Electrophysiology publications

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.

In this study, we examined the relatively unexplored realm of face perception, investigating the activities within human brain face-selective regions during the observation of faces at both subordinate and superordinate levels. We recorded intracranial EEG signals from the ventral temporal cortex in neurosurgical patients implanted with subdural electrodes during viewing of face subcategories (human, mammal, bird, and marine faces) as well as various non-face control stimuli. The results revealed a noteworthy correlation in response patterns across all face-selective areas in the ventral temporal cortex, not only within the same face category but also extending to different face categories. Intriguingly, we observed a systematic decrease in response correlation coupled with an increased response onset time from human face to mammalian face, bird face and marine faces. Our result aligns with the notion that distinctions at the basic level category (e.g., human face versus non-human face) emerges earlier than those at the superordinate level (e.g., animate versus inanimate). This indicates response gradient in the representation of facial images within human face-sensitive regions, transitioning progressively from human faces to non-face stimuli. Our findings provide insights into spatiotemporal dynamic of face representations which varies spatially and at different timescales depending on the face subcategory represented.

Pairing vagus nerve stimulation (VNS) with sounds has improved auditory processing in the auditory cortex of normal-hearing rats and autism models of rats. This study tests the ability of VNS-sound pairing to restore auditory processing in the inferior colliculus (IC) of valproic acid (VPA)-exposed rats. Pairing VNS with tones significantly reversed the degraded sound processing in the IC in VPA-exposed rats. The findings provide evidence that auditory processing in autism rat models can be improved through VNS.

Objective: To analyze the Benefit of Modulated Masking (BMM) on hearing in young, adult and elderly normal-hearing individuals. Methods: The sample included 60 normal-hearing individuals aged 18-75 years who underwent behavioral assessment (sentence recognition test in the presence of steady and modulated noise) and electrophysiological assessment (cortical Auditory Evoked Potential) to investigate BMM. The results were analyzed comparatively using the paired t-test and ANOVA for repeated measures, followed by the Bonferroni post-hoc test (p-value < 0.05). Results: A decrease in latencies and an increase in amplitudes of cortical components (P1-N1-P2) was observed due to noise modulation in all age groups. Modulated noise generated better auditory threshold responses (electrophysiological and behavioral), compared to steady noise. The elderly presented a higher threshold in both hearing domains, compared to the other participants, as well as a lower BMM magnitude. Conclusion: It was possible to conclude that the modulated noise generated less interference in the magnitude of the neural response (smaller latencies) and in the neural processing time (larger amplitudes) for the speech stimulus in all participants. The higher auditory thresholds (electrophysiological and behavioral) and the lower BMM magnitude observed in the elderly group, even in the face of noise modulation, suggest a lower temporal auditory performance in this population, and may indicate a deficit in the temporal resolution capacity, associated with the process of aging. Level of evidence: 3:

Impaired sleep is a common aspect of aging and often precedes the onset of Alzheimer's disease. Here, we compare the effects of sleep deprivation in young wild-type mice and their APP/PS1 littermates, a murine model of Alzheimer's disease. After 7 h of sleep deprivation, both genotypes exhibit an increase in EEG slow-wave activity. However, only the wild-type mice demonstrate an increase in the power of infraslow norepinephrine oscillations, which are characteristic of healthy non-rapid eye movement sleep. Notably, the APP/PS1 mice fail to enhance norepinephrine oscillations 24 h after sleep deprivation, coinciding with an accumulation of cerebral amyloid-β protein. Proteome analysis of cerebrospinal fluid and extracellular fluid further supports these findings by showing altered protein clearance in APP/PS1 mice. We propose that the suppression of infraslow norepinephrine oscillations following sleep deprivation contributes to increased vulnerability to sleep loss and heightens the risk of developing amyloid pathology in early stages of Alzheimer's disease.

The goal of the present study was to determine, through a detailed study of the auditory brainstem response (ABR) waves, the possible existence of an early functional marker for the onset of presbycusis in an animal model. Toward this goal, Wistar rats were divided into four age groups: 3-month-old (3M, n = 6, control), 9-month-old (9M, n = 6), 14-month-old (14M, n = 6), and 20-month-old (20M, n = 6). ABR recordings were performed at 0.5, 1, 2, 4, 8, 16, and 32 kHz. The novel result reported here is that wave amplitudes, particularly wave II, were significantly diminished in the 9M group, even though there was no evidence of significant age-related threshold shift at that age. A significant increase in auditory thresholds with age was first detected at 14M, which further progressed at 20M, confirming our previous findings. These findings suggest that measurable alterations in ABR waves may precede age-related threshold shift and could serve as early markers to detect the onset of age-related hearing loss. Upon translation to humans, they could be used to implement early objective diagnosis, crucial to prevent or mitigate the negative consequences of presbycusis, a common, progressive, and irreversible neurodegenerative age-related disorder. This may allow, for instance, a better preservation of residual hearing, thus delaying the progression of the disease and minimizing the impact of hearing loss, ultimately improving the quality of life for those who suffer from this neurodegenerative condition.

Introduction In primary auditory cortex (A1), nicotinic acetylcholine receptors (nAChRs) containing α2 subunits are expressed in layer 5 Martinotti cells (MCs)—inhibitory interneurons that send a main axon to superficial layers to inhibit distal apical dendrites of pyramidal cells (PCs). MCs also contact interneurons in supragranular layers that, in turn, inhibit PCs. Thus, MCs may regulate PCs via inhibition and disinhibition, respectively, of distal and proximal apical dendrites. Auditory inputs to PCs include thalamocortical inputs to middle layers relaying information about characteristic frequency (CF) and near-CF stimuli, and intracortical long-distance (“horizontal”) projections to multiple layers carrying information about spectrally distant (“nonCF”) stimuli. CF and nonCF inputs integrate to create broad frequency receptive fields (RFs). Systemic administration of nicotine activates nAChRs to “sharpen” RFs—to increase gain within a narrowed RF—resulting in enhanced responses to CF stimuli and reduced responses to nonCF stimuli. While nicotinic mechanisms to increase gain have been identified, the mechanism underlying RF narrowing is unknown. Methods Here, we examine the role of α2 nAChRs in mice with α2 nAChR-expressing neurons labeled fluorescently, and in mice with α2 nAChRs genetically deleted. Results The distribution of fluorescent neurons in auditory cortex was consistent with previous studies demonstrating α2 nAChRs in layer 5 MCs, including nonpyramidal somata in layer 5 and dense processes in layer 1. We also observed label in subcortical auditory regions, including processes, but no somata, in the medial geniculate body, and both fibers and somata in the inferior colliculus. Using electrophysiological (current-source density) recordings in α2 nAChR knock-out mice, we found that systemic nicotine failed to enhance CF-evoked inputs to layer 4, suggesting a role for subcortical α2 nAChRs, and failed to reduce nonCF-evoked responses, suggesting that α2 nAChRs regulate horizontal projections to produce RF narrowing. Discussion The results support the hypothesis that α2 nAChRs function to simultaneously enhance RF gain and narrow RF breadth in A1. Notably, a similar neural circuit may recur throughout cortex and hippocampus, suggesting widespread conserved functions regulated by α2 nAChRs.

Myh1 is a mouse deafness gene with an unknown function in the auditory system. Hearing loss in Myh1 -knockout mice is characterized by an elevated threshold for the auditory brainstem response and the absence of a threshold for distortion product otoacoustic emission. Here, we investigated the role of MYH1 in outer hair cells (OHCs), crucial structures in the organ of Corti responsible for regulating cochlear amplification. Direct whole-cell voltage-clamp recordings of OHCs revealed that prestin activity was lower in Myh1 -knockout mice than in wild-type mice, indicating abnormal OHC electromotility. We analyzed whole-exome sequencing data from 437 patients with hearing loss of unknown genetic causes and identified biallelic missense variants of MYH1 in five unrelated families. Hearing loss in individuals harboring biallelic MYH1 variants was non-progressive, with an onset ranging from congenital to childhood. Three of five individuals with MYH1 variants displayed osteopenia. Structural prediction by AlphaFold2 followed by molecular dynamic simulations revealed that the identified variants presented structural abnormalities compared with wild-type MYH1. In a heterogeneous overexpression system, MYH1 variants, particularly those in the head domain, abolished MYH1 functions, such as by increasing prestin activity and modulating the membrane traction force. Overall, our findings suggest an essential function of MYH1 in OHCs, as observed in Myh1-deficient mice, and provide genetic evidence linking biallelic MYH1 variants to autosomal recessive hearing loss in humans.

Otolithic endorgans such as the saccule were thought to be strictly vestibular in amniotes (reptiles, birds, and mammals), with little evidence supporting the auditory function found in fish and amphibians (frogs and salamanders). Here, we demonstrate an auditory role for the saccule in the tokay gecko (Gekko gecko). The nucleus vestibularis ovalis (VeO) in the hindbrain exclusively receives input from the saccule and projects to the auditory midbrain, the torus semicircularis, via an ascending pathway parallel to cochlear pathways. Single-unit recordings show that VeO is exquisitely sensitive to low-frequency vibrations. Moreover, VeO is present in other lepidosaurs, including snakes and Sphenodon. These findings indicate that the ancestral auditory function of the saccule is likely preserved at least in the lepidosaurian lineage of amniotes and mediates sensitive encoding of vibration. VIDEO ABSTRACT.

Leptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass by regulating the activity of specific neural populations controlling appetite and metabolism 1 . Leptin regulates food intake by inhibiting orexigenic agouti-related protein (AGRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons 2 . However, whereas AGRP neurons regulate food intake on a rapid time scale, acute activation of POMC neurons has only a minimal effect 3–5 . This has raised the possibility that there is a heretofore unidentified leptin-regulated neural population that rapidly suppresses appetite. Here we report the discovery of a new population of leptin-target neurons expressing basonuclin 2 ( Bnc2 ) in the arcuate nucleus that acutely suppress appetite by directly inhibiting AGRP neurons. Opposite to the effect of AGRP activation, BNC2 neuronal activation elicited a place preference indicative of positive valence in hungry but not fed mice. The activity of BNC2 neurons is modulated by leptin, sensory food cues and nutritional status. Finally, deleting leptin receptors in BNC2 neurons caused marked hyperphagia and obesity, similar to that observed in a leptin receptor knockout in AGRP neurons. These data indicate that BNC2-expressing neurons are a key component of the neural circuit that maintains energy balance, thus filling an important gap in our understanding of the regulation of food intake and leptin action.

Barn owls enable investigation of neural mechanisms underlying stimulus selection of concurrent stimuli. The audiovisual space map in the optic tectum (OT), avian homolog of the superior colliculus, encodes relative strength of concurrent auditory stimuli through spike response rate and interneuronal spike train synchrony (STS). Open questions remain regarding stimulus selection in downstream forebrain regions lacking topographic coding of auditory space, including the functional consequences of interneuronal STS on interregional signaling. To this end, we presented concurrent stimuli at different locations and manipulated relative strength while simultaneously recording neural responses from OT and its downstream thalamic target, nucleus rotundus (nRt), in awake barn owls of both sexes. Results demonstrated that broadly spatially tuned nRt units exhibit different spike response patterns to competition depending on spatial tuning preferences. Modeling suggests nRt units integrate convergent inputs from distant locations across midbrain map regions. Additionally, STS within nRt reflects the temporal properties of the strongest stimulus. Furthermore, interregional STS between OT and nRt was strongest when spatial tuning overlap between units across regions was large and when the strongest stimulus location during competition was favorable for units in both regions. Additionally, though gamma oscillations synthesized within OT are weakly propagated within nRt, average gamma power across regions correlates with strength of interregional STS. Overall, we demonstrate that nRt integrates inputs across distant areas of OT, retains spatial information through differences in strength of inputs from various locations of the midbrain map across neurons, and prioritizes coding of identity features to the strongest sound.

Background: Many studies have demonstrated the benefits of long-term music training (i.e., musicianship) on the neural processing of sound, including simple tones and speech. However, the effects of musicianship on the encoding of simultaneously presented pitches, in the form of complex musical chords, is less well established. Presumably, musicians’ stronger familiarity and active experience with tonal music might enhance harmonic pitch representations, perhaps in an attention-dependent manner. Additionally, attention might influence chordal encoding differently across the auditory system. To this end, we explored the effects of long-term music training and attention on the processing of musical chords at the brainstem and cortical levels. Method: Young adult participants were separated into musician and nonmusician groups based on the extent of formal music training. While recording EEG, listeners heard isolated musical triads that differed only in the chordal third: major, minor, and detuned (4% sharper third from major). Participants were asked to correctly identify chords via key press during active stimulus blocks and watched a silent movie during passive blocks. We logged behavioral identification accuracy and reaction times and calculated information transfer based on the behavioral chord confusion patterns. EEG data were analyzed separately to distinguish between cortical (event-related potential, ERP) and subcortical (frequency-following response, FFR) evoked responses. Results: We found musicians were (expectedly) more accurate, though not faster, than nonmusicians in chordal identification. For subcortical FFRs, responses showed stimulus chord effects but no group differences. However, for cortical ERPs, whereas musicians displayed P2 (~150 ms) responses that were invariant to attention, nonmusicians displayed reduced P2 during passive listening. Listeners’ degree of behavioral information transfer (i.e., success in distinguishing chords) was also better in musicians and correlated with their neural differentiation of chords in the ERPs (but not high-frequency FFRs). Conclusions: Our preliminary results suggest long-term music training strengthens even the passive cortical processing of musical sounds, supporting more automated brain processing of musical chords with less reliance on attention. Our results also suggest that the degree to which listeners can behaviorally distinguish chordal triads is directly related to their neural specificity to musical sounds primarily at cortical rather than subcortical levels. FFR attention effects were likely not observed due to the use of high-frequency stimuli (>220 Hz), which restrict FFRs to brainstem sources.

The human auditory cortex is organized according to the timing and spectral characteristics of speech sounds during speech perception. During listening, the posterior superior temporal gyrus is organized according to onset responses, which segment acoustic boundaries in speech, and sustained responses, which further process phonological content. When we speak, the auditory system is actively processing the sound of our own voice to detect and correct speech errors in real time. This manifests in neural recordings as suppression of auditory responses during speech production compared with perception, but whether this differentially affects the onset and sustained temporal profiles is not known. Here, we investigated this question using intracranial EEG recorded from seventeen pediatric, adolescent, and adult patients with medication-resistant epilepsy while they performed a reading/listening task. We identified onset and sustained responses to speech in the bilateral auditory cortex and observed a selective suppression of onset responses during speech production. We conclude that onset responses provide a temporal landmark during speech perception that is redundant with forward prediction during speech production and are therefore suppressed. Phonological feature tuning in these “onset suppression” electrodes remained stable between perception and production. Notably, auditory onset responses and phonological feature tuning were present in the posterior insula during both speech perception and production, suggesting an anatomically and functionally separate auditory processing zone that we believe to be involved in multisensory integration during speech perception and feedback control.

Micro-electrocorticography (µECoG) electrodes have emerged to balance the trade-off between invasiveness and signal quality in brain recordings. However, its large-scale applicability is still hindered by a lack of comparative studies assessing the relationship between ECoG and traditional recording methods such as penetrating electrodes. This study aimed to compare somatosensory evoked potentials (SEPs) through the lenses of a µECoG and an intracortical microelectrode array (MEA). The electrodes were implanted in the pig’s primary somatosensory cortex, while SEPs were generated by applying electrical stimulation to the ulnar nerve. The SEP amplitude, signal-to-noise ratio (SNR), power spectral density (PSD), and correlation structure were analysed. Overall, SEPs resulting from MEA recordings had higher amplitudes and contained significantly more spectral power, especially at higher frequencies. However, the SNRs were similar between the interfaces. These results demonstrate the feasibility of using µECoG to decode SEPs with wide-range applications in physiology monitoring and brain–computer interfaces.

Cortical feedback connections are extremely numerous but the logic of connectivity between higher and lower areas remains poorly understood. Feedback from higher visual areas to primary visual cortex (V1) has been shown to enhance responses on perceptual figures compared to backgrounds, an effect known as figure-background modulation (FBM). A likely source of this feedback are border-ownership (BO) selective cells in mid-tier visual areas (e.g. V4) which represent the location of figures. We examined the connectivity between V4 cells and V1 cells using noise-correlations and micro-stimulation to estimate connectivity strength. We show that connectivity is consistent with a model in which BO-tuned V4 cells send positive feedback in the direction of their preferred figure and negative feedback in the opposite direction. This connectivity scheme can recreate patterns of FBM observed in previous studies. These results provide insights into the cortical connectivity underlying figure-background perception and establish a link between FBM and BO-tuning.

Animal vocalizations and human speech are typically characterized by a complex spectrotemporal structure, composed of multiple harmonics, and patterned as temporally organized sequences. However, auditory research often employed simple artificial acoustic stimuli or their combinations. Here we addressed the question of whether the neuronal responses to natural echolocation call sequences can be predicted by manipulated sequences of incomplete constituents at the midbrain inferior colliculus (IC). We characterized the extracellular single-unit activity of IC neurons in the great roundleaf bat, Hipposideros armiger (both sexes), using natural call sequences, various manipulated sequences of incomplete vocalizations, and pure tones. We report that approximately two-thirds of IC neurons exhibited a harmonic interaction. Neurons with high harmonic interactions exhibited greater selectivity to natural call sequences, and the degree of harmonic interaction was robust to the natural amplitude variations between call harmonics. For 81% of the IC neurons, the responses to the natural echolocation call sequence could not be predicted by altered sequences of missing call components. Surprisingly, nearly 70% of the neurons that showed a harmonic interaction were characterized by a single excitatory response peak as revealed by pure tones. Our results suggest that prevalent harmonic processing has already emerged in the auditory midbrain IC in the echolocating bat.

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.

Offset responses are traditionally viewed as indicators of sound cessation. Here, we investigate offset responses to auditory click trains, examining how they are modulated by inter-click intervals (ICIs) and train duration. Using extracellular recordings and electrocorticography (ECoG) in non-human primates, alongside electroencephalography (EEG) in humans, we show that offset responses are significantly influenced by both ICI and train length, thereby establishing them as markers of temporal integration. We introduce the concept of the 'Neuronal Integrative Window' (NIW), defined as the temporal span during which neurons integrate stimuli to produce or modulate the temporal integration signal. Our data reveal that on the neuronal level, the auditory cortex (AC) exhibits a more expansive NIW than the medial geniculate body (MGB), integrating stimuli over longer durations and showing a preference for larger ICIs. Furthermore, our results indicate that offset responses could serve as potential biomarkers for neurological and psychiatric conditions, highlighted by their sensitivity to pharmacological modulation with ketamine. This study advances our understanding of auditory temporal processing and proposes a novel approach for assessing and monitoring brain health.

Anesthesia modifies sensory representations in the thalamo-cortical circuit but is considered to have a milder impact on peripheral sensory processing. Here, tracking the same neurons across wakefulness and isoflurane or ketamine medetomidine anesthesia, we show that the amplitude and sign of single neuron responses to sounds are massively modified by anesthesia in the cochlear nucleus of the brainstem, the first relay of the auditory system. The reorganization of activity is so profound that decoding of sound representation under anesthesia is not possible based on awake activity. However, population-level parameters, such as average tuning strength and population decoding accuracy, are weakly affected by anesthesia, explaining why its effect has previously gone unnoticed when comparing independently sampled neurons. Together, our results indicate that the functional organization of the auditory brainstem largely depends on the network state and is ill-defined under anesthesia. This demonstrates a remarkable sensitivity of an early sensory stage to anesthesia, which is bound to disrupt downstream processing.

Neural hyperexcitability of the central auditory system is a key pathological characteristic of tinnitus, but its underlying molecular mechanisms remain elusive. The large-conductance Ca2+-activated K+ channel (BK) plays a crucial role in down- or upregulating neuronal activity. This study aims to investigate the role of BK channels in mediating tinnitus-associated neural hyperexcitability and elucidate the mechanisms behind it. Immunofluorescent staining revealed extensive expression of the BK channels on neurons within the central auditory system of rats. After long-term systemic administration of salicylate, a stable tinnitus inducer, we observed a significant change in the expression levels of BKα and β4 subunits in the rat central auditory system. In addition, salicylate was found to enhance the outward potassium currents mediated by the BK channel when exogenously expressed in HEK293 cells. Interestingly, this effect could be blocked by ryanodine, a potent inhibitor of ryanodine receptors (RyRs). Molecular docking identified Gln4020 within the central domain of RyR as a key residue in RyR-salicylate interactions. The results indicated that salicylate might directly activate RyRs leading to Ca2+ release from endoplasmic reticulum, and increased BK currents subsequently. Systemic treatment with paxilline, a potent blocker of BK channel, selectively reversed the increased P4/P1 amplitude ratios in the frequency region of tinnitus perception induced by single-dose salicylate administration. These results suggest that BK channels and ryanodine receptors may play a selective role in salicylate-induced tinnitus.