Electrophysiology publications

A novel PEDOT-ionic liquid polymer coating was synthesized for improving the performance of MEAs implanted in the brain.

We study the feasibility and capability of the kernel temporal difference (KTD)( λ ) algorithm for neural decoding. KTD( λ ) is an online, kernel-based learning algorithm, which has been introduced to estimate value functions in reinforcement learning. This algorithm combines kernel-based representations with the temporal difference approach to learning. One of our key observations is that by using strictly positive definite kernels, algorithm’s convergence can be guaranteed for policy evaluation. The algorithm’s nonlinear functional approximation capabilities are shown in both simulations of policy evaluation and neural decoding problems (policy improvement). KTD can handle high-dimensional neural states containing spatial-temporal information at a reasonable computational complexity allowing real-time applications. When the algorithm seeks a proper mapping between a monkey’s neural states and desired positions of a computer cursor or a robot arm, in both open-loop and closed-loop experiments, it can effectively learn the neural state to action mapping. Finally, a visualization of the coadaptation process between the decoder and the subject shows the algorithm’s capabilities in reinforcement learning brain machine interfaces.

The robust representation of the environment from unreliable sensory cues is vital for the efficient function of the brain. However, how the neural processing captures the most reliable cues is unknown. The interaural time difference (ITD) is the primary cue to localize sound in horizontal space. ITD is encoded in the firing rate of neurons that detect interaural phase difference (IPD). Due to the filtering effect of the head, IPD for a given location varies depending on the environmental context. We found that, in barn owls, at each location there is a frequency range where the head filtering yields the most reliable IPDs across contexts. Remarkably, the frequency tuning of space-specific neurons in the owl's midbrain varies with their preferred sound location, matching the range that carries the most reliable IPD. Thus, frequency tuning in the owl's space-specific neurons reflects a higher-order feature of the code that captures cue reliability.

Acoustic communication plays a key role for mate attraction in grasshoppers. Males use songs to advertise themselves to females. Females evaluate the song pattern, a repetitive structure of sound syllables separated by short pauses, to recognize a conspecific male and as proxy to its fitness. In their natural habitat females often receive songs with degraded temporal structure. Perturbations may, for example, result from the overlap with other songs. We studied the response behavior of females to songs that show different signal degradations. A perturbation of an otherwise attractive song at later positions in the syllable diminished the behavioral response, whereas the same perturbation at the onset of a syllable did not affect song attractiveness. We applied naïve Bayes classifiers to the spike trains of identified neurons in the auditory pathway to explore how sensory evidence about the acoustic stimulus and its attractiveness is represented in the neuronal responses. We find that populations of three or more neurons were sufficient to reliably decode the acoustic stimulus and to predict its behavioral relevance from the single-trial integrated firing rate. A simple model of decision making simulates the female response behavior. It computes for each syllable the likelihood for the presence of an attractive song pattern as evidenced by the population firing rate. Integration across syllables allows the likelihood to reach a decision threshold and to elicit the behavioral response. The close match between model performance and animal behavior shows that a spike rate code is sufficient to enable song pattern recognition.

Objective The goal of this work is to establish a new dual‐modal brain‐mapping technique based on diffuse optical tomography ( DOT ) and electroencephalographic source localization ( ESL ) that can chronically/intracranially record optical/electroencephalography ( EEG ) data to precisely map seizures and localize the seizure‐onset zone and associated epileptic brain network. Methods The dual‐modal imaging system was employed to image seizures in an experimental acute bicuculline methiodide rat model of focal epilepsy. Depth information derived from DOT was used as constraint in ESL to enhance the image reconstruction. Groups of animals were compared based on localization of seizure foci, either at different positions or at different depths. Results This novel imaging technique successfully localized the seizure‐onset zone in rat induced by bicuculline methiodide injected at a depth of 1, 2, and 3 mm, respectively. The results demonstrated that the incorporation of the depth information from DOT into the ESL image reconstruction resulted in more accurate and reliable ESL images. Although the ESL images showed a horizontal shift of the source localization, the DOT identified the seizure focus accurately. In one case, when the bicuculline methiodide (BMI) was injected at a site outside the field of view ( FOV ) of the DOT / ESL interface, ESL gave false‐positive detection of the focus, while DOT showed negative detection. Significance This study represents the first to identify seizure‐onset zone using implantable DOT . In addition, the combination of DOT / ESL has never been documented in neuroscience and epilepsy imaging. This technology will enable us to precisely measure the neural activity and hemodynamic response at exactly the same tissue site and at both cortical and subcortical levels.

While the timing of neuronal activity in the olfactory bulb (OB) relative to sniffing has been the object of many studies, the behavioral relevance of timing information generated by patterned activation within the bulbar response has not been explored. Here we show, using sniff-triggered, dynamic, 2-D, optogenetic stimulation of mitral/tufted cells, that virtual odors that differ by as little as 13 ms are distinguishable by mice. Further, mice are capable of discriminating a virtual odor movie based on an optically imaged OB odor response versus the same virtual odor devoid of temporal dynamics-independently of the sniff-phase. Together with studies showing the behavioral relevance of graded glomerular responses and the response timing relative to odor sampling, these results imply that the mammalian olfactory system is capable of very high transient information transmission rates.

The interaural level difference (ILD) cue to sound location is first encoded in the lateral superior olive (LSO). ILD sensitivity results because the LSO receives excitatory input from the ipsilateral cochlear nucleus and inhibitory input indirectly from the contralateral cochlear nucleus via glycinergic neurons of the ipsilateral medial nucleus of the trapezoid body (MNTB). It is hypothesized that in order for LSO neurons to encode ILDs, the sound spectra at both ears must be accurately encoded via spike rate by their afferents. This spectral-coding hypothesis has not been directly tested in MNTB, likely because MNTB neurons have been mostly described and studied recently in regards to their abilities to encode temporal aspects of sounds, not spectral. Here, we test the hypothesis that MNTB neurons and their inputs from the cochlear nucleus and auditory nerve code sound spectra via discharge rate. The Random Spectral Shape (RSS) method was used to estimate how the levels of 100-ms duration spectrally stationary stimuli were weighted, both linearly and non-linearly, across a wide band of frequencies. In general, MNTB neurons, and their globular bushy cell inputs, were found to be well-modeled by a linear weighting of spectra demonstrating that the pathways through the MNTB can accurately encode sound spectra including those resulting from the acoustical cues to sound location provided by head-related directional transfer functions (DTFs). Together with the anatomical and biophysical specializations for timing in the MNTB-LSO complex, these mechanisms may allow ILDs to be computed for complex stimuli with rapid spectrotemporally-modulated envelopes such as speech and animal vocalizations and moving sound sources.

Mice that carry a mutation in a calcium binding domain of Otoferlin, the putative calcium sensor at hair cell synapses, have normal distortion product otoacoustic emissions (DPOAEs), but auditory brain stem responses (ABRs) are absent. In mutant mice mechanotransduction is normal but transmission of acoustic information to the auditory pathway is blocked even before the onset of hearing. The cross-sectional area of the auditory nerve of mutant mice is reduced by 54%, and the volume of ventral cochlear nuclei is reduced by 46% relative to hearing control mice. While the tonotopic organization was not detectably changed in mutant mice, the axons to end bulbs of Held and the end bulbs themselves were smaller. In mutant mice bushy cells in the anteroventral cochlear nucleus (aVCN) have the electrophysiological hallmarks of control cells. Spontaneous miniature excitatory postsynaptic currents (EPSCs) occur with similar frequencies and have similar shapes in deaf as in hearing animals, but they are 24% larger in deaf mice. Bushy cells in deaf mutant mice are contacted by ∼2.6 auditory nerve fibers compared with ∼2.0 in hearing control mice. Furthermore, each fiber delivers more synaptic current, on average 4.8 nA compared with 3.4 nA, in deaf versus hearing control mice. The quantal content of evoked EPSCs is not different between mutant and control mice; the increase in synaptic current delivered in mutant mice is accounted for by the increased response to the size of the quanta. Although responses to shocks presented at long intervals are larger in mutant mice, they depress more rapidly than in hearing control mice.

Assemblies of vertically connected neurons in the cerebral cortex form information processing units (columns) that participate in the distribution and segregation of sensory signals. Despite well-accepted models of columnar architecture, functional mechanisms of inter-laminar communication remain poorly understood. Hence, the purpose of the present investigation was to examine the effects of sensory information features on columnar response properties. Using acute recording techniques, extracellular response activity was collected from the right hemisphere of eight mature cats (felis catus). Recordings were conducted with multichannel electrodes that permitted the simultaneous acquisition of neuronal activity within primary auditory cortex columns. Neuronal responses to simple (pure tones), complex (noise burst and frequency modulated sweeps), and ecologically relevant (con-specific vocalizations) acoustic signals were measured. Collectively, the present investigation demonstrates that despite consistencies in neuronal tuning (characteristic frequency), irregularities in discharge activity between neurons of individual A1 columns increase as a function of spectral (signal complexity) and temporal (duration) acoustic variations.

Music perception builds on expectancy in harmony, melody, and rhythm. Neural responses to the violations of such expectations are observed in event-related potentials (ERPs) measured using electroencephalography. Most previous ERP studies demonstrating sensitivity to musical violations used stimuli that were temporally regular and musically structured, with less-frequent deviant events that differed from a specific expectation in some feature such as pitch, harmony, or rhythm. Here, we asked whether expectancies about Western musical scale are strong enough to elicit ERP deviance components. Specifically, we explored whether pitches inconsistent with an established scale context elicit deviant components even though equally rare pitches that fit into the established context do not, and even when their timing is unpredictable. We used Markov chains to create temporally irregular pseudo-random sequences of notes chosen from one of two diatonic scales. The Markov pitch-transition probabilities resulted in sequences that favored notes within the scale, but that lacked clear melodic, harmonic, or rhythmic structure. At the random positions, the sequence contained probe tones that were either within the established scale or were out of key. Our subjects ignored the note sequences, watching a self-selected silent movie with subtitles. Compared to the in-key probes, the out-of-key probes elicited a significantly larger P2 ERP component. Results show that random note sequences establish expectations of the "first-order" statistical property of musical key, even in listeners not actively monitoring the sequences.

Objective: The dorsal root ganglion is an attractive target for implanting neural electrode arrays that restore sensory function or provide therapy via stimulation. However, penetrating microelectrodes designed for these applications are small and deliver low currents. For long-term performance of microstimulation devices, novel coating materials are needed in part to decrease impedance values at the electrode-tissue interface and to increase charge storage capacity. Approach: Conductive polymer poly(3,4-ethylenedioxythiophene) (PEDOT) and multi-wall carbon nanotubes (CNTs) were coated on the electrode surface and doped with the anti-inflammatory drug, dexamethasone. Electrode characteristics and the tissue reaction around neural electrodes as a result of stimulation, coating and drug release were characterized. Hematoxylin and eosin staining along with antibodies recognizing Iba1 (microglia/macrophages), NF200 (neuronal axons), NeuN (neurons), vimentin (fibroblasts), caspase-3 (cell death) and L1 (neural cell adhesion molecule) were used. Quantitative image analyses were performed using MATLAB. Main results: Our results indicate that coated microelectrodes have lower in vitro and in vivo impedance values. Significantly less neuronal death/damage was observed with coated electrodes as compared to non-coated controls. The inflammatory response with the PEDOT/CNT-coated electrodes was also reduced. Significance: This study is the first to report on the utility of these coatings in stimulation applications. Our results indicate PEDOT/CNT coatings may be valuable additions to implantable electrodes used as therapeutic modalities.

Processing of complex signals in the hearing organ remains poorly understood. This paper aims to contribute to this topic by presenting investigations on the mechanical and neuronal response of the hearing organ of the tropical bushcricket species Mecopoda elongata to simple pure tone signals as well as to the conspecific song as a complex acoustic signal. The high-frequency hearing organ of bushcrickets, the crista acustica (CA), is tonotopically tuned to frequencies between about 4 and 70 kHz. Laser Doppler vibrometer measurements revealed a strong and dominant low-frequency-induced motion of the CA when stimulated with either pure tone or complex stimuli. Consequently, the high-frequency distal area of the CA is more strongly deflected by low-frequency-induced waves than by high-frequency-induced waves. This low-frequency dominance will have strong effects on the processing of complex signals. Therefore, we additionally studied the neuronal response of the CA to native and frequency-manipulated chirps. Again, we found a dominant influence of low-frequency components within the conspecific song, indicating that the mechanical vibration pattern highly determines the neuronal response of the sensory cells. Thus, we conclude that the encoding of communication signals is modulated by ear mechanics.

Chronic implantation of microelectrodes into the cortex has been shown to lead to inflammatory gliosis and neuronal loss in the microenvironment immediately surrounding the probe, a hypothesized cause of neural recording failure. Caspase-1 (aka Interleukin 1β converting enzyme) is known to play a key role in both inflammation and programmed cell death, particularly in stroke and neurodegenerative diseases. Caspase-1 knockout (KO) mice are resistant to apoptosis and these mice have preserved neurologic function by reducing ischemia-induced brain injury in stroke models. Local ischemic injury can occur following neural probe insertion and thus in this study we investigated the hypothesis that caspase-1 KO mice would have less ischemic injury surrounding the neural probe. In this study, caspase-1 KO mice were implanted with chronic single shank 3 mm Michigan probes into V1m cortex. Electrophysiology recording showed significantly improved single-unit recording performance (yield and signal to noise ratio) of caspase-1 KO mice compared to wild type C57B6 (WT) mice over the course of up to 6 months for the majority of the depth. The higher yield is supported by the improved neuronal survival in the caspase-1 KO mice. Impedance fluctuates over time but appears to be steadier in the caspase-1 KO especially at longer time points, suggesting milder glia scarring. These findings show that caspase-1 is a promising target for pharmacologic interventions.

Cortical reorganization following sensory deprivation is characterized by alterations in the connectivity between neurons encoding spared and deprived cortical inputs. The extent to which this alteration depends on Spike Timing Dependent Plasticity (STDP), however, is largely unknown. We quantified changes in the functional connectivity between layer V neurons in the vibrissal primary somatosensory cortex (vSI) (barrel cortex) of rats following sensory deprivation. One week after chronic implantation of a microelectrode array in vSI, sensory-evoked activity resulting from mechanical deflections of individual whiskers was recorded (control data) after which two whiskers on the contralateral side were paired by sparing them while trimming all other whiskers on the rat's mystacial pad. The rats' environment was then enriched by placing novel objects in the cages to encourage exploratory behavior with the spared whiskers. Sensory-evoked activity in response to individual stimulation of spared whiskers and adjacent re-grown whiskers was then recorded under anesthesia 1-2 days and 6-7 days post-trimming (plasticity data). We analyzed spike trains within 100 ms of stimulus onset and confirmed previously published reports documenting changes in receptive field sizes in the spared whisker barrels. We analyzed the same data using Dynamic Bayesian Networks (DBNs) to infer the functional connectivity between the recorded neurons. We found that DBNs inferred from population responses to stimulation of each of the spared whiskers exhibited graded increase in similarity that was proportional to the pairing duration. A significant early increase in network similarity in the spared-whisker barrels was detected 1-2 days post pairing, but not when single neuron responses were examined during the same period. These results suggest that rapid reorganization of cortical neurons following sensory deprivation may be mediated by an STDP mechanism.

Connections unifying hemispheric sensory representations of vision and touch occur in cortex, but for hearing, commissural connections earlier in the pathway may be important. The brainstem auditory pathways course bilaterally to the inferior colliculi (ICs). Each IC represents one side of auditory space but they are interconnected by a commissure. By deactivating one IC in guinea pig with cooling or microdialysis of procaine, and recording neural activity to sound in the other, we found that commissural input influences fundamental aspects of auditory processing. The areas of nonV frequency response areas (FRAs) were modulated, but the areas of almost all V-shaped FRAs were not. The supra-threshold sensitivity of rate level functions decreased during deactivation and the ability to signal changes in sound level was decremented. This commissural enhancement suggests the ICs should be viewed as a single entity in which the representation of sound in each is governed by the other.

Mutation of the Cacna1a gene for the P/Q (Ca V 2.1) calcium channel invariably leads to cerebellar dysfunction. The dysfunction has been attributed to disrupted rhythmicity of cerebellar Purkinje cells, but the hypothesis remains unproven. If irregular firing rates cause cerebellar dysfunction, then the irregularity and behavioral deficits should covary in a series of mutant strains of escalating severity. We compared firing irregularity in floccular and anterior vermis Purkinje cells in the mildly affected rocker and moderately affected tottering Cacna1a mutants and normal C57BL/6 mice. We also measured the amplitude and timing of modulations of floccular Purkinje cell firing rate during the horizontal vestibuloocular reflex (VOR, 0.25–1 Hz) and the horizontal and vertical optokinetic reflex (OKR, 0.125–1 Hz). We recorded Purkinje cells selective for rotational stimulation about the vertical axis (VAPCs) and a horizontal axis (HAPCs). Irregularity scaled with behavioral deficit severity in the flocculus but failed to do so in the vermis, challenging the irregularity hypothesis. Mutant VAPCs exhibited unusually strong modulation during VOR and OKR, the response augmentation scaling with phenotypic severity. HAPCs exhibited increased OKR modulation but in tottering only. The data contradict prior claims that modulation amplitude is unaffected in tottering but support the idea that attenuated compensatory eye movements in Cacna1a mutants arise from defective transfer of Purkinje cell signals to downstream circuitry, rather than attenuated synaptic transmission within the cerebellar cortex. Shifts in the relative sizes of the VAPC and HAPC populations raise the possibility that Cacna1a mutations influence the development of floccular zone architecture.

Sodium salicylate (SS) is a widely used medication with side effects on hearing. In order to understand these side effects, we recorded sound-driven local-field potentials in a neural structure, the dorsal cortex of the inferior colliculus (ICd). Using a microiontophoretic technique, we applied SS at sites of recording and studied how auditory responses were affected by the drug. Furthermore, we studied how the responses were affected by combined local application of SS and an agonists/antagonist of the type-A or type-B γ-aminobutyric acid receptor (GABAA or GABAB receptor). Results revealed that SS applied alone enhanced auditory responses in the ICd, indicating that the drug had local targets in the structure. Simultaneous application of the drug and a GABAergic receptor antagonist synergistically enhanced amplitudes of responses. The synergistic interaction between SS and a GABAA receptor antagonist had a relatively early start in reference to the onset of acoustic stimulation and the duration of this interaction was independent of sound intensity. The interaction between SS and a GABAB receptor antagonist had a relatively late start, and the duration of this interaction was dependent on sound intensity. Simultaneous application of the drug and a GABAergic receptor agonist produced an effect different from the sum of effects produced by the two drugs released individually. These differences between simultaneous and individual drug applications suggest that SS modified GABAergic inhibition in the ICd. Our results indicate that SS can affect sound-driven activity in the ICd by modulating local GABAergic inhibition.

The long-term stability and low-frequency composition of local field potentials (LFPs) offer important advantages for robust and efficient neuroprostheses. However, cortical LFPs recorded by multi-electrode arrays are often assumed to contain only redundant information arising from the activity of large neuronal populations. Here we show that multichannel LFPs in monkey motor cortex each contain a slightly different mixture of distinctive slow potentials that accompany neuronal firing. As a result, the firing rates of individual neurons can be estimated with surprising accuracy. We implemented this method in a real-time biofeedback brain–machine interface, and found that monkeys could learn to modulate the activity of arbitrary neurons using feedback derived solely from LFPs. These findings provide a principled method for monitoring individual neurons without long-term recording of action potentials.

The hemodynamic and metabolic response of the cortex depends spatially and temporally on the activity of multiple cell types. Optogenetics enables specific cell types to be modulated with high temporal precision and is therefore an emerging method for studying neurovascular and neurometabolic coupling. Going beyond temporal investigations, we developed a microprojection system to apply spatial photostimulus patterns in vivo. We monitored vascular and metabolic fluorescence signals after photostimulation in Thy1-channelrhodopsin-2 mice. Cerebral arteries increased in diameter rapidly after photostimulation, while nearby veins showed a slower smaller response. The amplitude of the arterial response was depended on the area of cortex stimulated. The fluorescence signal emitted at 450/100 nm and excited with ultraviolet is indicative of reduced nicotinamide adenine dinucleotide, an endogenous fluorescent enzyme involved in glycolysis and the citric acid cycle. This fluorescence signal decreased quickly and transiently after optogenetic stimulation, suggesting that glucose metabolism is tightly locked to optogenetic stimulation. To verify optogenetic stimulation of the cortex, we used a transparent substrate microelectrode array to map cortical potentials resulting from optogenetic stimulation. Spatial optogenetic stimulation is a new tool for studying neurovascular and neurometabolic coupling.

Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning. We therefore sought to further examine anxiety and emotional learning in an environmentally induced animal model of ASD that utilizes the administration of the known teratogen, valproic acid (VPA) during gestation. Specifically we exposed dams to one of two different doses of VPA (500 and 600 mg/kg) or vehicle on day 12.5 of gestation and examined the resultant progeny. Our data indicate that animals exposed to VPA in utero exhibit enhanced anxiety in the open field test and normal object recognition memory compared to control animals. Animals exposed to 500 mg/kg of VPA displayed normal acquisition of auditory fear conditioning, and exhibited reduced extinction of fear memory and normal litter survival rates as compared to control animals. We observed that animals exposed to 600 mg/kg of VPA exhibited a significant reduction in the acquisition of fear conditioning, a significant reduction in social interaction and a significant reduction in litter survival rates as compared to control animals. VPA (600 mg/kg) exposed animals exhibited similar shock sensitivity and hearing as compared to control animals indicating the fear conditioning deficit observed in these animals was not likely due to sensory deficits, but rather due to deficits in learning or memory retrieval. In conclusion, considering that progeny from dams exposed to rather similar doses of VPA exhibit striking differences in emotional learning, the VPA model may serve as a useful tool to explore the molecular and cellular mechanisms that contribute to not only ASD, but also emotional learning.