Electrical Stimulation publications

Background Transcranial electrical stimulation (TES) has limited spatial focus and depth penetration, constraining its therapeutic efficacy. Intersectional Short-Pulse (ISP) stimulation was developed to overcome these limitations by delivering rapidly switching pulses that can be temporally integrated by neuronal membranes. Here, we aimed to establish the biophysical basis of ISP-induced temporal summation and to test whether this mechanism enables effective brain modulation in vivo. Methods We combined finite-element modeling, cadaver measurements ( n = 2 human cadavers), and biophysically realistic NEURON simulations to characterize the spatial and temporal properties of ISP-induced electric fields. In vivo whole-cell patch-clamp recordings were performed in the rat somatosensory cortex (female Wistar rat) to test the membrane-level integration of sequential electric field pulses. Functional efficacy was evaluated using closed-loop ISP stimulation in a hippocampal kindling model of temporal lobe epilepsy in male Long–Evans rats ( n = 11 animals, >500 induced seizures analyzed across conditions). Results Here we show that neurons integrate sequential ISP pulses in a non-vectorial, temporally accumulative manner, consistent with membrane-level charge integration rather than extracellular field superposition. ISP and conventional TES simulations produced similar instantaneous field magnitudes, but ISP stimulation resulted in more uniform neuronal excitability across brain depths. Closed-loop ISP stimulation significantly outperformed conventional TES in reducing seizure duration and severity. ISP reduced hippocampal seizure duration by 45% and 35% compared to SHAM stimulation and conventional TES, and significantly reduced motor seizure severity. Conclusions ISP stimulation provides a non-invasive neuromodulation approach that enhances deep brain engagement through rapid, temporally structured pulse sequences. These findings demonstrate effective seizure suppression in a rodent model and support the translational potential of ISP for disorders involving pathological neural dynamics.

Introduction: Spatial hearing is most accurate using both ears, but accuracy decreases in persons with asymmetrical hearing between ears. In participants with deafness in one ear but normal hearing in the other ear (single-sided deafness [SSD]), this difference can be compensated by a unilateral cochlear implant (CI). It has been shown that a CI can restore sound localization performance, but it is still unclear to what extent auditory spatial discrimination can be improved. Methods: The present study investigated auditory spatial discrimination using minimum audible angles (MAAs) in 18 CI-SSD participants. Results were compared to 120 age-matched normal-hearing (NH) listeners. Low-frequency (LF) and high-frequency (HF) noise bursts were presented from 4°, 30°, and 60° azimuth on the CI side and on the NH side. MAA thresholds were tested for correlation with localization performance in the same participants. Results: There were eight good performers and ten poor performers. There were more poor performers for LF signals than for HF signals. Performance on the CI side was comparable to performance on the NH side. Most difficulties occurred at 4° and at 30°. Eight of the good performers in the localization task were also good performers in the MAA task. Only the localization ability at 4° on the CI side was positively correlated with the MAA at that location. Conclusion: Our data suggest that a CI can restore localization ability but not necessarily auditory spatial discrimination at the same time. The ability to discriminate between adjacent locations may be trainable during rehabilitation to enhance important auditory skills.

Although the etiology of major depressive disorder remains poorly understood, reduced gamma oscillations is an emerging biomarker. Olfactory bulbectomy, an established model of depression that reduces limbic gamma oscillations, suffers from non-specific effects of structural damage. Here, we show that transient functional suppression of olfactory bulb neurons or their piriform cortex efferents decreased gamma oscillation power in limbic areas and induced depression-like behaviors in rodents. Enhancing transmission of gamma oscillations from olfactory bulb to limbic structures by closed-loop electrical neuromodulation alleviated these behaviors. By contrast, silencing gamma transmission by anti-phase closed-loop stimulation strengthened depression-like behaviors in naive animals. These induced behaviors were neutralized by ketamine treatment that restored limbic gamma power. Taken together, our results reveal a causal link between limbic gamma oscillations and depression-like behaviors in rodents. Interfering with these endogenous rhythms can affect behaviors in rodent models of depression, suggesting that restoring gamma oscillations may alleviate depressive symptoms.

There is a weak relationship between clinical and self-reported speech perception outcomes in cochlear implant (CI) listeners. Such poor correspondence may be due to differences in clinical and “real-world” listening environments and stimuli. Speech in the real world is often accompanied by visual cues, background environmental noise, and is generally in a conversational context, all factors that could affect listening demand. Thus, our objectives were to determine if brain responses to naturalistic speech could index speech perception and listening demand in CI users. Accordingly, we recorded high-density electroencephalogram (EEG) while CI users listened/watched a naturalistic stimulus (i.e., the television show, “The Office”). We used continuous EEG to quantify “speech neural tracking” (i.e., TRFs, temporal response functions) to the show’s soundtrack and 8–12 Hz (alpha) brain rhythms commonly related to listening effort. Background noise at three different signal-to-noise ratios (SNRs), +5, +10, and +15 dB were presented to vary the difficulty of following the television show, mimicking a natural noisy environment. The task also included an audio-only (no video) condition. After each condition, participants subjectively rated listening demand and the degree of words and conversations they felt they understood. Fifteen CI users reported progressively higher degrees of listening demand and less words and conversation with increasing background noise. Listening demand and conversation understanding in the audio-only condition was comparable to that of the highest noise condition (+5 dB). Increasing background noise affected speech neural tracking at a group level, in addition to eliciting strong individual differences. Mixed effect modeling showed that listening demand and conversation understanding were correlated to early cortical speech tracking, such that high demand and low conversation understanding occurred with lower amplitude TRFs. In the high noise condition, greater listening demand was negatively correlated to parietal alpha power, where higher demand was related to lower alpha power. No significant correlations were observed between TRF/alpha and clinical speech perception scores. These results are similar to previous findings showing little relationship between clinical speech perception and quality-of-life in CI users. However, physiological responses to complex natural speech may provide an objective measure of aspects of quality-of-life measures like self-perceived listening demand.

Facial nerve (FN) injury can lead to debilitating and permanent facial paresis/paralysis (FP), where facial muscles progressively lose tone, atrophy, and ultimately reduce to scar tissue. Despite considerable efforts in the recent decades, therapies for FP still possess high failure rates and provide inadequate recovery of muscle function. In this pilot study, we used a feline model to demonstrate the potential for chronically implanted multichannel dual-cuff electrodes (MCE) to selectively stimulate injured facial nerves at low current intensities to avoid stimulus-induced neural injury. Selective facial muscle activation was achieved over six months after FN injury and MCE implantation in two domestic shorthaired cats (Felis catus). Through utilization of bipolar stimulation, specific muscles were activated at significantly lower electrical currents than was achievable with single channel stimulation. Moreover, interval increases in subthreshold current intensities using bipolar stimulation enabled a graded EMG voltage response while maintaining muscle selectivity. Histological examination of neural tissue at implant sites showed no appreciable signs of stimulation-induced nerve injury. Thus, by selectively activating facial musculature six months following initial FN injury and MCE implantation, we demonstrated the potential for our neural stimulator system to be safely and effectively applied to the chronic setting, with implications for FP treatment.

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.

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.

Spatial hearing is crucial in real life but deteriorates in participants with severe sensorineural hearing loss or single-sided deafness. This ability can potentially be improved with a unilateral cochlear implant (CI). The present study investigated measures of sound localization in participants with single-sided deafness provided with a CI. Sound localization was measured separately at eight loudspeaker positions (4°, 30°, 60°, and 90°) on the CI side and on the normal-hearing side. Low- and high-frequency noise bursts were used in the tests to investigate possible differences in the processing of interaural time and level differences. Data were compared to normal-hearing adults aged between 20 and 83. In addition, the benefit of the CI in speech understanding in noise was compared to the localization ability. Fifteen out of 18 participants were able to localize signals on the CI side and on the normal-hearing side, although performance was highly variable across participants. Three participants always pointed to the normal-hearing side, irrespective of the location of the signal. The comparison with control data showed that participants had particular difficulties localizing sounds at frontal locations and on the CI side. In contrast to most previous results, participants were able to localize low-frequency signals, although they localized high-frequency signals more accurately. Speech understanding in noise was better with the CI compared to testing without CI, but only at a position where the CI also improved sound localization. Our data suggest that a CI can, to a large extent, restore localization in participants with single-sided deafness. Difficulties may remain at frontal locations and on the CI side. However, speech understanding in noise improves when wearing the CI. The treatment with a CI in these participants might provide real-world benefits, such as improved orientation in traffic and speech understanding in difficult listening situations.

Interactions between the mediodorsal thalamus and the prefrontal cortex are critical for cognition. Studies in humans indicate that these interactions may resolve uncertainty in decision-making 1 , but the precise mechanisms are unknown. Here we identify two distinct mediodorsal projections to the prefrontal cortex that have complementary mechanistic roles in decision-making under uncertainty. Specifically, we found that a dopamine receptor (D2)-expressing projection amplifies prefrontal signals when task inputs are sparse and a kainate receptor (GRIK4) expressing-projection suppresses prefrontal noise when task inputs are dense but conflicting. Collectively, our data suggest that there are distinct brain mechanisms for handling uncertainty due to low signals versus uncertainty due to high noise, and provide a mechanistic entry point for correcting decision-making abnormalities in disorders that have a prominent prefrontal component 2–6 .

Listening to speech in noise is effortful for individuals with hearing loss, even if they have received a hearing prosthesis such as a hearing aid or cochlear implant (CI). At present, little is known about the neural functions that support listening effort. One form of neural activity that has been suggested to reflect listening effort is the power of 8–12 Hz (alpha) oscillations measured by electroencephalography (EEG). Alpha power in two cortical regions has been associated with effortful listening—left inferior frontal gyrus (IFG), and parietal cortex—but these relationships have not been examined in the same listeners. Further, there are few studies available investigating neural correlates of effort in the individuals with cochlear implants. Here we tested 16 CI users in a novel effort-focused speech-in-noise listening paradigm, and confirm a relationship between alpha power and self-reported effort ratings in parietal regions, but not left IFG. The parietal relationship was not linear but quadratic, with alpha power comparatively lower when effort ratings were at the top and bottom of the effort scale, and higher when effort ratings were in the middle of the scale. Results are discussed in terms of cognitive systems that are engaged in difficult listening situations, and the implication for clinical translation.

Hearing impairment disrupts processes of selective attention that help listeners attend to one sound source over competing sounds in the environment. Hearing prostheses (hearing aids and cochlear implants, CIs), do not fully remedy these issues. In normal hearing, mechanisms of selective attention arise through the facilitation and suppression of neural activity that represents sound sources. However, it is unclear how hearing impairment affects these neural processes, which is key to understanding why listening difficulty remains. Here, severely-impaired listeners treated with a CI, and age-matched normal-hearing controls, attended to one of two identical but spatially separated talkers while multichannel EEG was recorded. Whereas neural representations of attended and ignored speech were differentiated at early (~ 150 ms) cortical processing stages in controls, differentiation of talker representations only occurred later (~250 ms) in CI users. CI users, but not controls, also showed evidence for spatial suppression of the ignored talker through lateralized alpha (7–14 Hz) oscillations. However, CI users’ perceptual performance was only predicted by early-stage talker differentiation. We conclude that multi-talker listening difficulty remains for impaired listeners due to deficits in early-stage separation of cortical speech representations, despite neural evidence that they use spatial information to guide selective attention.

Spike-and-wave discharges (SWDs) of absence epilepsy are considered as pathologic alterations of sleep spindles; however, their network-level relationship has never been convincingly revealed. In order to observe the development and generalization of the thalamocortical SWDs and the concomitant alterations of sleep related oscillations, we performed local field potential (LFP) and single unit recordings in rats for three months during their maturation. We found that while SWDs and spindles look similar in young, they become different with maturation and shift to appear in different brain states. Thus, despite being generated by the same network, they are likely two distinct manifestations of the thalamocortical activity. We show that while spindles are already mainly global oscillations, SWDs appear mainly only focally in young. They become capable to generalize later with maturation, when the out-of-focus brain regions develop a decreased inhibitory/excitatory balance. These results suggest that a hyperexcitable focus is not sufficient alone to drive generalized absence seizures. Importantly, we also found the gradual age dependent disappearance of sleep spindles coinciding with the simultaneous gradual emergence of spike and waves, which both could be reversed by the proper dosing of ethosuximide (ETX). Based on these observations we conclude that the absence seizure development might be a multi-step process, which might involve the functional impairment of cortical interneurons and network-level changes that negatively affect sleep quality.

Vocal communication is a sensory-motor process requiring auditory self-monitoring to correct errors and to ensure accurate vocal production. When presented with altered speech feedback, humans rapidly change their speech to compensate. Although previous evidence has demonstrated suppression of auditory cortex during both speech and animal vocalization, the specific role of auditory cortex in such feedback-dependent control is unknown. Here we show the relationship between neural activity in the auditory cortex and feedback-dependent vocal control in marmoset monkeys. We demonstrate that marmosets, like humans, exhibit feedback control of vocal acoustics. We further show that feedback-sensitive activity of auditory cortex neurons predict such compensatory vocal changes. Finally, we demonstrate that electrical microstimulation of auditory cortex rapidly evokes similar changes in vocal production. These results are evidence for a causal role of auditory cortex in vocal self-monitoring and feedback-dependent control, and have implications for understanding human speech motor control.

Closed-loop brain stimulation is a promising alternative to treat drug-resistant epilepsies. In contrast to optogenetic interventions, transcranial electrical stimulation (TES) does not require cellular modification of neurons to be effective, and it is less invasive compared to deep brain stimulation. Furthermore, on-demand TES of targeted brain regions allows the potential for normal function of these networks during interictal periods, a possibility that is eliminated by resective surgical treatment approaches. To further explore the translation of closed-loop TES for treatment of epilepsy, we show here for the first time that unsupervised closed-loop TES in rats can consistently interrupt seizures for 6 weeks and has the potential to control seizure activity up to 4 months (longest periods examined). On-demand TES significantly reduced the time spent in seizure and the individual seizure duration, although significantly higher seizure rate was observed during the treatment. The 6 week long stimulation had no residual adverse effects on the electrophysiologic characteristics of the brain after the termination of the treatment and did not induce glial remodelling in the brain. Our findings demonstrate the safety and effectiveness of minimally invasive, potentially lifelong TES treatment of epilepsy either alone or as a complement to drug treatments.

Auditory information relayed by auditory nerve fibers and somatosensory information relayed by granule cell parallel fibers converge on the fusiform cells (FCs) of the dorsal cochlear nucleus, the first brain station of the auditory pathway. In vitro, parallel fiber synapses on FCs exhibit spike-timing-dependent plasticity with Hebbian learning rules, partially mediated by the NMDA receptor (NMDAr). Well-timed bimodal auditory-somatosensory stimulation, in vivo equivalent of spike-timing-dependent plasticity, can induce stimulus-timing-dependent plasticity (StTDP) of the FCs spontaneous and tone-evoked firing rates. In healthy guinea pigs, the resulting distribution of StTDP learning rules across a FC neural population is dominated by a Hebbian profile while anti-Hebbian, suppressive and enhancing LRs are less frequent. In this study, we investigate in vivo, the NMDAr contribution to FC baseline activity and long term plasticity. We find that blocking the NMDAr decreases the synchronization of FC- spontaneous activity and mediates differential modulation of FC rate-level functions such that low, and high threshold units are more likely to increase, and decrease, respectively, their maximum amplitudes. Three significant alterations in mean learning-rule profiles were identified: transitions from an initial Hebbian profile towards (1) an anti-Hebbian; (2) a suppressive profile; and (3) transitions from an anti-Hebbian to a Hebbian profile. FC units preserving their learning rules showed instead, NMDAr-dependent plasticity to unimodal acoustic stimulation, with persistent depression of tone-evoked responses changing to persistent enhancement following the NMDAr antagonist. These results reveal a crucial role of the NMDAr in mediating FC baseline activity and long-term plasticity which have important implications for signal processing and auditory pathologies related to maladaptive plasticity of dorsal cochlear nucleus circuitry.

Adaptations to an organism's environment often involve sensory system modifications. In this study, we address how evolutionary divergence in sensory perception relates to the physiological coding of stimuli. Mormyrid fishes that can detect subtle variations in electric communication signals encode signal waveform into spike-timing differences between sensory receptors. In contrast, the receptors of species insensitive to waveform variation produce spontaneously oscillating potentials. We found that oscillating receptors respond to electric pulses by resetting their phase, resulting in transient synchrony among receptors that encodes signal timing and location, but not waveform. These receptors were most sensitive to frequencies found only in the collective signals of groups of conspecifics, and this was correlated with increased behavioral responses to these frequencies. Thus, different perceptual capabilities correspond to different receptor physiologies. We hypothesize that these divergent mechanisms represent adaptations for different social environments. Our findings provide the first evidence for sensory coding through oscillatory synchrony.