Electrophysiology publications

The limitations of electrical neuromodulation are driving the development of neuroprosthetic systems enhanced with complementary modalities. A key technological challenge however remains the integration of the necessary hardware components (optical, thermal, fluidic, electrical) into miniaturized implants. Here we present a design framework, inspired by fast prototyping, that promises to reduce the complexity, fabrication time, and device bulk of multimodal neural interface systems. By combining extrusion‐based 3D printing of silicones and discrete electronic components, we integrated thermal neuromodulation and electrical recording capabilities in soft packages suitable for placement on the cortical surface of rodents. When linked to an autonomous auxiliary driver unit, these packages establish rapid, stable and localized hypothermia together with ElectroCorticoGraphy (ECoG) recording. In a rodent model of epilepsy (4‐aminopyridine), we demonstrate hypothermia‐induced suppression of seizure‐like activity. Our approach may advance the clinical translation of focal hypothermia as an alternative therapy for drug‐resistant focal epilepsies.

The inferior colliculus (IC) is a major midbrain convergence site critical for processing complex sounds and undergoes fundamental changes with age-related hearing loss (ARHL). Local field potentials (LFPs) represent pre-synaptic integration of excitatory and inhibitory signals in local neural populations. Here, we assessed age-related changes in sound-evoked IC LFPs in the CBA/CaJ mouse model of ARHL across the tonotopic axis. We recorded from 495 sites across four age groups (young: 4-6 months; middle: 8-14 months; old: 24-25 months; “oldest old”: 27-31 months), examining LFP responses from dorsal (low-frequency), medial (mid-frequency), and ventral (high-frequency) IC regions. Analysis of the onset depolarization (N1 component) in response to broadband noise bursts revealed significant age-related hyperexcitability in medial and dorsal regions, with oldest old animals showing enhanced responses while ventral regions were unaffected. Amplitude-intensity functions demonstrated significant age × level interactions across all regions, with oldest old animals exhibiting level-dependent hyperexcitability most pronounced at suprathreshold intensities. Time-frequency analysis of LFP spectral content (30-100 Hz) revealed a crossover pattern across medial and dorsal regions, with oldest old animals showing reduced power at low-to-moderate stimulus levels but enhanced power at high stimulus levels. Ventral regions showed a low-level reduction without suprathreshold enhancement. These findings reveal paradoxical enhancement of neural activity in the aging IC, with the most pronounced changes in dorsal and medial regions rather than ventral regions most affected by peripheral hearing loss, suggesting that central hyperexcitability depends on residual afferent drive and implicating region-specific alterations in excitatory-inhibitory balance underlying central presbycusis.

Auditory hypersensitivity or decreased sound tolerance is a common phenotype of Fragile X Syndrome (FXS). Impairments in adaptation, defined as the reduction in the neuronal responsiveness to repeating sounds, can contribute to this prevalent phenotype. Previous studies on event-related potential observed impairments in mismatch negativity (MMN) in both FXS individuals and in the FMR1 -knockout (KO) mouse model of FXS. Therefore, in the present study we characterized stimulus-specific adaptation (SSA), a neural correlate of MMN, at the auditory cortex (AC) of anesthetized (with ketamine/xylazine) female and male postnatal day 20 (P20) wild-type (WT) and FMR1 -KO mice, using the oddball paradigm with either 4 Hz or 1 Hz repetition rate. We observed robust SSA at the 4 Hz repetition rate of the oddball paradigm in the AC neurons of all four groups of animals. We also noted that the strength of SSA diminished between 4 to 1 Hz repetition rate. In addition, at both the 4 Hz and 1 Hz repetition rate, reduced SSA was observed particularly in the male FMR1 -KO mice compared to their WT counterparts, while female WT and FMR1 -KO mice displayed similar SSA. In terms of sex differences, male FMR1 -KO mice had lower SSA than female FMR1 -KO mice, while SSA was similar in male and female WT mice. Overall, our observation of reduced SSA in the male FMR1 -KO mice suggests that impairments in neuronal adaptation potentially contribute to the auditory hypersensitivity phenotype particularly within the male population.

The brain computes sound location from auditory spatial cues. Humans and barn owls both localize sounds accurately, yet they rely on fundamentally different cue configurations shaped by their ear anatomy and neural circuitry. In humans, symmetrical ears provide interaural time and level differences (ITD and ILD) for horizontal localization, while vertical localization depends primarily on high‐frequency, monaural spectral cues generated by the pinnae. Barn owls, by contrast, possess asymmetrical ears and use binaural cues for both azimuth and elevation. Because auditory pathways are tuned to species‐specific cue statistics, it remains unclear whether humans can adapt when binaural level cues are also made informative about elevation. We tested this by fitting human listeners with asymmetric ear molds that disrupted normal spectral cues, introduced elevation‐dependent ILDs, and left ITDs unaffected. Participants wore the molds during daily life and were tested with broadband, high‐pass, and low‐pass noise bursts. Acute mold exposure severely degraded elevation localization, whereas horizontal localization remained largely unaffected. With prolonged exposure, elevation localization improved, but adaptation was limited, variable across listeners, and fluctuated across sessions. Improvement was strongest for broadband sounds. Because broadband and high‐pass sounds both contained high‐frequency information, this broadband advantage cannot be explained by access to additional spectral cues alone. Instead, it suggests that low‐frequency ITDs helped listeners exploit the altered binaural cue structure, including the elevation‐dependent ILDs introduced by the molds. These findings show that humans can partially adapt to asymmetric outer‐ear acoustics when complementary spatial cues help resolve ambiguity in the altered cue structure.

Interpersonal coordination is fundamental to social evolution. We investigate its phenomenology and neural underpinnings in humans and macaques, examining the behavioral adaptations required for mutual coordination during motor interactions and the extent to which the underlying brain mechanisms are shared across species. Using a common interpersonal coordination paradigm, we conducted functional magnetic resonance imaging (fMRI) in humans and intracranial local field potential (LFP) recordings in macaques. Despite between-species behavioral discrepancies, both monkeys and humans coordinate through adjustments that proved to be based on proactive adaptation of motor planning and execution. Evidence from fMRI and time-resolved decoding analysis of LFPs converged to show modulation of premotor brain activity associated with interpersonal coordination and its effectiveness. Moreover, a dynamic sequential coding emerged, whereby the action context is represented early during planning, and coordination features near movement onset. Our findings reveal an evolutionarily conserved cortical architecture across primates that supports cooperative motor behavior.

Background Peripheral hearing loss is associated with auditory hallucinations and increased risk for psychotic disorder, particularly in genetically vulnerable individuals. Moreover, both hearing loss and schizophrenia disrupt auditory temporal acuity, a sensitive measure of auditory brain function. Here, we used mouse models of hearing loss and schizophrenia to reveal how neural mechanisms of auditory cortical temporal acuity depend on sensory and genetic risk factors for psychosis. Methods We quantified auditory cortical temporal acuity in mice with or without hearing loss and with or without the 22q11.2 deletion — one of the strongest known genetic risk factors for schizophrenia. Cortical single-unit and population activity were recorded in awake mice (N = 23) during presentations of loudness-adjusted gap-in-noise stimuli with varying durations of silent gap, which are commonly used to assess auditory temporal acuity in humans. Results Both hearing loss and the 22q11.2 deletion disrupted auditory cortical temporal acuity, but through distinct mechanisms. Hearing loss broadly degraded temporal acuity at the level of single-unit responses and neural population activity. In contrast, the 22q11.2 deletion selectively impaired gap duration thresholds in regular-spiking (putative excitatory) but not fast-spiking (putative inhibitory) neurons. Mice with comorbid hearing loss and 22q11.2 deletion exhibited both abnormalities in auditory cortical temporal acuity. Conclusions Sensory and genetic risk factors for psychosis can disrupt auditory cortical temporal acuity via distinct mechanisms that remain partially dissociable even under comorbid conditions. These findings underscore the importance of accounting for hearing loss comorbidity when interpreting auditory cortical dysfunction in psychotic disorder.

Humans localise sounds in the horizontal plane by processing level and timing differences between the ears. This neurocomputational process is continuously and adaptively calibrated using visual input, as seen in the ventriloquism aftereffect: a shift in sound perception toward a previously seen light. It is unknown from where in the brain this aftereffect originates; adaptation could occur at an early level in the auditory system where neurons are narrowly tuned to frequency, at a later level in the auditory system where localisation cues are extracted, or outside the auditory system at a higher-level spatial map. To investigate this, we examined how the ventriloquism aftereffect generalises across sound frequencies. Participants localised seven narrowband sounds (0.5–8 kHz), targeting different localisation cues. We found that sound localisation accuracy in darkness varied slightly with frequency. When sounds were paired with a visual stimulus that was offset by 10 deg, participants exhibited a pronounced bias toward the light of about ~ 63%, corresponding to the well-known ventriloquism effect. The bias was stronger for narrowband compared to broadband sounds. After exposure to a block of these audiovisual stimuli, a ventriloquism aftereffect in the form of a spatial bias of ~ 12% was observed across all tested frequencies, largely independent of the frequency of the exposure sound. Together with earlier reports of both frequency-specific and frequency-general recalibration, our results indicate that under conditions of a fixed and consistent audiovisual spatial offset, the ventriloquism aftereffect generalises across sound frequencies, consistent with adaptation at a frequency-independent multisensory spatial stage.

This work presents three open datasets featuring various levels of processing, containing neural recordings from the auditory cortex of rats. These recordings were obtained during experiments using the auditory oddball paradigm before, during and after the local microiontophoretic application of acetylcholine. The primary objective of these datasets is to investigate how the brain processes predictable versus unexpected auditory stimuli, and the role of cholinergic inputs during such processing. The data include multi-unit recordings of neuronal activity during the presentation of standard and deviant tones, classified by stimulus type and cortical sub-region. These resources enable quantitative investigations of deviance detection, stimulus-specific adaptation, cholinergic modulation and predictive-coding mechanisms at multiple temporal scales.

Spatial disorientation is emerging as an early cognitive biomarker of dementia, but the underlying neural mechanisms remain undefined. The anterodorsal nucleus of the thalamus (ADn) exhibits early and selective vulnerability to pathological misfolded forms of tau, a major hallmark of Alzheimer's disease. As the ADn contains a high density of head direction (HD) cells, we hypothesized that ptau disrupts HD cell activity, promoting spatial disorientation. To test this, we virally expressed human mutant tau in the ADn of adult wild-type and C1ql2-Cre mice. ADn-tau mice were defined by phosphorylated and oligomeric forms of tau in ADn somata and axon terminals. During initial spatial learning, ADn-tau mice exhibited increased looping behavior, indicative of spatial disorientation. Using in vivo extracellular recordings, we found that ADn cells had reduced directionality, lower directional coherence, and altered burst firing. These findings suggest that early alterations in HD signaling are predictive of future cognitive decline.

Impulsivity is a core pathological feature of various psychiatric disorders including obsessive‐compulsive disorder, attention‐deficit/hyperactivity disorder, and schizophrenia, which is conceptualized as dysregulated motivational and inhibitory processes. However, the underlying neural mechanism is poorly known. Using an olfactory cued Go/No‐Go task, this work finds increased false alarm rate, shortened licking onset latency, elevated licking frequency and reduced inter‐trial consistency in mice treated by the NMDAR antagonist (MK‐801). Fiber optic recordings reveal MK‐801 enhanced cue‐evoked neuronal responses in the olfactory bulb (OB), orbitofrontal cortex (OFC), ventral tegmental area (VTA), and nucleus accumbens (NAc), while reducing reward‐predictive cue selectivity and increasing NAc dopamine release. Additionally, in vivo electrophysiological recordings demonstrate that theta oscillation power in the NAc and its coherence with OB, OFC, and VTA are also amplified. MK‐801 treatment enhances the correlation between firing rates of NAc neurons and cue, decreases the association with reward, strengthens the correlation with licking and increases the probability of firing peak preceding lick onset. Furthermore, this work confirms that the application of the trace amine‐associated receptor 1 agonist SEP‐363856 could correct the abnormal responses of NAc neurons and behavioral deficits. These findings elucidate the neural basis of impulsivity and support the potential therapeutic effect of SEP.

Autism is an early‐onset neurodevelopmental disorder characterized by restricted, repetitive behaviors and atypical patterns of social communication and interaction. A considerable proportion of autistic individuals experience divergent auditory perception, which can interfere with their ability to navigate everyday sound environments. Auditory brainstem responses are electrophysiological potentials elicited by auditory stimuli that evaluate neural activity along the auditory nerve and brainstem. Importantly, the auditory brainstem response varies by sex, with females typically showing higher amplitudes and shorter latencies than males. This sex‐specific neurophysiological profile is especially relevant in autism research, where the male‐to‐female diagnosis ratio is approximately 3:1. Thus, exploring the neurobiological mechanisms underlying sex‐specific variations in autistic traits is essential. Furthermore, autism sensory profiles may vary based on the independent and mutual effects of environmental and genetic factors. To deepen this understanding, we examined auditory brainstem responses in two rat models of autism: the GRIN2B rare mutation model and the prenatal valproic acid induction model, alongside control animals. We assessed peak amplitudes and latencies (Waves I through V), inter‐peak intervals (I–III, I–V, and III–V), and amplitude ratios (III:I, V:I, and V:III). Female rats generally exhibited greater amplitudes and longer latencies across waveforms. Regarding rat models, control animals consistently showed larger amplitudes and shorter latencies compared to autism‐like models. Exploratory analyses further suggested pairwise interactions between sex and rat model, indicating modulation of auditory phenotypes linked to autism. Thus, our findings reveal key insights into the effects of sex and rat model, as well as their interactions.

Introduction Prenatal exposure to valproic acid (VPA) is a common environmental cause of autism spectrum disorder (ASD) and often leads to expressive and receptive language impairments. Similar communication difficulties among individuals with ASD are often linked to abnormal subcortical and cortical sound processing. Rodents prenatally exposed to VPA exhibit degraded cortical responses to speech and an impaired ability to behaviorally discriminate speech sounds. Methods We sought to determine whether sound processing could be restored with paired vagus nerve stimulation (VNS). In a first experiment, we evaluated whether sound-paired VNS would alter in vivo extracellular multi-unit responses to tones, noise burst trains, and speech sounds from the anterior auditory field. We next sought to evaluate whether improvements to neural sound processing led to improvements in sound discrimination ability. In a second experiment, rats underwent go/no-go sound discrimination testing where VNS was paired with successful trials. Results We found that VPA-exposed rats had degraded spectral, temporal, and speech sound processing compared to saline-exposed control rats. VPA-exposed rats which received sound-paired VNS exhibited a partial or full restoration of processing across sound types. However, across several sound discrimination tasks, we did not observe changes in behavioral performance in response to prenatal exposure to VPA or VNS. Discussion Our study is the first to show that speech-paired VNS leads to a generalized improvement in cortical sound processing across sound types, rescuing neural processing among VPA-exposed rats. These results provide a framework for future studies to develop VNS-based interventions for communication disorders.

The mediodorsal thalamic nucleus (MD) forms neural circuits with various brain regions, including the prefrontal cortex (PFC), the reticular thalamic nucleus (TRN), and the midbrain reticular nucleus (MRN). However, the specific roles and underlying mechanisms in auditory information processing remain unclear. Here, we perform multi-channel electrophysiological recordings in awake mice to investigate the response patterns of the MD to auditory stimuli, as well as the regulatory effects of PFC, MRN, and TRN inputs. We identify two distinct types of sound-evoked responses. The Phasic-response features a transient burst firing to the stimulus with short latency, rapidly adapting to baseline and corresponding to the onset fluctuation of the local field potential. The Sustained-response is marked by prolonged firing with longer latency and is accompanied by persistent enhancement of oscillatory power following stimulus offset. The response patterns of MD neurons remain consistent across different types of auditory stimuli. Optogenetic inactivation of the MRN suppresses both response types in the MD. The Sustained-response is attenuated by PFC inactivation but enhanced by TRN inactivation, while the Phasic-response remains unaffected by inactivation of either the PFC or TRN. Our findings expand the understanding of the MD's role in sound information integration and auditory cognitive regulation.

During sleep, behavioral responsiveness to external stimuli is decreased. This classical definition of sleep has been applied effectively across the animal kingdom to identify this common behavioral state in a growing list of creatures, from mammals to invertebrates. Yet, it remains unclear whether decreased behavioral responsiveness during sleep is necessarily associated with decreased responsiveness in brain activity, especially in insects. Here, we performed long-term multichannel electrophysiology in tethered Drosophila melanogaster flies exposed continuously to repetitive visual stimuli. Flies were still able to sleep under these visual stimulation conditions, as determined by traditional immobility duration criteria for the field. Interestingly, we did not find any difference between responses to repetitive visual stimuli during sleep compared with wake when we recorded local field potentials (LFPs) across a transect of the fly brain from optic lobes to the central brain. However, we did find LFP responses to be altered when visual stimuli were variable and of lower probability, especially in the central brain. Central brain responses to less predictable or ‘deviant’ stimuli were lower during the deepest stage of sleep, a time of quiescence characterized by more regular proboscis extensions. This shows that the sleeping fly brain processes low-probability visual stimuli in a different way from more repeated stimuli, and presents Drosophila as a promising model for studying the potential role of sleep in regulating predictive processing.

Simultaneous fiber photometry and optogenetics is a powerful emerging technique for precisely studying the interactions of neuronal brain networks. However, spectral overlap between photometry and optogenetic components has severely limited the application of an all-optical approach. Due to spectral overlap, light from optogenetic stimulation saturates the photosensor and occludes photometry fluorescence, which is especially problematic in physically smaller model organism brains like mice. Here, we demonstrate the multi-frequency interpolation X-talk removal algorithm (MuFIX or μFIX) for recovering crosstalk-contaminated photometry responses recorded with lock-in amplification. μFIX exploits multifrequency lock-in amplification by modeling the remaining uncontaminated data to interpolate across crosstalk-affected segments (R2 ≈ 1.0); we found that this approach accurately recovers the original photometry response after demodulation (Pearson's r ≈ 1.0). When applied to crosstalk-contaminated data, μFIX recovered a photometry response closely resembling the dynamics of noncrosstalk photometry recorded simultaneously. Upon further verification using simulated and empirical data, we demonstrated that μFIX reproduces any signal that underwent simulated crosstalk contamination (r ≈ 1.0). We believe adopting μFIX will enable experimental designs using simultaneous fiber photometry and optogenetics that were previously not feasible due to crosstalk.

In bats, which express a complex vocal repertoire and are considered vocal learners, the frontal auditory field (FAF) is supposedly placed in a frontal cortico‐striatal network for vocal–motor control. The FAF receives input from the auditory cortex (AC) and other auditory nuclei via multiple pathways. However, not much is known about the transition of information on vocalizations from the AC to the FAF. The bat AC consists of different subfields, among which the dorsal fields (dAC) are characterized by precise coding of the temporal envelope of vocalizations. The dAC should, therefore, be a major source of auditory feedback information about self‐produced or perceived vocalizations to the FAF. Our study aimed to investigate the specificity of encoding for different types of vocalizations in FAF and dAC neurons. Using extracellular recordings in anesthetized Phyllostomus discolor , we describe basic response properties in both cortical areas and compare responses to different types of prerecorded vocalizations. The specificity of encoding for different behaviorally relevant call categories and single calls was higher in dAC than in FAF neurons, both in terms of temporal firing patterns and response strength. These findings highlight the importance of the dAC in the neural network for control of vocal communication in bats.

Noise exposure is one of the most common causes of hearing loss and hyperacusis. Studies have shown that noise exposure can induce a cortical gain to compensate for reduced input of the cochlea, which may contribute to the increased sound sensitivity. However, many people with hyperacusis have no measurable cochlear lesion after being exposed to loud sound. In this experiment, we studied the neurological alterations in the cortical and subcortical areas following a prolonged moderate level of noise exposure (84 dB SPL, 8 h/day for 4 weeks) in the laboratory mice. The cochlear function was monitored by auditory brainstem responses (ABRs). The behavioral auditory sensitivity and temporal processing were evaluated using the acoustic startle response (ASR) and gap‐induced prepulse inhibition (gap‐PPI). The central auditory functions were determined by electrophysiological recordings of the inferior colliculus (IC) and the auditory cortex (AC). Our results showed that although there was no significant difference in the ABR thresholds, the noise group showed enhanced ASR and gap‐PPI compared to the control group. Increased neural activity in both the IC and the AC was recorded in the noise‐exposed mice compared to the control group, suggesting a central gain in both the subcortical and cortical regions. The current source density (CSD) analysis of the AC response revealed an increased columnar excitation and reduced corticocortical projection in the noise group, different from the central gain model of noise‐induced hearing loss. Our results suggest that chronic “nondestructive” noise can increase the gain of the central auditory system by altering the balance of auditory thalamocortical and intracortical inputs, which may contribute to the increased sound sensitivity in people with normal hearing.

This study involves longitudinal neuro-electrophysiological analysis using motor-evoked potentials (MEP) and the Basso, Beattie, and Bresnahan behavioral examinations (BBB) to evaluate moderate mid-thoracic contusive spinal cord injury (SCI) in a rat model. Objectives/Background: The objective of the study is to characterize the onset and progression of contusive SCI over an eight-week period using a clinically applicable tool in an in vivo model. The background highlights the importance of a reliable and reproducible injury model and assessment tools for SCI. Methods: The methods section describes the experimental setup, including randomly assigned rats in three groups: Sham, Control, and Injury (undergoing a moderate contusive SCI using the NYU-Impactor). MEP monitoring and BBB examinations are conducted at baseline and weekly for eight weeks post-injury. Results: The results indicate that the relative MEP power spectral decreased to 11% and 22% in the left and right hindlimbs, respectively, during the first week post-SCI. In the second week, a slight spontaneous recovery was observed, reaching 17% in the left and 31% in the right hindlimbs. Over the following four weeks post-SCI, continuing deterioration of MEP signal power was observed with no detectable recovery. Conclusions: SCI attenuates hindlimb MEP power spectral and reduces locomotion, though the changes in MEP and locomotion exhibit distinct temporal patterns. The MEP monitoring provides valuable insights into the functional integrity of motor pathways following SCI and offer a sensitive and reliable assessment. By implementing MEP monitoring, researchers can track the progression of SCI and evaluate the efficacy of therapeutic interventions quantitatively.

Tinnitus has been identified as a potential contributor to anxiety. Thalamo-cortical pathway plays a crucial role in the transmission of auditory and emotional information, but its casual link to tinnitus-associated anxiety remains unclear. In this study, we explore the neural activities in the thalamus and cortex of the sodium salicylate (NaSal)-treated mice, which exhibit both hyperacusis and anxiety-like behaviors. We find an increase in gamma band oscillations (GBO) in both auditory cortex (AC) and prefrontal cortex (PFC), as well as phase-locking between cortical GBO and thalamic neural activity. These changes are attributable to a suppression of GABAergic neuron activity in thalamic reticular nucleus (TRN), and optogenetic activation of TRN reduces NaSal-induced hyperacusis and anxiety-like behaviors. The elevation of endocannabinoid (eCB)/ cannabinoid receptor 1 (CB1R) transmission in TRN contributes to the NaSal-induced abnormalities. Our results highlight the regulative role of TRN in the auditory and limbic thalamic-cortical pathways.

This study aimed to investigate the effects of the intravenous administration of lidocaine in the auditory cortex after the systemic administration of salicylate. Healthy male albino Hartley guinea pigs were divided into two groups. The control group received only lidocaine, whereas the experimental group received lidocaine after checking for the effects of salicylate. Extracellular recordings of spikes in the primary auditory cortex and dorsocaudal areas in healthy albino Hartley guinea pigs were continuously documented (pre- and post-lidocaine, pre- and post-salicylate, and post-salicylate after adding lidocaine to post-salicylate). We recorded 160 single units in the primary auditory cortex from five guinea pigs and 155 single units in the dorsocaudal area from another five guinea pigs to confirm the effects of lidocaine on untreated animals. No significant change was detected in either the threshold or Q 10dB value after lidocaine administration in the primary auditory cortex and dorsocaudal areas. Spontaneous firing activity significantly decreased after lidocaine administration in the primary auditory cortex and dorsocaudal areas. Next, we recorded 160 single units in the primary auditory cortex from five guinea pigs and 137 single units in the dorsocaudal area from another five guinea pigs to determine the effects of lidocaine on salicylate-treated animals. The threshold was significantly elevated after salicylate administration; however, no additional change was detected after adding lidocaine to the primary auditory cortex and dorsocaudal areas. Regarding the Q 10dB value, lidocaine negated the significant changes induced by salicylate in the primary auditory cortex and dorsocaudal areas. Moreover, lidocaine negated the significant changes in spontaneous firing activities induced by salicylate in the primary auditory cortex and dorsocaudal areas. In conclusion, changes in the Q 10dB value and spontaneous firing activities induced by salicylate administration are abolished by lidocaine administration, suggesting that these changes are related to the presence of tinnitus.