis at constant velocity (between 0–64 Hz), in an otherwise-unmodulated broadband white-noise. Spectral and temporal modulations elicited band-pass filtered sensitivity characteristics, with fastest detection rates around 1 cycle/oct and 32 Hz for normal-hearing conditions. These results closely resemble data from other studies that typically used the modulation-depth threshold as a sensitivity criterion. To simulate hearing-impairment, stimuli were processed with a 6-channel cochlear-implant vocoder, and a hearing-aid simulation that introduced separate spectral smearing and low-pass filtering. Reaction times were always much slower compared to normal hearing, especially for the highest spectral densities. Binaural performance was predicted well by the benchmark race model of binaural independence, which models statistical facilitation of independent monaural channels. For the impaired-hearing simulations this implied a “best-of-both-worlds” principle in which the listeners relied on the hearing-aid ear to detect spectral modulations, and on the cochlear-implant ear for temporal-modulation detection. Although singular-value decomposition indicated that the joint spectrotemporal sensitivity matrix could be largely reconstructed from independent temporal and spectral sensitivity functions, in line with time-spectrum separability, a substantial inseparable spectral-temporal interaction was present in all hearing conditions. These results suggest that the reaction-time task yields a valid and effective objective measure of acoustic spectrotemporal-modulation sensitivity.

Significance Impulsive overeating is a common, disabling feature of eating disorders. Calcium imaging using fiber photometry has emerged as an in vivo methodology to measure neuronal population activity immune to electrical stimulation artifact from deep brain stimulation (DBS). Thus, when used simultaneously, calcium imaging can elucidate poorly understood DBS mechanisms. We show that nucleus accumbens D1 medial spiny calcium signaling increases in preparation of hedonic feeding of high-fat food. Further, responsive, over continuous, DBS strategies effectively disrupt this activity leading to decreased consumption. Implementation of this methodology to better understand mechanisms of these and other forms of neuromodulation for various indications may help advance the field to identify novel therapeutic targets with applications extending beyond obesity.