Publications using the RX6

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.

In nature, animals learn to replace predisposed behaviors with new strategies, yet the neural constraints on these transitions are unclear. Using an ethological search task in mice, we reveal medial prefrontal cortical (mPFC) neural correlates of a predisposed win-stay strategy that decays as animals learn to follow a more reliable auditory cue. Auditory cortex (ACx) activity predicts correct trial-by-trial sound-guided search, even on day one of training. This prognostic coding strengthens with learning and emerges from suppressed spiking, most pronounced in neurons tuned laterally to the cue’s spectrum. Chemogenetic disruption reveals ACx contributions to improving performance. Unexpectedly, the global silencing of mPFC accelerates successful usage of sound-tracking, contrary to its canonical role in flexible or stimulus-dependent behavior. Instead, a decentralized multiexpert competition model best predicts behavior and causal perturbations. These findings suggest that mPFC implements a default strategy based on prior knowledge, which actively hinders the expression of more efficient strategies.

Platinum electrodes are used in many bionic devices; however, they have limited charge injection capacity (CIC) and signal‐to‐noise ratio (SNR), restricting performance. Iridium oxide has substantially larger CIC and reduced impedance compared to platinum. While these types of electrochemical measurements are typically used to infer improved electrophysiological performance, there are no studies demonstrating this correlation. This article compares the electrochemical and acute electrophysiological recording performance of iridium and electrochemically activated IrOx. Increased iridium activation reduced total impedance at low‐intermediate frequencies and steady‐state electroactive area but had no impact on linear diffusion electroactive area. The total impedance had a poor correlation with background noise, SNR and spike count. The results contribute to the previous literature indicating linear diffusion electroactive area determines the number of neurons within recording distance of the electrode, impacting SNR and spike count. Measurements of impedance are mainly of benefit as an indirect measure of linear diffusion electroactive area, in which case the measurement and analysis must be performed appropriately. A wide range of IrOx activation states can be produced with increased CIC, without concern of neural recording performance impacts. However, higher oxidation states resulting in electrode dissolution or increase in electrode resistance may limit IrOx chronic performance.

Auditory brainstem response (ABR) recordings are widely used in neuroscience as a cross-species translational tool to evaluate hearing sensitivity and auditory processing. In animal models, ABR recordings typically require the use of anesthesia to minimize myogenic artifacts, necessitating the development of anesthetic regimens that balance safety, adequate immobilization, and preservation of neural responses. Using a within-subject design in male and female Long-Evans rats, this study systematically evaluated the safety and auditory signal fidelity of five anesthetic regimens -ketamine/xylazine (K/X), ketamine/dexmedetomidine (K/D), dexmedetomidine alone (DEX), dexmedetomidine plus low dose (0.5%) isoflurane (D/I), and high dose (2%) isoflurane (ISO). Anesthetic safety and efficacy were assessed by induction time, recovery time, blood oxygen saturation (SpO₂), and survival rate. ABR signal quality was quantified by threshold, signal strength, wave amplitude, wave latency, and inter-trial phase coherence. K/X anesthesia produced ABRs with low thresholds and well-defined waveforms, but also exhibited the least favorable safety profile, with prolonged recovery times and reduced survival rates. Conversely, isoflurane regimens (ISO and D/I) had a favorable safety profile but significantly elevated thresholds and degraded ABR signal quality, even at low doses. K/D and DEX achieved survival and recovery outcomes equal to or better than conventional anesthetics (K/X and ISO) while also preserving ABR waveform morphology and trial-to-trial reliability. Together, these results highlight dexmedetomidine, particularly when combined with ketamine, as a safe and effective anesthetic for ABR recordings that preserves key metrics of auditory sensitivity and signal integrity.

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.

How neuronal firing within a circuit encodes behavioural intensity, like running speed, is largely unknown. Projections from temporal association cortex (TeA) and superior colliculus (SC) to dorsal periaqueductal grey (dPAG) circuit can both trigger running behaviour. Using in vivo loose-patch recordings with circuit manipulations in mice, we quantified a firing - speed relationship and established its encoding model. Here, we report two behavioural patterns induced by circuit activation: backing away and rebound running. Mechanistically, dPAG CaMKIIα neurons receiving inputs from either TeA or SC, function as distinct “behavioural units”, controlling two “unit behaviours” of running and backing away, respectively. The unidirectional inhibition from the backing away unit to the running unit is mediated by somatostatin (SOM) neurons in dPAG, enabling transitions among four behavioural states: running, backing away, stopping, and rebound running. Both running and backing away behaviours follow a unified motor encoding model, quantified by a single-phase association equation.

A central goal in neuroscience is to clarify how neural circuits translate sensory input into adaptive behaviours. Although unisensory evoked escape circuits in mice are well defined, it remains unclear whether a single nucleus contains specialized sensory, sensory‒motor decision, and motor command neurons for escapes driven by distinct sensory cues, and how these neurons form functional microcircuits. Using multiple sensory stimuli in mice, we identified the temporal association cortex (TeA) as a critical escape hub. Combining in vivo electrophysiology, optogenetics and chemogenetics, we characterized three distinct neuron subtypes within TeA layer 5 (L5) CaMKII neurons that correspond to these three functional classes. Intratelencephalic (IT) neurons serve as sensory‒motor decision neurons, while layer matched pyramidal tract (PT) neurons projecting to the dorsal periaqueductal grey (dPAG) act as motor command neurons. We reveal a laminar IT–PT microcircuit that converts sensory input into sensory-motor decisions and commands for escape locomotion.

In the auditory cortex, neural responses to stimuli inside receptive fields (RFs) can be further facilitated by behavioral demands, such as attending to a spatial location. It is less clear how off-RF stimuli modulate neural responses and contribute to behavioral tasks. Our recent study revealed a particular form of location-specific facilitation evoked by repeated stimulation from an off-RF location, suggesting behavioral modulation of spatial RFs. To further explore this question, we trained marmosets to attend to sound locations that were either inside or outside the RFs of auditory cortical neurons. The majority of neurons showed increased firing rates at target locations inside their RFs. Interestingly, this increase also occurred outside the RFs, sometimes exceeding the responses at the RF center during passive listening. This task-related off-RF facilitation was much more common in the caudal area than in the rostral area and the primary auditory cortex. A normalization model reproduced the off-RF facilitation using widespread suppression. The model’s prediction was confirmed by experimental observations of widespread reductions in firing rate and hyperpolarized membrane potentials for off-RF stimuli. These results suggest that behavioral task demands recruit a broader range of neurons than those that are responsive to a target sound in the passive state.

A major threat to the declining European hedgehog (Erinaceus europaeus) is road traffic. Devising methods to reduce the number of collisions would increase hedgehog welfare in an urbanized world and serve to protect this flagship species, and this goal might be advanced by an understanding of their hearing. This study investigates the auditory capabilities and anatomy of the ear of the European hedgehog. Using auditory brainstem response testing on 20 live hedgehogs from Danish wildlife rescue centres, we measured hearing thresholds across 4–85 kHz and found a peak sensitivity around 40 kHz, revealing that European hedgehogs can hear sound frequencies of at least 4–85 kHz. Complementary postmortem micro-CT scans enabled a detailed three-dimensional reconstruction of the inner ear, revealing small middle ear bones with a cochlear spiral of approximately 1.7 turns. Results show that hedgehogs can perceive a broad ultrasonic range, which provides important cues for directional hearing and may additionally function in prey detection and communication. These findings provide critical insights into hedgehog sensory biology and inform the potential development of ultrasonic repellents to mitigate traffic collisions and habitat disturbances, contributing to conservation strategies for this declining species.

The acoustic flutter is processed through complementary monotonic rate coding and cannot be modulated by other acoustic parameters in the auditory cortex (AC). However, it remains unclear how the inferior colliculus (IC) encodes acoustic flutter, especially when changing other acoustic parameters. Here, we recorded IC neural activity in response to acoustic flutter and determined the existence of conjunctive processing between repetition rate and other acoustic parameters. We found that most IC neurons also encode the repetition rate at the flutter range through complementary monotonic rate coding. In addition, although the acoustic parameters did not change their monotonicity, most IC neurons encode both repetition rate and other acoustic parameters, different from the flutter processing in AC. Thus, complementary monotonic rate coding for acoustic flutter was widespread in the auditory system; however, coding specificity for repetition rate increased from IC to AC, and the capacity for conjunctive coding with other acoustic parameters decreased.

It is widely accepted that tinnitus arises from maladaptive neuroplasticity in the central auditory system, which compensates for reduced peripheral input; notably, the loss of inner hair cell (IHC) synapses is considered a key underlying factor. IHC synapses can immediately and permanently degenerate after noise exposure, independent of hair cell loss, whereas the cell bodies and central projections of cochlear neurons can survive for months to years, providing an extended therapeutic window for improving afferent input through synapse regeneration. Using NHPN-1010 (a combination of 2,4-disulfophenyl-N-tert-butylnitrone and N-acetylcysteine), we propose a delayed treatment strategy (≥ 4 weeks after trauma) for noise-induced tinnitus (NIT) in rats. NHPN-1010 enhanced gap-prepulse inhibition of acoustic startle responses-indicative of diminished tinnitus-like deficits-coupled with a concomitant upregulation of GABAergic inhibition in the dorsal cochlear nucleus, relative to vehicle alone (saline). Furthermore, NHPN-1010, compared to saline, led to increased wave-I amplitudes of auditory brainstem responses, the effect accompanied by a corresponding rise in the number of presynaptic ribbons in IHCs. Our findings suggest that NHPN-1010 plays a therapeutic role in NIT by promoting cochlear synaptogenesis and normalizing central auditory signaling.

Harmonicity is a property of complex sounds such as vocalizations or music, but it remains unclear how harmonicity is processed in the auditory cortex (ACtx). Subregions of ACtx are thought to process harmonic stimuli differently. Selective responses to sound features in ACtx emerge hierarchically from primary ACtx (A1) L4 and secondary ACtx (A2) layer (L)2/3, which is believed to be the most responsive to harmonic sounds. Since harmonic stacks can range from 2 to >10 components, being more similar to naturalistic vocalizations, harmonic sensitivity might also arise hierarchically across layers and areas. We studied responses to harmonic stacks of 2–10 frequencies across A1 L4, A1 L2/3, and A2 L2/3 in adult male and female mice using in vivo two-photon microscopy. We found harmonic-sensitive neurons (HNs) responding only to harmonic stacks but not to individual frequencies in all areas at similar proportions. HNs showed highly nonlinear spectral integration of harmonic frequencies that decreased as the harmonic stacks became more complex. Specifically, onset-biased HNs showed greater nonlinearity than offset-biased HNs only in A1 L4. Moreover, HNs in A1 L4 exhibited higher signal correlation than A2 L2/3. Sound-responsive neurons in A1 L4 have the weakest noise correlation compared with A1 L2/3 and A2 L2/3. Together, harmonic sensitivity is not a unique feature of A2 L2/3 but is already established in A1 L4, where neurons robustly encode harmonic sounds through sparse connections.

Cell types are the basic units of the cerebral cortex. Broad and narrow spike waveforms (BW and NW) are the primary criteria for classifying putative excitatory and inhibitory cortical neurons, particularly in non-human primates where genetic accessibility is limited. We have classified cell types in the auditory cortex of marmosets using spike waveforms and firing patterns and identified a new type of neuron: the NW-burst neuron. NW-burst neurons are excitatory, as they drive but do not suppress the firing of connected neurons. Furthermore, NW-burst neurons displayed shorter response latencies, lower response variability, smaller receptive fields, stronger correlations between spatial and non-spatial selectivity, and higher decoding accuracy than other neurons. Together, these findings suggest that cortical NW-burst neurons in non-human primates represent a distinct excitatory cell type. Significance Statement Classifying cell types in non-human primates is challenging due to limited genetic tools. Traditionally, neurons with narrow spikes are assumed to be inhibitory. Challenging this view, we analyzed 1,816 high-quality single units in the marmoset auditory cortex and discovered that narrow-spike burst-firing neurons were excitatory. These neurons exhibited shorter response latencies, smaller receptive fields, and higher decoding accuracy. Crucially, they showed a positive correlation between "where" and "what" selectivity, defying the standard trade-off between spatial and non-spatial response properties. These findings reveal a specific excitatory cell type in the auditory cortex of a non-human primate species that integrates sound information with high temporal fidelity and feature selectivity.

No pharmacological interventions exist that can restore or preserve auditory function in the mammalian cochlea. Auditory hair cells (HCs) do not spontaneously regenerate, leading to permanent hearing loss. In non-mammalian vertebrates, HC regeneration happens through proliferation and differentiation of their clonally related supporting cells (SCs). The present study supports the potential of quinoxaline (Qx), a nonsteroidal anti-inflammatory compound, to stimulate SC proliferation in the auditory sensory epithelium, a process that may prime the tissue for future HC regeneration. We synthesized a series of Qx derivatives by introducing various substitutions, ranging from hydrophilic to lipophilic. Seventy analogs were generated and tested in vitro and in vivo. Among those, only one (Qx-100) exhibited the best medicinal chemistry profile and was further modified to expand the structure–activity relationship of the chemotype, develop additional analogs, and optimize potency, bioavailability, and in vivo efficacy. Ten new lead variants were generated. Of those, Qx-294 and Qx-301 demonstrated promising in vitro Absorption, Distribution, Metabolism, and Excretion (ADME) profiles and were selected for further testing. Overall, both compounds were rapidly absorbed in zebrafish and mice and promoted cell proliferation in vitro and in vivo without signs of apoptosis, supporting their potential for sensory HC regeneration.

The thalamocortical pathways exhibit neuroplasticity not only during the critical period but also in adulthood. In this study, we investigated how cholecystokinin (CCK) modulates age-dependent thalamocortical plasticity. Our findings demonstrated that CCK is expressed in thalamocortical neurons and that high-frequency stimulation (HFS) of the thalamocortical pathway triggers the release of CCK in auditory cortex (ACx), as detected by a CCK sensor. HFS of the medial geniculate body (MGB) induced thalamocortical long-term potentiation (LTP) in wild-type young adult mice. However, knockdown of CCK expression in MGB neurons or blockade of the CCK-B receptor (CCKBR) in the ACx abolished HFS-induced LTP. Interestingly, this LTP could not be elicited in juvenile (3-week-old) or aged mice (over 18-month-old) due to distinct mechanisms: the absence of CCKBR in juveniles and the inability to release CCK in aged mice. Notably, exogenous administration of CCK into the ACx rescued LTP in aged mice and significantly improved frequency discrimination. These findings highlight the potential of CCK as a therapeutic intervention for ameliorating neuroplasticity deficits associated with thalamocortical connectivity.

Speech comprehension, especially in the presence of background sounds, allegedly declines as a consequence of noise-induced hearing loss. However, the connection between noise overexposure and deteriorated speech-in-noise perception despite normal audiometric thresholds (hidden hearing loss) is not yet clear. This study investigates speech-in-noise discrimination in young-adult Mongolian gerbils before and after an acoustic trauma to examine the link between noise exposure and speech-in-noise perception. Nine young-adult gerbils were trained to discriminate a deviant consonant-vowel-consonant combination (CVC) or vowel-consonant-vowel combination (VCV) in a sequence of CVC or VCV standards, respectively. The logatomes were spoken by different speakers and masked by a steady-state speech-shaped noise. After the gerbils obtained the behavioral baseline data, they underwent an acoustic trauma and participated in the behavioral experiments again. Applying multidimensional scaling, response latencies were used to generate perceptual maps reflecting the gerbils’ internal representations of the sounds pre- and post-trauma. To evaluate how the discrimination of vowels and consonants was altered after noise exposure, changes in response latencies between phoneme pairs were investigated in relation to their articulatory features. Numbers of intact inner hair cell synapses were counted, and auditory brainstem responses were measured to assess peripheral auditory function. Perceptual maps of vowels and consonants were very similar before and after noise exposure. Interestingly, the gerbils’ overall vowel discrimination ability was improved after the acoustic trauma, even though the gerbils suffered from noise-induced hearing loss with a temporary threshold shift for frequencies above 4 kHz. In contrast, there were only minor changes in the gerbils’ consonant discrimination ability. Moreover, noise exposure showed a differential influence on response latencies for vowel and consonant discriminations depending on the articulatory features. Altogether, the results show that an acoustic trauma followed by a temporary threshold shift is not necessarily linked to speech-in-noise perception difficulties associated with hidden hearing loss.

Sound harmonicity is foundational in complex auditory stimuli like music and vocalizations but it remains unclear how such spectrally complex stimuli are processed in the auditory cortex (ACtx). Subregions of the auditory cortex process are thought to process harmonic stimuli differently, and secondary ACtx (A2) layer (L) 2/3 is believed to be the most selective. Selective responses to sound features in ACtx are thought to emerge hierarchically starting from A1 L4. Since the spectral complexity of harmonic stacks can range from two to more than ten components, harmonic selectivity and sensitivity might also arise hierarchically across layers and areas. We studied responses to simple and complex harmonic stacks across A1 L4, A1 L2/3, and A2 L2/3 in adult mice using in vivo two-photon microscopy. We found harmonic-sensitive neurons (HN) responding only to harmonic stacks but not to their pure-tone components in all areas at similar proportions. HNs showed non-linear processing of component tones with onset-responsive HNs showing greater nonlinearity, which decreased with harmonic complexity. Co-tuned HNs in A1 L4 exhibited the highest signal correlation, regardless of harmonic complexity. A1 L4 HNs also showed the lowest noise correlation with other neurons. Moreover, A1 L4 HNs achieve robust spectral integration and harmonic sensitivity by receiving diverse inputs and maintaining high signal correlation, ensuring independent, strong responses to harmonic stimuli. Therefore, harmonic sensitivity is present in A1 L4 and is not a unique feature of A2. Thus, tuning to complex spectral sounds is a fundamental property of ACtx and is already established in A1 L4. Significance statement Harmonics are essential in auditory perception, influencing how we process complex sounds like music and speech. This study reveals that neurons in the primary auditory cortex (A1) and secondary auditory cortex (A2) integrate simple and complex harmonic structures with distinct mechanisms of neuronal recruitment. A1 L4 harmonic-sensitive neurons (HNs) demonstrated strong, independent responses through high signal correlation and minimal noise correlation, suggesting a robust mechanism for spectral integration. Our results show that harmonic relationships are already extracted at the input layers of A1, and that HNs show non-linear facilitative integration. Thus, tuning to sounds of complex spectral contents might be a fundamental processing function of the auditory cortex and is already established in A1 L4, which receives major thalamic inputs.

Atypical sensory processing, particularly in the auditory domain, is one of the most common and quality-of-life affecting symptoms seen in autism spectrum disorders (ASD). Fragile X Syndrome (FXS) is a leading inherited cause of ASD and a majority of FXS individuals present with auditory processing alterations. While auditory hypersensitivity is a common phenotype observed in FXS and Fmr1 knockout (KO) rodent models, it is important to consider other auditory coding impairments that could contribute to sound processing difficulties and disrupted language comprehension in FXS. We have shown previously that a Fmr1 KO rat model of FXS exhibits heightened sound sensitivity that coincided with abnormal perceptual integration of stimulus bandwidth, indicative of altered spectral processing. Frequency discrimination is a fundamental aspect of sound encoding that is important for a range of auditory processes, such as source segregation and speech comprehension, and disrupted frequency coding could thus contribute to a range of auditory issues in FXS and ASD. Here we explicitly characterized spectral processing deficits in male Fmr1 KO rats using an operant conditioning tone discrimination assay and in vivo electrophysiological recordings from the auditory cortex and inferior colliculus. We found that Fmr1 KO rats exhibited poorer frequency resolution, which corresponded with neuronal hyperactivity and broader frequency tuning in auditory cortical but not collicular neurons. Using an experimentally informed population model, we show that these cortical physiological differences can recapitulate the observed behavior discrimination deficits, with decoder performance being tightly linked to differences in cortical tuning width and signal-to-noise ratios. Together, these findings indicate that cortical hyperexcitability in Fmr1 KO rats may act to preserve signal-to-noise ratios and signal detection threshold at the expense of sound sensitivity and fine feature discrimination, highlighting a potential mechanistic locus for a range of auditory behavioral phenotypes in FXS.

Analyzing the functional connectivity of the brain is an enormous challenge, as deciphering functional connectivity requires knowledge of functional responses and connections. One promising strategy is analyzing the spatial pattern of activity correlations across cell populations. In the primary auditory cortex (A1), cells respond to different sound features. On the large scale, there exists a tonotopic map, which is fractured at the small scale, raising the question of whether functional connections are spatially ordered or disordered. To test whether functional connectivity on a local and a global scale is also disordered, we first designed a robust statistical model to estimate parameters and test for the significance of the estimated correlation maps. We developed an inference method that allows efficient model fitting and statistical testing to project the correlation maps to 2D space. We then performed in vivo two-photon calcium imaging in layer 2/3 of A1 with pure tones (PT) or a combination of two tones (TT; harmonically related or not). We found that the spatial patterns of signal correlations (SCs) depend on the type of sound stimuli that were presented. The functional 2D maps of PT-driven SCs are more restricted to local neurons than TT signal correlations which showed more global textures. 2D SC patterns for harmonic stimuli showed spatially distinct relationships. TT SCs revealed spatially precise functional connectivity between harmonically related neurons. Thus, even though the frequency preference of neighboring neurons in A1 is functionally diverse, the functional connection pattern of these neurons is functionally precise and harmonically related.

Electroanalytical methods are used to understand, modify, and control bionic devices. Bionic devices can record or stimulate cells to understand and/or control normal or abnormal biological processes. These devices contain electrodes that transduce electrical current within the electrical circuit into ionic current within a tissue. Despite the similarity between electroanalysis and electrophysiology, there remains a poor understanding of the relationship between the two techniques, including their methodology and theory. This paper investigates the electrochemical and acute electrophysiological recording performance of neural electrodes. A range of behaviors is achieved by modifying electrodes with the conducting polymer poly(3,4‐ethylenedioxythiophene) (PEDOT) doped with chondroitin sulfate, dextran sulfate, or para ‐toluene sulfonate. The results support previous studies showing that increased electrode area reduced total impedance below the Maxwell–Wagner relaxation frequency and thermal noise while increasing the signal‐to‐noise ratio and neural spike count. The results allowed novel investigation of relative contributions of biological and electrode properties to electrophysiological performance, with increased electrode area having a larger impact on neural population within recording range rather than reducing thermal noise. The utility of measuring electrode impedance for predicting electrophysiological performance is mainly for an indirect measure of electrode area. The results provide insight into noise sources from electrophysiological recordings and limitations in cable theory in neuroscience.