Electrophysiology publications

Listeners use the spatial location or change in spatial location of coherent acoustic cues to aid in auditory object formation. From stimulus-evoked onset responses in normal-hearing listeners using electroencephalography (EEG), we have previously shown measurable tuning to stimuli changing location in quiet, revealing a potential window into the cortical representations of auditory scene analysis. These earlier studies used non-fluctuating, spectrally narrow stimuli, so it was still unknown whether previous observations would translate to speech stimuli, and whether responses would be preserved for stimuli in the presence of background maskers. To examine the effects that selective auditory attention and interferers have on object formation, we measured cortical responses to speech changing location in the free field with and without background babble (+6 dB SNR) during both passive and active conditions. Active conditions required listeners to respond to the onset of the speech stream when it occurred at a new location, explicitly indicating ‘yes’ or ‘no’ to whether the stimulus occurred at a block-specific location either 30 degrees to the left or right of midline. In the aggregate, results show similar evoked responses to speech stimuli changing location in quiet compared to babble background. However, the effect of the two background environments diverges somewhat when considering the magnitude and direction of the location change and where the subject was attending. In quiet, attention to the right hemifield appeared to evoke a stronger response than attention to the left hemifield when speech shifted in the rightward direction. No such difference was found in babble conditions. Therefore, consistent with challenges associated with cocktail party listening, directed spatial attention could be compromised in the presence of stimulus noise and likely leads to poorer use of spatial cues in auditory streaming.

Differences in the timing and intensity of sounds arriving at the two ears provide fundamental binaural cues that help us localize and segregate sounds in the environment. Neural encoding of these cues is commonly represented asymmetrically in the cortex with stronger activation in the hemisphere contralateral to the perceived spatial location. Although advancing age is known to degrade the perception of binaural cues, less is known about how the neural representation of such cues is impacted by age. Here, we use electroencephalography (EEG) to investigate age-related changes in the hemispheric distribution of interaural time difference (ITD) encoding based on cortical auditory evoked potentials (CAEPs) and derived binaural interaction component (BIC) measures in ten younger and ten older normal-hearing adults. Sensor-level analyses of the CAEP and BIC showed age-related differences in global field power, where older listeners had significantly larger responses than younger for both binaural metrics. Source-level analyses showed hemispheric differences in auditory cortex activity for left and right lateralized stimuli in younger adults, consistent with a contralateral activation model for processing ITDs. Older adults, however, showed reduced hemispheric asymmetry across ITDs, despite having overall larger responses than younger adults. Further, when averaged across ITD condition to evaluate changes in cortical asymmetry over time, there was a significant shift in laterality corresponding to the peak components (P1, N1, P2) in the source waveform that also was affected by age. These novel results demonstrate across-hemisphere cortical dynamics during binaural temporal processing that are altered with advancing age.

The process by which sensory evidence contributes to perceptual choices requires an understanding of its transformation into decision variables. Here, we address this issue by evaluating the neural representation of acoustic information in the auditory cortex-recipient parietal cortex, while gerbils either performed a two-alternative forced-choice auditory discrimination task or while they passively listened to identical acoustic stimuli. During task engagement, stimulus identity decoding performance from simultaneously recorded parietal neurons significantly correlated with psychometric sensitivity. In contrast, decoding performance during passive listening was significantly reduced. Principal component and geometric analyses revealed the emergence of low-dimensional encoding of linearly separable manifolds with respect to stimulus identity and decision, but only during task engagement. These findings confirm that the parietal cortex mediates a transition of acoustic representations into decision-related variables. Finally, using a clustering analysis, we identified three functionally distinct subpopulations of neurons that each encoded task-relevant information during separate temporal segments of a trial. Taken together, our findings demonstrate how parietal cortex neurons integrate and transform encoded auditory information to guide sound-driven perceptual decisions.

The ability to localize a sound source in complex environments is essential for communication and navigation. Spatial hearing relies predominantly on the comparison of differences in the arrival time of sound between the two ears, the interaural time differences (ITDs). Hearing impairments are highly detrimental to sound localization. While cochlear implants (CIs) have been successful in restoring many crucial hearing capabilities, sound localization via ITD detection with bilateral CIs remains poor. The underlying reasons are not well understood. Neuronally, ITD sensitivity is generated by coincidence detection between excitatory and inhibitory inputs from the two ears performed by specialized brainstem neurons. Due to the lack of electrophysiological brainstem recordings during CI stimulation, it is unclear to what extent the apparent deficits are caused by the binaural comparator neurons or arise already on the input level. Here, we use a bottom-up approach to compare response features between electric and acoustic stimulation in an animal model of CI hearing. Conducting extracellular single neuron recordings in gerbils, we find severe hyper-precision and moderate hyper-entrainment of both the excitatory and inhibitory brainstem inputs to the binaural comparator neurons during electrical pulse-train stimulation. This finding establishes conclusively that the binaural processing stage must cope with highly altered input statistics during CI stimulation. To estimate the consequences of these effects on ITD sensitivity, we used a computational model of the auditory brainstem. After tuning the model parameters to match its response properties to our physiological data during either stimulation type, the model predicted that ITD sensitivity to electrical pulses is maintained even for the hyper-precise inputs. However, the model exhibits severely altered spatial sensitivity during electrical stimulation compared to acoustic: while resolution of ITDs near midline was increased, more lateralized adjacent source locations became inseparable. These results directly resemble recent findings in rodent and human CI listeners. Notably, decreasing the phase-locking precision of inputs during electrical stimulation recovered a wider range of separable ITDs. Together, our findings suggest that a central problem underlying the diminished ITD sensitivity in CI users might be the temporal hyper-precision of inputs to the binaural comparator stage induced by electrical stimulation.

There is growing evidence on the efficacy of electrical stimulation delivered via spinal neural interfaces to improve functional recovery following spinal cord injury. For such interfaces, carbon-based neural arrays are fast becoming recognized as a compelling material and platform due to biocompatibility and long-term electrochemical stability. Here, we introduce the design, fabrication, and in vivo characterization of a novel cervical epidural implant with carbon-based surface electrodes. Through finite element analysis and mechanical load tests, we demonstrated that the array could safely withstand loads applied to it during implantation and natural movement of the subject with minimal stress levels. Furthermore, the long-term in vivo performance of this neural array consisting of glassy carbon surface electrodes was investigated through acute and chronic spinal motor evoked potential recordings and electrode impedance tests in rats. We demonstrated stable stimulation performance for at least four weeks in a rat model of spinal cord injury. Lastly, we found that impedance measurements on all carbon-based spinal arrays were generally stable over time up to four weeks after implantation, with a slight increase in impedance in subsequent weeks when tested in spinally injured rats. Taken together, this study demonstrated the potential for carbon-based electrodes as a spinal neural interface to accelerate both mechanistic research and functional restoration in animal models of spinal cord injury.

Sleep is not homogenous but contains a highly diverse microstructural composition influenced by neuromodulators. Prior methods used to measure neuromodulator levels in vivo have been limited by low time resolution or technical difficulties in achieving recordings in a freely moving setting, which is essential for natural sleep. In this protocol, we demonstrate the combination of electroencephalographic (EEG)/electromyographic (EMG) recordings with fiber photometric measurements of fluorescent biosensors for neuromodulators in freely moving mice. This allows for real-time assessment of extracellular neuromodulator levels during distinct phases of sleep with a high temporal resolution.

Considerable work suggests the dominant syllable rhythm of the acoustic envelope is remarkably similar across languages (∼4–5 Hz) and that oscillatory brain activity tracks these quasiperiodic rhythms to facilitate speech processing. However, whether this fundamental periodicity represents a common organizing principle in both auditory and motor systems involved in speech has not been explicitly tested. To evaluate relations between entrainment in the perceptual and production domains, we measured individuals’ (i) neuroacoustic tracking of the EEG to speech trains and their (ii) simultaneous and non-simultaneous productions synchronized to syllable rates between 2.5 and 8.5 Hz. Productions made without concurrent auditory presentation isolated motor speech functions more purely. We show that neural synchronization flexibly adapts to the heard stimuli in a rate-dependent manner, but that phase locking is boosted near ∼4.5 Hz, the purported dominant rate of speech. Cued speech productions (recruit sensorimotor interaction) were optimal between 2.5 and 4.5 Hz, suggesting a low-frequency constraint on motor output and/or sensorimotor integration. In contrast, “pure” motor productions (without concurrent sound cues) were most precisely generated at rates of 4.5 and 5.5 Hz, paralleling the neuroacoustic data. Correlations further revealed strong links between receptive (EEG) and production synchronization abilities; individuals with stronger auditory-perceptual entrainment better matched speech rhythms motorically. Together, our findings support an intimate link between exogenous and endogenous rhythmic processing that is optimized at 4–5 Hz in both auditory and motor systems. Parallels across modalities could result from dynamics of the speech motor system coupled with experience-dependent tuning of the perceptual system via the sensorimotor interface.

The environment noise may disturb animal behavior and echolocation via three potential mechanisms: acoustic masking, reduced attention and noise avoidance. Compared with the mechanisms of reduced attention and noise avoidance, acoustic masking is thought to occur only when the signal and background noise overlap spectrally and temporally. In this study, we investigated the effects of spectrally non-overlapping noise on echolocation pulses and electrophysiological responses of a constant frequency–frequency modulation (CF-FM) bat, Hipposideros pratti. We found that H. pratti called at higher intensities while keeping the CFs of their echolocation pulses consistent. Electrophysiological tests indicated that the noise could decrease auditory sensitivity and sharp intensity tuning, suggesting that spectrally non-overlapping noise imparts an acoustic masking effect. Because anthropogenic noises are usually concentrated at low frequencies and are spectrally non-overlapping with the bat’s echolocation pulses, our results provide further evidence of negative consequences of anthropogenic noise. On this basis, we sound a warning against noise in the foraging habitats of echolocating bats.

We examined the effect of neonatal deafening on frequency-specific pathways for processing of interaural time differences (ITDs) in cochlear-implant stimuli. Animal studies have demonstrated differences in neural ITD sensitivity in the inferior colliculus (IC) depending on the intracochlear location of intracochlear stimulating electrodes. We used neonatally deafened (ND) rats of both sexes and recorded the responses of single neurons in the IC to electrical stimuli with ITDs delivered to the apical or basal cochlea and compared them with acutely deafened (AD) rats of both sexes with normal hearing (NH) during development. We found that neonatal deafness significantly impacted the ITD sensitivity and the ITD tuning patterns restricted to apically driven IC neurons. In ND rats, the ITD sensitivity of apically driven neurons is reduced to values similar to basally driven neurons. The prevalence of ITD-sensitive apical neurons with a peak-shaped ITD tuning curve, which may reflect predominant input from the medial superior olivary (MSO) complex, in ND rats was diminished compared with that in AD rats (67%, AD vs 40%, ND). Conversely, monotonic-type responses rarely occurred in AD rats (14%) but were approximately equally as prevalent as peak-type tuning curves in ND rats (42%). Nevertheless, in ND rats, the ITD at the maximum slope of the ITD tuning curve was still more concentrated within the physiological ITD range in apically driven than in basally driven neurons. These results indicate that the development of high ITD sensitivity processed by low-frequency pathways depends on normal auditory experience and associated biases in ITD tuning strategies.

Human cognitive abilities naturally vary along a spectrum, even among those we call "neurotypical". Individuals differ in their ability to selectively attend to goal-relevant auditory stimuli. We sought to characterize this variability in a cohort of people with diverse attentional functioning. We recruited both neurotypical (N = 20) and ADHD (N = 25) young adults, all with normal hearing. Participants listened to one of three concurrent, spatially separated speech streams and reported the order of the syllables in that stream while we recorded electroencephalography (EEG). We tested both the ability to sustain attentional focus on a single "Target" stream and the ability to monitor the Target but flexibly either ignore or switch attention to an unpredictable "Interrupter" stream from another direction that sometimes appeared. Although differences in both stimulus structure and task demands affected behavioral performance, ADHD status did not. In both groups, the Interrupter evoked larger neural responses when it was to be attended compared to when it was irrelevant, including for the P3a "reorienting" response previously described as involuntary. This attentional modulation was weaker in ADHD listeners, even though their behavioral performance was the same. Across the entire cohort, individual performance correlated with the degree of top-down modulation of neural responses. These results demonstrate that listeners differ in their ability to modulate neural representations of sound based on task goals, while suggesting that adults with ADHD may have weaker volitional control of attentional processes than their neurotypical counterparts.

RESUMO Objetivo analisar o efeito do mascaramento estável e modulado no Potencial Evocado Auditivo Cortical com estímulo de fala em adultos-jovens. Método participaram 14 indivíduos com idades entre 19 e 28 anos de ambos os sexos e sem perda auditiva. O exame de Potencial Evocado Auditivo Cortical foi realizado com estímulo de fala sintética /ba/ simultâneo ao ruído Speech Shaped Noise apresentado em três condições: ruído estável com intensidade de 30 dB NPSpe (ruído estável fraco), ruído estável com intensidade de 65 dB NPSpe (ruído estável forte) e ruído modulado em intensidade de 30 dB NPSpe e 65 dB NPSpe em 25Hz e com período de modulação de 40 ms. Resultados foram observadas maiores latências nos componentes corticais, exceto P2, na condição de ruído estável forte e medidas mais robustas de amplitude dos componentes corticais P1, N1 e P2 na condição de ruído modulado com diferença estatística significativa na comparação com a condição de ruído estável forte. Houve pior morfologia na condição de ruído estável forte, quando comparado aos demais registros. Os limiares eletrofisiológicos médios para as condições de ruído estável forte e ruído modulado foram 60 dB NPSpe e 49 dB NPSpe, respectivamente, mostrando 11,7 dB de diferença média. Conclusão podemos inferir que houve um menor efeito mascarante do ruído modulado, comparado à condição de ruído estável forte, nas medidas de amplitude dos componentes corticais e uma diferença média de 11,7 dB entre os limiares eletrofisiológicos (interpretado como a medida do Benefício do Mascaramento Modulado).

The lateral septum (LS) is a forebrain structure that has been implicated in a wide range of behavioral and physiological responses to stress. However, the specific populations of neurons in the LS that mediate stress responses remain incompletely understood. Here, we show that neurons in the dorsal lateral septum (LSd) that express the somatostatin gene (hereafter, LSdSst neurons) are activated by diverse stressors. Retrograde tracing from LSdSst neurons revealed that these neurons are directly innervated by neurons in the locus coeruleus (LC), the primary source of norepinephrine well-known to mediate diverse stress-related functions in the brain. Consistently, we found that norepinephrine increased excitatory synaptic transmission onto LSdSst neurons, suggesting the functional connectivity between LSdSst neurons and LC noradrenergic neurons. However, optogenetic stimulation of LSdSst neurons did not affect stress-related behaviors or autonomic functions, likely owing to the functional heterogeneity within this population. Together, our findings show that LSdSst neurons are activated by diverse stressors and suggest that norepinephrine released from the LC may modulate the activity of LSdSst neurons under stressful circumstances.

Spinal cord injury (SCI) frequently results in complete, permanent paralysis. Although it is possible to reverse the effects of incomplete paralysis, complete paralysis effects are permanent. At present, there is no cure for SCI, but engineers can bypass the spinal cord and restore the connection from the brain to the muscles through brain-machine or brain-computer interfaces (BMIs or BCIs). These experiments initially began with rodents and non-human primates (NHPs), which were trained to move cursors, joysticks or robots with their minds beginning in the 20th century. Research progressed to human clinical trials in the late 20th century. In this paper, I present the work done to train a new NHP model for behavioural experiments, how these NHPs were trained, and the neurophysiology involved in training BMI algorithms. With this knowledge, we then moved to non-invasive human clinical trials, in which 8 SCI and 6 control subjects were able to control the opening and closing of their hands with a BCI system using electroencephalographic (EEG) signals from the motor cortex. Finally, we used these algorithms with a SCI subject in an invasive human clinical trial. The subject successfully completed activities of daily living (ADLs) and was able to control an ambulatory device that enabled him to walk upright. The overall accuracy for the BMI was approximately 90% for the upper extremity task and 85% for the lower extremity task. In addition, the subject improved in performance and speed on the Jebsen Hand Function Test (JHFT) during the 20 weeks of the study. Our subject was then sent home with a mechanical glove to continue performing upper-extremity ADLs in the home environment.

Hearing loss is a major health problem and psychological burden in humans. Mouse models offer a possibility to elucidate genes involved in the underlying developmental and pathophysiological mechanisms of hearing impairment. To this end, large-scale mouse phenotyping programs include auditory phenotyping of single-gene knockout mouse lines. Using the auditory brainstem response (ABR) procedure, the German Mouse Clinic and similar facilities worldwide have produced large, uniform data sets of averaged ABR raw data of mutant and wildtype mice. In the course of standard ABR analysis, hearing thresholds are assessed visually by trained staff from series of signal curves of increasing sound pressure level. This is time-consuming and prone to be biased by the reader as well as the graphical display quality and scale.In an attempt to reduce workload and improve quality and reproducibility, we developed and compared two methods for automated hearing threshold identification from averaged ABR raw data: a supervised approach involving two combined neural networks trained on human-generated labels and a self-supervised approach, which exploits the signal power spectrum and combines random forest sound level estimation with a piece-wise curve fitting algorithm for threshold finding.We show that both models work well and are suitable for fast, reliable, and unbiased hearing threshold detection and quality control. In a high-throughput mouse phenotyping environment, both methods perform well as part of an automated end-to-end screening pipeline to detect candidate genes for hearing involvement. Code for both models as well as data used for this work are freely available.

Broadly congruent mirror neurons, responding to any grasp movement, and strictly congruent mirror neurons, responding only to specific grasp movements, have been reported in single-cell studies with primates. Delineating grasp properties in humans is essential to understand the human mirror neuron system with implications for behavior and social cognition. We analyzed electrocorticography data from a natural reach-and-grasp movement observation and delayed imitation task with 3 different natural grasp types of everyday objects. We focused on the classification of grasp types from high-frequency broadband mirror activation patterns found in classic mirror system areas, including sensorimotor, supplementary motor, inferior frontal, and parietal cortices. Classification of grasp types was successful during movement observation and execution intervals but not during movement retention. Our grasp type classification from combined and single mirror electrodes provides evidence for grasp-congruent activity in the human mirror neuron system potentially arising from strictly congruent mirror neurons.

Evoked neural responses to sensory stimuli have been extensively investigated in humans and animal models both to enhance our understanding of brain function and to aid in clinical diagnosis of neurological and neuropsychiatric conditions. Recording and imaging techniques such as electroencephalography (EEG), magnetoencephalography (MEG), local field potentials (LFPs), and calcium imaging provide complementary information about different aspects of brain activity at different spatial and temporal scales. Modeling and simulations provide a way to integrate these different types of information to clarify underlying neural mechanisms. In this study, we aimed to shed light on the neural dynamics underlying auditory evoked responses by fitting a rate-based model to LFPs recorded via multi-contact electrodes which simultaneously sampled neural activity across cortical laminae. Recordings included neural population responses to best-frequency (BF) and non-BF tones at four representative sites in primary auditory cortex (A1) of awake monkeys. The model considered major neural populations of excitatory, parvalbumin-expressing (PV), and somatostatin-expressing (SOM) neurons across layers 2/3, 4, and 5/6. Unknown parameters, including the connection strength between the populations, were fitted to the data. Our results revealed similar population dynamics, fitted model parameters, predicted equivalent current dipoles (ECD), tuning curves, and lateral inhibition profiles across recording sites and animals, in spite of quite different extracellular current distributions. We found that PV firing rates were higher in BF than in non-BF responses, mainly due to different strengths of tonotopic thalamic input, whereas SOM firing rates were higher in non-BF than in BF responses due to lateral inhibition. In conclusion, we demonstrate the feasibility of the model-fitting approach in identifying the contributions of cell-type specific population activity to stimulus-evoked LFPs across cortical laminae, providing a foundation for further investigations into the dynamics of neural circuits underlying cortical sensory processing.

Cardiac arrest (CA) remains the leading cause of coma, and early arousal recovery indicators are needed to allocate critical care resources properly. High-frequency oscillations (HFOs) of somatosensory evoked potentials (SSEPs) have been shown to indicate responsive wakefulness days following CA. Nonetheless, their potential in the acute recovery phase, where the injury is reversible, has not been tested. We hypothesize that time-frequency (TF) analysis of HFOs can determine arousal recovery in the acute recovery phase. To test our hypothesis, eleven adult male Wistar rats were subjected to asphyxial CA (five with 3-min mild and six with 7-min moderate to severe CA) and SSEPs were recorded for 60 min post-resuscitation. Arousal level was quantified by the neurological deficit scale (NDS) at 4 h. Our results demonstrated that continuous wavelet transform (CWT) of SSEPs localizes HFOs in the TF domain under baseline conditions. The energy dispersed immediately after injury and gradually recovered. We proposed a novel TF-domain measure of HFO: the total power in the normal time-frequency space (NTFS) of HFO. We found that the NTFS power significantly separated the favorable and unfavorable outcome groups. We conclude that the NTFS power of HFOs provides earlier and objective determination of arousal recovery after CA.

Noninvasive electronic bone growth stimulators (EBGSs) have been in clinical use for decades. However, systematic reviews show inconsistent and limited clinical efficacy. Further, noninvasive EBGS studies in small animals, where the stimulation electrode is closer to the fracture site, have shown promising efficacy, which has not translated to large animals or humans. We propose that this is due to the weaker electric fields reaching the fracture site when scaling from small animals to large animals and humans. To address this gap, we measured the electric field strength reaching the bone during noninvasive EBGS therapy in human and sheep cadaver legs and in finite element method (FEM) models of human and sheep legs. During application of 1100 V/m with an external EBGS, only 21 V/m reached the fracture site in humans. Substantially weaker electric fields reached the fracture site during the later stages of healing and at increased bone depths. To augment the electric field strength reaching the fracture site during noninvasive EBGS therapy, we introduced the Injectrode, an injectable electrode that spans the distance between the bone and subcutaneous tissue. Our study lays the groundwork to improve the efficacy of noninvasive EBGSs by increasing the electric field strength reaching the fracture site.

Microglia are critical regulators of brain development that engulf synaptic proteins during postnatal synapse remodeling. However, the mechanisms through which microglia sense the brain environment are not well defined. Here, we characterized the regulatory program downstream of interleukin-33 (IL-33), a cytokine that promotes microglial synapse remodeling. Exposing the developing brain to a supraphysiological dose of IL-33 altered the microglial enhancer landscape and increased binding of stimulus-dependent transcription factors including AP-1/FOS. This induced a gene expression program enriched for the expression of pattern recognition receptors, including the scavenger receptor MARCO. CNS-specific deletion of IL-33 led to increased excitatory/inhibitory synaptic balance, spontaneous absence-like epileptiform activity in juvenile mice, and increased seizure susceptibility in response to chemoconvulsants. We found that MARCO promoted synapse engulfment, and Marco-deficient animals had excess thalamic excitatory synapses and increased seizure susceptibility. Taken together, these data define coordinated epigenetic and functional changes in microglia and uncover pattern recognition receptors as potential regulators of postnatal synaptic refinement.