Electrophysiology publications

Cochlear implant listeners receive auditory stimulation through amplitude-modulated electric pulse trains. Auditory nerve studies in animals demonstrate qualitatively different patterns of firing elicited by low versus high pulse rates, suggesting that stimulus pulse rate might influence the transmission of temporal information through the auditory pathway. We tested in awake guinea pigs the temporal acuity of auditory cortical neurons for gaps in cochlear implant pulse trains. Consistent with results using anesthetized conditions, temporal acuity improved with increasing pulse rates. Unlike the anesthetized condition, however, cortical neurons responded in the awake state to multiple distinct features of the gap-containing pulse trains, with the dominant features varying with stimulus pulse rate. Responses to the onset of the trailing pulse train (Trail-ON) provided the most sensitive gap detection at 1,017 and 4,069 pulse-per-second (pps) rates, particularly for short (25 ms) leading pulse trains. In contrast, under conditions of 254 pps rate and long (200 ms) leading pulse trains, a sizeable fraction of units demonstrated greater temporal acuity in the form of robust responses to the offsets of the leading pulse train (Lead-OFF). Finally, TONIC responses exhibited decrements in firing rate during gaps, but were rarely the most sensitive feature. Unlike results from anesthetized conditions, temporal acuity of the most sensitive units was nearly as sharp for brief as for long leading bursts. The differences in stimulus coding across pulse rates likely originate from pulse rate-dependent variations in adaptation in the auditory nerve. Two marked differences from responses to acoustic stimulation were: first, Trail-ON responses to 4,069 pps trains encoded substantially shorter gaps than have been observed with acoustic stimuli; and second, the Lead-OFF gap coding seen for <15 ms gaps in 254 pps stimuli is not seen in responses to sounds. The current results may help to explain why moderate pulse rates around 1,000 pps are favored by many cochlear implant listeners.

Impaired neural conductivity shown by delayed latency and reduced amplitude of characteristic peaks in somatosensory evoked potentials (SSEPs), has been used to monitor hypoxic-ischemic brain injury after cardiac arrest (CA). However, rather than characteristic peak deferral and suppression, the time jitter of the peak in SSEP related with time-variant neurological abnormalities is diminished by the commonly used ensemble average method. This paper utilizes the second order blind identification (SOBI) technique to extract characteristic peak information from one trial of SSEPs. Sixteen male Wistar rats were subjected to 7 or 9 min of asphyxial CA (n=8 per group). The SSEPs from median nerve stimulation were recorded for 4h after CA and then for 15 min periods at 24, 48 and 72 h. Neurological outcomes were evaluated by neurologic deficit score (NDS) at 72 h post-CA. The SSEP signal was analyzed offline with SOBI processing in Matlab. The N10 feature of SSEP was compared between good (NDS≥50) and bad (NDS<50) outcomes. After processed by SOBI, the N10 detection rate was significantly increased (p<0.001) from 90 min post-CA. Statistical difference of the latency variance of the N10 between good and bad outcome groups existed at 24, 48 and 72 h post-CA (p≤0.001). Our study is the first application using SOBI detecting variance in neural signals like SSEP. N10 latency variance, related with neurophysiological dysfunction, increased after hypoxic-ischemic injury. The SOBI technique is an efficient method in the identification of peak detection and offers a favorable alternative to reveal the neural transmission variation.

Directional selectivity, in which neurons respond strongly to an object moving in a given direction (“preferred”) but respond weakly or not at all to an object moving in the opposite direction (“null”), is a critical computation achieved in brain circuits. Previous measures of direction selectivity have compared the numbers of action potentials elicited by each direction of movement, but most sensory neurons display patterning, such as bursting, in their spike trains. To examine the contribution of patterned responses to direction selectivity, we recorded from midbrain neurons in weakly electric fish and found that most neurons responded with a combination of both bursts and isolated spikes to moving object stimuli. In these neurons, we separated bursts and isolated spikes using an interspike interval (ISI) threshold. The directional bias of bursts was significantly higher than that of either the full spike train or the isolated spike train. To examine the encoding and decoding of bursts, we built biologically plausible models that examine 1) the upstream mechanisms that generate these spiking patterns and 2) downstream decoders of bursts. Our model of upstream mechanisms uses an interaction between afferent input and subthreshold calcium channels to give rise to burst firing that occurs preferentially for one direction of movement. We tested this model in vivo by application of calcium antagonists, which reduced burst firing and eliminated the differences in direction selectivity between bursts, isolated spikes, and the full spike train. Our model of downstream decoders used strong synaptic facilitation to achieve qualitatively similar results to those obtained using the ISI threshold criterion. This model shows that direction selective information carried by bursts can be decoded by downstream neurons using biophysically plausible mechanisms.

Intracortical microstimulation (ICMS), which has shown promise in the visual, auditory and somatosensory systems as a platform for sensory prostheses, typically relies on charged balanced, symmetric, biphasic stimulation. However, neural stimulation models as well as experiments conducted in cochlear implant users have suggested that charge balanced asymmetric pulses could generate lower detection thresholds for stimulation in terms of charge per phase. For this study, rats were chronically implanted with microelectrode arrays unilaterally in their right auditory cortex and then trained to detect ICMS delivered through a single electrode site in order to determine their behavioral threshold. This model was used in two experiments. The first experiment addressed the effect of lead phase direction, asymmetry, and phase duration on detection threshold. The second experiment fixed the cathode phase duration at 123 μs and varied only the phase asymmetry and lead phase direction. Taken together, the results of these experiments suggest that, for ICMS, the primary determinant of threshold level is cathode phase duration, and that asymmetry provides no significant advantage when compared to symmetric, cathode leading pulses. However, symmetric anode leading pulses of less than or equal to 205 μs per phase consistently showed higher thresholds when compared to all other pulses of equal cathode phase duration.

Performance evaluation is a critical feature of motor learning. In the vocal system, it requires the integration of auditory feedback signals with vocal motor commands. The network activity that supports such integration is unknown, but it has been proposed that vocal performance evaluation occurs offline. Recording from NIf, a sensorimotor structure in the avian song system, we show that short bouts of singing in adult male zebra finches ( Taeniopygia guttata ) induce persistent increases in firing activity and coherent oscillations in the fast gamma range (90–150 Hz). Single units are strongly phase locked to these oscillations, which can last up to 30 s, often outlasting vocal activity by an order of magnitude. In other systems, oscillations often are triggered by events or behavioral tasks but rarely outlast the event that triggered them by more than 1 s. The present observations are the longest reported gamma oscillations triggered by an isolated behavioral event. In mammals, gamma oscillations have been associated with memory consolidation and are hypothesized to facilitate communication between brain regions. We suggest that the timing and persistent nature of NIf's fast gamma oscillations make them well suited to facilitate the integration of auditory and vocal motor traces associated with vocal performance evaluation.

Persistent‐firing neurons in the entorhinal cortex (EC) and the lateral nucleus of the amygdala (LA) continue to discharge long after the termination of the original, spike‐initiating current. An emerging theory proposes that endogenous persistent firing helps support a transient memory system. This study demonstrated that persistent‐firing neurons are also prevalent in rat perirhinal cortex (PR), which lies immediately adjacent to and is reciprocally connected with EC and LA. Several characteristics of persistent‐firing neurons in PR were similar to those previously reported in LA and EC. Persistent firing in PR was enabled by the application of carbachol, a nonselective cholinergic agonist, and it was induced by injecting a suprathreshold current or by stimulating suprathreshold excitatory synaptic inputs to the neuron. Once induced, persistent firing lasted for seconds to minutes. Persistent firing could always be terminated by a sufficiently large and prolonged hyperpolarizing current; it was prevented by antagonists of muscarinic cholinergic receptors (mAChRs); and it was blocked by flufenamic acid. The latter has been suggested to inhibit a Ca 2+ ‐activated nonspecific cation conductance ( G CAN ) that normally furnishes the sustained depolarization during persistent firing. In many PR neurons, the discharge rate during persistent firing was a graded function of depolarizing and/or hyperpolarizing inputs. Persistent firing was not prevented by blocking fast excitatory and inhibitory synaptic transmission, demonstrating that it can be generated endogenously. We suggest that persistent‐firing neurons in PR, EC, LA, and certain other brain regions may cooperate in support of a transient‐memory system. © 2011 Wiley Periodicals, Inc.

Gamma-band oscillations are a ubiquitous phenomenon in the nervous system and have been implicated in multiple aspects of cognition. In particular, the strength of gamma oscillations at the time a stimulus is encoded predicts its subsequent retrieval, suggesting that gamma may reflect enhanced mnemonic processing. Likewise, activity in the gamma-band can modulate plasticity in vitro . However, it is unclear whether experience-dependent plasticity in vivo is also related to gamma-band activation. The aim of the present study was to determine whether gamma activation in primary auditory cortex modulates both the associative memory for an auditory stimulus during classical conditioning and its accompanying specific receptive field plasticity. Rats received multiple daily sessions of single tone/shock trace and two-tone discrimination conditioning, during which local field potentials and multiunit discharges were recorded from chronically implanted electrodes. We found that the strength of tone-induced gamma predicted the acquisition of associative memory 24 h later and ceased to predict subsequent performance once asymptote was reached. Gamma activation also predicted receptive field plasticity that specifically enhanced representation of the signal tone. This concordance provides a long-sought link between gamma oscillations, cortical plasticity, and the formation of new memories.

The superior paraolivary nucleus (SPON) is a prominent structure in the auditory brainstem. In contrast to the principal superior olivary nuclei with identified roles in processing binaural sound localization cues, the role of the SPON in hearing is not well understood. A combined in vitro and in vivo approach was used to investigate the cellular properties of SPON neurons in the mouse. Patch-clamp recordings in brain slices revealed that brief and well timed postinhibitory rebound spiking, generated by the interaction of two subthreshold-activated ion currents, is a hallmark of SPON neurons. The I h current determines the timing of the rebound, whereas the T-type Ca 2+ current boosts the rebound to spike threshold. This precisely timed rebound spiking provides a physiological explanation for the sensitivity of SPON neurons to sinusoidally amplitude-modulated (SAM) tones in vivo , where peaks in the sound envelope drive inhibitory inputs and SPON neurons fire action potentials during the waveform troughs. Consistent with this notion, SPON neurons display intrinsic tuning to frequency-modulated sinusoidal currents (1–15Hz) in vitro and discharge with strong synchrony to SAMs with modulation frequencies between 1 and 20 Hz in vivo . The results of this study suggest that the SPON is particularly well suited to encode rhythmic sound patterns. Such temporal periodicity information is likely important for detection of communication cues, such as the acoustic envelopes of animal vocalizations and speech signals.

The deafness locus DFNB1 contains GJB2, the gene encoding connexin26 and GJB6, encoding connexin30, which appear to be coordinately regulated in the inner ear. In this work, we investigated the expression and function of connexin26 and connexin30 from postnatal day 5 to adult age in double transgenic Cx26(Sox10Cre) mice, which we obtained by crossing connexin26 floxed mice with a deleter Sox10-Cre line. Cx26(Sox10Cre) mice presented with complete connexin26 ablation in the epithelial gap junction network of the cochlea, whereas connexin30 expression was developmentally delayed; immunolabeling patterns for both connexins were normal in the cochlear lateral wall. In vivo electrophysiological measurements in Cx26(Sox10Cre) mice revealed profound hearing loss accompanied by reduction of endocochlear potential, and functional experiments performed in postnatal cochlear organotypic cultures showed impaired gap junction coupling. Transduction of these cultures with a bovine adeno associated virus vector restored connexin26 protein expression and rescued gap junction coupling. These results suggest that restoration of normal connexin levels by gene delivery via recombinant adeno associated virus could be a way to rescue hearing function in DFNB1 mouse models and, in future, lead to the development of therapeutic interventions in humans.

Spontaneous activity of cortical neurons exhibits alternative fluctuations of membrane potential consisting of phased depolarization called "up-state" and persistent hyperpolarization called "down-state" during slow wave sleep and anesthesia. Here, we examined the effects of sound stimuli (noise bursts) on neuronal activity by intracellular recording in vivo from the rat auditory cortex (AC). Noise bursts increased the average time in the up-state by 0.81±0.65 s (range, 0.27-1.74 s) related to a 10 s recording duration. The rise times of the spontaneous up-events averaged 69.41±18.04 ms (range, 40.10-119.21 ms), while those of the sound-evoked up-events were significantly shorter (p<0.001) averaging only 22.54±8.81 ms (range, 9.31-45.74 ms). Sound stimulation did not influence ongoing spontaneous up-events. Our data suggest that a sound stimulus does not interfere with ongoing spontaneous neuronal activity in auditory cortex but can evoke new depolarizations in addition to the spontaneous ones.

Stimulus-specific adaptation (SSA) is the specific decrease in the response to a frequent ('standard') stimulus, which does not generalize, or generalizes only partially, to another, rare stimulus ('deviant'). Stimulus-specific adaptation could result simply from the depression of the responses to the standard. Alternatively, there may be an increase in the responses to the deviant stimulus due to the violation of expectations set by the standard, indicating the presence of true deviance detection. We studied SSA in the auditory cortex of halothane-anesthetized rats, recording local field potentials and multi-unit activity. We tested the responses to pure tones of one frequency when embedded in sequences that differed from each other in the frequency and probability of the tones composing them. The responses to tones of the same frequency were larger when deviant than when standard, even with inter-stimulus time intervals of almost 2 seconds. Thus, SSA is present and strong in rat auditory cortex. SSA was present even when the frequency difference between deviants and standards was as small as 10%, substantially smaller than the typical width of cortical tuning curves, revealing hyper-resolution in frequency. Strong responses were evoked also by a rare tone presented by itself, and by rare tones presented as part of a sequence of many widely spaced frequencies. On the other hand, when presented within a sequence of narrowly spaced frequencies, the responses to a tone, even when rare, were smaller. A model of SSA that included only adaptation of the responses in narrow frequency channels predicted responses to the deviants that were substantially smaller than the observed ones. Thus, the response to a deviant is at least partially due to the change it represents relative to the regularity set by the standard tone, indicating the presence of true deviance detection in rat auditory cortex.

We have previously shown that neurons in primary auditory cortex (A1) of anaesthetized (ketamine/medetomidine) ferrets respond more strongly and reliably to dynamic stimuli whose statistics follow "natural" 1/f dynamics than to stimuli exhibiting pitch and amplitude modulations that are faster (1/f(0.5)) or slower (1/f(2)) than 1/f. To investigate where along the central auditory pathway this 1/f-modulation tuning arises, we have now characterized responses of neurons in the central nucleus of the inferior colliculus (ICC) and the ventral division of the mediate geniculate nucleus of the thalamus (MGV) to 1/f(γ) distributed stimuli with γ varying between 0.5 and 2.8. We found that, while the great majority of neurons recorded from the ICC showed a strong preference for the most rapidly varying (1/f(0.5) distributed) stimuli, responses from MGV neurons did not exhibit marked or systematic preferences for any particular γ exponent. Only in A1 did a majority of neurons respond with higher firing rates to stimuli in which γ takes values near 1. These results indicate that 1/f tuning emerges at forebrain levels of the ascending auditory pathway.

Generative models of neuroimaging and electrophysiological data present new opportunities for accessing hidden or latent brain states. Dynamic causal modeling (DCM) uses Bayesian model inversion and selection to infer the synaptic mechanisms underlying empirically observed brain responses. DCM for electrophysiological data, in particular, aims to estimate the relative strength of synaptic transmission at different cell types and via specific neurotransmitters. Here, we report a DCM validation study concerning inference on excitatory and inhibitory synaptic transmission, using different doses of a volatile anaesthetic agent (isoflurane) to parametrically modify excitatory and inhibitory synaptic processing while recording local field potentials (LFPs) from primary auditory cortex (A1) and the posterior auditory field (PAF) in the auditory belt region in rodents. We test whether DCM can infer, from the LFP measurements, the expected drug-induced changes in synaptic transmission mediated via fast ionotropic receptors; i.e., excitatory (glutamatergic) AMPA and inhibitory GABA(A) receptors. Cross- and auto-spectra from the two regions were used to optimise three DCMs based on biologically plausible neural mass models and specific network architectures. Consistent with known extrinsic connectivity patterns in sensory hierarchies, we found that a model comprising forward connections from A1 to PAF and backward connections from PAF to A1 outperformed a model with forward connections from PAF to A1 and backward connections from A1 to PAF and a model with reciprocal lateral connections. The parameter estimates from the most plausible model indicated that the amplitude of fast glutamatergic excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) behaved as predicted by previous neurophysiological studies. Specifically, with increasing levels of anaesthesia, glutamatergic EPSPs decreased linearly, whereas fast GABAergic IPSPs displayed a nonlinear (saturating) increase. The consistency of our model-based in vivo results with experimental in vitro results lends further validity to the capacity of DCM to infer on synaptic processes using macroscopic neurophysiological data.

Non-penetrating surface electrode recording techniques are typically associated with field potential recordings, while extracellular recordings from single neurons are made using penetrating metal wire or microfabricated microelectrode arrays. Here, we report on single- and multi-unit neuronal recordings made using non-penetrating electrodes placed on the epineural surface of the dorsal root ganglia (DRG). Across four experiments in anesthetized cats, approximately 40% of the electrodes recorded single- and multi-unit spiking activity with spike-rates that covaried significantly with hindlimb movement. In two intraoperative experiments in humans, compound activity was recorded from the DRG surface in response to peripheral stimulation of the common peroneal nerve. This approach may have advantages over penetrating electrode arrays in terms of clinical acceptability and recording longevity.

In neuroprostheses that use functional electrical stimulation (FES) to restore motor function, closed-loop feedback control may compensate for muscle fatigue, perturbations and nonlinearities in the behavior of the effected muscles. Kinematic state information is naturally represented in the firing rates of primary afferent neurons, which may be recorded with multi-electrode arrays at the level of the dorsal root ganglia (DRG). Previous work in cats has shown that it is feasible to estimate the kinematic state of the hind limb with a multivariate linear regression model of the neural activity in the DRG. In this study we extend these results to estimate the limb state in real-time during intramuscular stimulation in an anesthetized cat. Furthermore, we used the limb state estimates as feedback to a finite state FES controller to generate rudimentary walking behavior. This work demonstrates the feasibility of using DRG activity in a closed-loop FES system.

Although high doses of sodium salicylate impair cochlear function, it paradoxically enhances sound-evoked activity in the auditory cortex (AC) and augments acoustic startle reflex responses, neural and behavioral metrics associated with hyperexcitability and hyperacusis. To explore the neural mechanisms underlying salicylate (SS)-induced hyperexcitability and "increased central gain," we examined the effects of GABA receptor agonists and antagonists on SS-induced hyperexcitability in the AC and startle reflex responses. Consistent with our previous findings, local or systemic application of SS significantly increased the amplitude of sound-evoked AC neural activity, but generally reduced spontaneous activity in the AC. Systemic injection of SS also significantly increased the acoustic startle reflex. S-baclofen or R-baclofen, GABA-B agonists, which suppressed sound-evoked AC neural firing rate and local field potentials, also suppressed the SS-induced enhancement of the AC field potential and the acoustic startle reflex. Local application of vigabatrin, which enhances GABA concentration in the brain, suppressed the SS-induced enhancement of AC firing rate. Systemic injection of vigabatrin also reduced the SS-induced enhancement of acoustic startle reflex. Collectively, these results suggest that the sound-evoked behavioral and neural hyperactivity induced by SS may arise from a SS-induced suppression of GABAergic inhibition in the AC.

Previous studies have demonstrated that single neurons in the central nucleus of the inferior colliculus (ICC) are sensitive to multiple sound localization cues. We investigated the hypothesis that ICC neurons are specialized to encode multiple sound localization cues that are aligned in space (as would naturally occur from a single broadband sound source). Sound localization cues including interaural time differences (ITDs), interaural level differences (ILDs), and spectral shapes (SSs) were measured in a marmoset monkey. Virtual space methods were used to generate stimuli with aligned and misaligned combinations of cues while recording in the ICC of the same monkey. Mutual information (MI) between spike rates and stimuli for aligned versus misaligned cues were compared. Neurons with best frequencies (BFs) less than ∼11 kHz mostly encoded information about a single sound localization cue, ITD or ILD depending on frequency, consistent with the dominance of ear acoustics by either ITD or ILD at those frequencies. Most neurons with BFs >11 kHz encoded information about multiple sound localization cues, usually ILD and SS, and were sensitive to their alignment. In some neurons MI between stimuli and spike responses was greater for aligned cues, while in others it was greater for misaligned cues. If SS cues were shifted to lower frequencies in the virtual space stimuli, a similar result was found for neurons with BFs <11 kHz, showing that the cue interaction reflects the spectra of the stimuli and not a specialization for representing SS cues. In general the results show that ICC neurons are sensitive to multiple localization cues if they are simultaneously present in the frequency response area of the neuron. However, the representation is diffuse in that there is not a specialization in the ICC for encoding aligned sound localization cues.

We examined multiunit responses to tones and to 1/3 and 2/3 octave band-pass noise (BPN) in the marmoset primary auditory cortex (A1) and the caudomedial belt (CM). In both areas, BPN was more effective than tones, evoking multiunit responses at lower intensity and across a wider frequency range. Typically, the best responses to BPN remained at the characteristic frequency. Additionally, in both areas responses to BPN tended to be of greater magnitude and shorter latency than responses to tones. These effects are consistent with the integration of more excitatory inputs driven by BPN than by tones. While it is generally thought that single units in A1 prefer narrow band sounds such as tones, we found that best responses for multi units in both A1 and CM were obtained with noises of narrow spectral bandwidths.

The whisker-to-barrel cortex is widely used to study neurovascular coupling, but the cellular basis that underlies the perfusion changes is still largely unknown. Here, we identified neurons recruited by whisker stimulation in the rat somatosensory cortex using double immunohistochemistry for c-Fos and markers of glutamatergic and GABAergic neurons, and investigated in vivo their contribution along with that of astrocytes in the evoked perfusion response. Whisker stimulation elicited cerebral blood flow (CBF) increases concomitantly with c-Fos upregulation in pyramidal cells that coexpressed cyclooxygenase-2 (COX-2) and GABA interneurons that coexpressed vasoactive intestinal polypeptide and/or choline acetyltransferase, but not somatostatin or parvalbumin. The evoked CBF response was decreased by blockade of NMDA (MK-801, -37%), group I metabotropic glutamate (MPEP+LY367385, -40%), and GABA-A (picrotoxin, -31%) receptors, but not by GABA-B, VIP, or muscarinic receptor antagonism. Picrotoxin decreased stimulus-induced somatosensory evoked potentials and CBF responses. Combined blockade of GABA-A and NMDA receptors yielded an additive decreasing effect (-61%) of the evoked CBF compared with each antagonist alone, demonstrating cooperation of both excitatory and inhibitory systems in the hyperemic response. Blockade of prostanoid synthesis by inhibiting COX-2 (indomethacin, NS-398), expressed by ∼40% of pyramidal cells but not by astrocytes, impaired the CBF response (-50%). The hyperemic response was also reduced (-40%) after inhibition of astroglial oxidative metabolism or epoxyeicosatrienoic acids synthesis. These results demonstrate that changes in pyramidal cell activity, sculpted by specific types of inhibitory GABA interneurons, drive the CBF response to whisker stimulation and, further, that metabolically active astrocytes are also required.

Acoustic communication has an important role in the reproductive behaviour of anurans. Although males of the concave-eared frog (Odorrana tormota) have shown an ultrasonic communication capacity adapted to the intense, predominately low-frequency ambient noise from local streams, whether the females communicate with ultrasound remains unclear. Here we present evidence that females exhibit no ultrasonic sensitivity. Acoustic playback experiments show that the calls from male evoke phonotaxis and vocal responses from gravid females, whereas the ultrasonic components (frequencies above 20 kHz) of the calls do not elicit any phonotaxis or vocalization in the females. Electrophysiological recordings from the auditory midbrain reveal an upper frequency limit at 16 kHz in females. Laser Doppler vibrometer measurements show that the velocity amplitude of the tympanic membranes peaks at 5 kHz in females and at ∼7 kHz in males. The auditory sex differences in O. tormota imply that ultrasonic hearing has evolved only in male anurans.