Electrophysiology publications

Brain–computer interface (BCI) technology decodes neural signals in real time to control external devices. In this study, chronic epidural micro-electrocorticographic recordings were performed over primary motor (M1) and dorsal premotor (PMd) cortex of three macaque monkeys. The differential gamma-band amplitude (75–105 Hz) from two arbitrarily chosen 300 μm electrodes (one located over each cortical area) was used for closed-loop control of a one-dimensional BCI device. Each monkey rapidly learned over a period of days to successfully control the velocity of a computer cursor. While both cortical areas contributed to success on the BCI task, the control signals from M1 were consistently modulated more strongly than those from PMd. Additionally, we observe that gamma-band power during active BCI control is always above resting brain activity. This suggests that purposeful gamma-band modulation is an active process that is obtained through increased cortical activation.

The activity of neural populations is determined not only by sensory inputs but also by internally generated patterns. During quiet wakefulness, the brain produces spontaneous firing events that can spread over large areas of cortex and have been suggested to underlie processes such as memory recall and consolidation. Here we demonstrate a different role for spontaneous activity in sensory cortex: gating of sensory inputs. We show that population activity in rat auditory cortex is composed of transient 50–100 ms packets of spiking activity that occur irregularly during silence and sustained tone stimuli, but reliably at tone onset. Population activity within these packets had broadly consistent spatiotemporal structure, but the rate and also precise relative timing of action potentials varied between stimuli. Packet frequency varied with cortical state, with desynchronized state activity consistent with superposition of multiple overlapping packets. We suggest that such packets reflect the sporadic opening of a “gate” that allows auditory cortex to broadcast a representation of external sounds to other brain regions.

In this paper, we report on a cost effective and simple method for fabricating a flexible multi-electrode array for subdural neural recording. The electrode was fabricated using a PDMS-Parylene bilayer to combine the major advantages of both materials. Mechanical and electrical characterizations were performed to confirm functionality of a 16-site electrode array under various flexed/bent conditions. The electrode array was helically wound around a 3 mm diameter cylindrical tube and laid over a 2 cm diameter sphere while maintaining its recording capability. Experimental results showed impedance values between 300 kΩ and 600 kΩ at 1 kHz for 90 μm diameter gold recording sites. Acoustically evoked neural activity was successfully recorded from rat auditory cortex, confirming in vivo functionality.

High-count microelectrode arrays implanted in peripheral nerves could restore motor function after spinal cord injury or sensory function after limb loss. In this study, we implanted Utah Slanted Electrode Arrays (USEAs) intrafascicularly at the elbow or shoulder in arm nerves of rhesus monkeys ( n = 4) under isoflurane anesthesia. Input-output curves indicated that pulse-width-modulated single-electrode stimulation in each arm nerve could recruit single muscles with little or no recruitment of other muscles. Stimulus trains evoked specific, natural, hand movements, which could be combined via multielectrode stimulation to elicit coordinated power or pinch grasp. Stimulation also elicited short-latency evoked potentials (EPs) in primary somatosensory cortex, which might be used to provide sensory feedback from a prosthetic limb. These results demonstrate a high-resolution, high-channel-count interface to the peripheral nervous system for restoring hand function after neural injury or disruption or for examining nerve structure.

In contrast to numerous studies of transcallosal communication in visual and somatosensory cortices, the functional properties of interhemispheric connections between auditory cortical fields have not been widely scrutinized. Therefore, the purpose of the present investigation was to measure the magnitude and type (inhibitory/excitatory) of modulatory properties of core auditory fields on contralateral primary auditory cortex (A1) activity. We combined single-unit neuronal recordings with reversible cooling deactivation techniques to measure variations in contralateral A1 response levels during A1, anterior auditory field (AAF), or simultaneous A1 and AAF neuronal discharge suppression epochs in cat auditory cortex. Cortical activity was evoked by presentation of pure tones, noise bursts, and frequency-modulated (FM) sweeps before, during, and after cortical deactivation periods. Comparisons of neuronal response changes before and during neuronal silencing revealed three major findings. First, deactivation of A1 and AAF-induced significant peak response reductions in contralateral A1 activity during simple (tonal) and complex (noise bursts and FM sweeps) acoustic exposure. Second, decreases in A1 neuronal activity appear to be in agreement with anatomical laminar termination patterns emanating from contralateral auditory cortex fields. Third, modulatory properties of core auditory areas lack hemispheric lateralization. These findings demonstrate that during periods of acoustic exposure, callosal projections emanating from core auditory areas modulate A1 neuronal activity via excitatory inputs.

Motor tics, a cardinal symptom of Tourette syndrome (TS), are hypothesized to arise from abnormalities within cerebro-basal ganglia circuits. Yet noninvasive neuroimaging of TS has previously identified robust activation in the cerebellum. To date, electrophysiological properties of cerebellar activation and its role in basal ganglia-mediated tic expression remain unknown. We performed multisite, multielectrode recordings of single-unit activity and local field potentials from the cerebellum, basal ganglia, and primary motor cortex using a pharmacologic monkey model of motor tics/TS. Following microinjections of bicuculline into the sensorimotor putamen, periodic tics occurred predominantly in the orofacial region, and a sizable number of cerebellar neurons showed phasic changes in activity associated with tic episodes. Specifically, 64% of the recorded cerebellar cortex neurons exhibited increases in activity, and 85% of the dentate nucleus neurons displayed excitatory, inhibitory, or multiphasic responses. Critically, abnormal discharges of cerebellar cortex neurons and excitatory-type dentate neurons mostly preceded behavioral tic onset, indicating their central origins. Latencies of pathological activity in the cerebellum and primary motor cortex substantially overlapped, suggesting that aberrant signals may be traveling along divergent pathways to these structures from the basal ganglia. Furthermore, the occurrence of tic movement was most closely associated with local field potential spikes in the cerebellum and primary motor cortex, implying that these structures may function as a gate to release overt tic movements. These findings indicate that tic-generating networks in basal ganglia mediated tic disorders extend beyond classical cerebro-basal ganglia circuits, leading to global network dysrhythmia including cerebellar circuits.

Objective: Hierarchical processing of auditory sensory information is believed to occur in two streams: a ventral stream responsible for stimulus identity and a dorsal stream responsible for processing spatial elements of a stimulus. The objective of the current study is to examine neural coding in this processing stream in the context of understanding the possibility for an auditory cortical neural prosthesis. Approach: We examined the selectivity for species-specific primate vocalizations in the ventral auditory processing stream by applying a statistical classifier to neural data recorded from microelectrode arrays. Multi-unit activity (MUA) and local field potential (LFP) data recorded simultaneously from primary auditory complex (AI) and rostral parabelt (PBr) were decoded on a trial-by-trial basis. Main results: While decode performance in AI was well above chance, mean performance in PBr did not deviate >15% from chance level. Mean performance levels were similar for MUA and LFP decodes. Increasing the spectral and temporal resolution improved decode performance; while inter-electrode spacing could be as large as 1.14 mm without degrading decode performance. Significance: These results serve as preliminary guidance for a human auditory cortical neural prosthesis; instructing interface implementation, microstimulation patterns and anatomical placement.

Monocular deprivation (MD) during a critical period of postnatal development produces significant changes in the anatomy and physiology of the visual cortex, and the deprived eye becomes amblyopic. Extracellular matrix molecules have a major role in restricting plasticity such that the ability to recover from MD decreases with age. Chondroitin sulfate proteoglycans (CSPGs) act as barriers to cell migration and axon growth. Previous studies showing that degradation of CSPGs by the bacterial enzyme chondroitinase can restore plasticity in the adult rat visual cortex suggest a potential treatment for amblyopia. Here MD was imposed in cats from the start of the critical period until 3.5 months of age. The deprived eye was reopened, the functional architecture of the visual cortex was assessed by optical imaging of intrinsic signals, and chondroitinase was injected into one hemisphere. Imaging was repeated 1 and 2 weeks postinjection, and visually evoked potentials (VEPs) and single-cell activity were recorded. Immunohistochemistry showed that digestion of CSPGs had been successful. After 2 weeks of binocular exposure, some recovery of deprived-eye responses occurred when chondroitinase had been injected into the hemisphere contralateral to that eye; when injected into the ipsilateral hemisphere, no recovery was seen. Deprived-eye VEPs were no larger in the injected hemisphere than in the opposite hemisphere. The small number of neurons dominated by the deprived eye exhibited poor tuning characteristics. These results suggest that despite structural effects of chondroitinase in adult cat V1, plasticity was not sufficiently restored to enable significant functional recovery of the deprived eye.

Auditory neurons that exhibit stimulus-specific adaptation (SSA) decrease their response to common tones while retaining responsiveness to rare ones. We recorded single-unit responses from the inferior colliculus (IC) where SSA is known to occur and we explored for the first time SSA in the cochlear nucleus (CN) of rats. We assessed an important functional outcome of SSA, the extent to which frequency discriminability depends on sensory context. For this purpose, pure tones were presented in an oddball sequence as standard (high probability of occurrence) or deviant (low probability of occurrence) stimuli. To study frequency discriminability under different probability contexts, we varied the probability of occurrence and the frequency separation between tones. The neuronal sensitivity was estimated in terms of spike-count probability using signal detection theory. We reproduced the finding that many neurons in the IC exhibited SSA, but we did not observe significant SSA in our CN sample. We concluded that strong SSA is not a ubiquitous phenomenon in the CN. As predicted, frequency discriminability was enhanced in IC when stimuli were presented in an oddball context, and this enhancement was correlated with the degree of SSA shown by the neurons. In contrast, frequency discrimination by CN neurons was independent of stimulus context. Our results demonstrated that SSA is not widespread along the entire auditory pathway, and suggest that SSA increases frequency discriminability of single neurons beyond that expected from their tuning curves.

In order to extract information in a rich environment, we focus on different features that allow us to direct attention to whatever source is of interest. The cortical network deployed during spatial attention, especially in vision, is well characterized. For example, visuospatial attention engages a frontoparietal network including the frontal eye fields (FEFs), which modulate activity in visual sensory areas to enhance the representation of an attended visual object. However, relatively little is known about the neural circuitry controlling attention directed to non-spatial features, or to auditory objects or features (either spatial or non-spatial). Here, using combined magnetoencephalography (MEG) and anatomical information obtained from MRI, we contrasted cortical activity when observers attended to different auditory features given the same acoustic mixture of two simultaneous spoken digits. Leveraging the fine temporal resolution of MEG, we establish that activity in left FEF is enhanced both prior to and throughout the auditory stimulus when listeners direct auditory attention to target location compared to when they focus on target pitch. In contrast, activity in the left posterior superior temporal sulcus (STS), a region previously associated with auditory pitch categorization, is greater when listeners direct attention to target pitch rather than target location. This differential enhancement is only significant after observers are instructed which cue to attend, but before the acoustic stimuli begin. We therefore argue that left FEF participates more strongly in directing auditory spatial attention, while the left STS aids auditory object selection based on the non-spatial acoustic feature of pitch.

Selective auditory attention is essential for human listeners to be able to communicate in multi-source environments. Selective attention is known to modulate the neural representation of the auditory scene, boosting the representation of a target sound relative to the background, but the strength of this modulation, and the mechanisms contributing to it, are not well understood. Here, listeners performed a behavioral experiment demanding sustained, focused spatial auditory attention while we measured cortical responses using electroencephalography (EEG). We presented three concurrent melodic streams; listeners were asked to attend and analyze the melodic contour of one of the streams, randomly selected from trial to trial. In a control task, listeners heard the same sound mixtures, but performed the contour judgment task on a series of visual arrows, ignoring all auditory streams. We found that the cortical responses could be fit as weighted sum of event-related potentials evoked by the stimulus onsets in the competing streams. The weighting to a given stream was roughly 10 dB higher when it was attended compared to when another auditory stream was attended; during the visual task, the auditory gains were intermediate. We then used a template-matching classification scheme to classify single-trial EEG results. We found that in all subjects, we could determine which stream the subject was attending significantly better than by chance. By directly quantifying the effect of selective attention on auditory cortical responses, these results reveal that focused auditory attention both suppresses the response to an unattended stream and enhances the response to an attended stream. The single-trial classification results add to the growing body of literature suggesting that auditory attentional modulation is sufficiently robust that it could be used as a control mechanism in brain-computer interfaces (BCIs).

Brain-machine interfaces (BMI) were born to control "actions from thoughts" in order to recover motor capability of patients with impaired functional connectivity between the central and peripheral nervous system. The final goal of our studies is the development of a new proof-of-concept BMI-a neuromorphic chip for brain repair-to reproduce the functional organization of a damaged part of the central nervous system. To reach this ambitious goal, we implemented a multidisciplinary "bottom-up" approach in which in vitro networks are the paradigm for the development of an in silico model to be incorporated into a neuromorphic device. In this paper we present the overall strategy and focus on the different building blocks of our studies: (i) the experimental characterization and modeling of "finite size networks" which represent the smallest and most general self-organized circuits capable of generating spontaneous collective dynamics; (ii) the induction of lesions in neuronal networks and the whole brain preparation with special attention on the impact on the functional organization of the circuits; (iii) the first production of a neuromorphic chip able to implement a real-time model of neuronal networks. A dynamical characterization of the finite size circuits with single cell resolution is provided. A neural network model based on Izhikevich neurons was able to replicate the experimental observations. Changes in the dynamics of the neuronal circuits induced by optical and ischemic lesions are presented respectively for in vitro neuronal networks and for a whole brain preparation. Finally the implementation of a neuromorphic chip reproducing the network dynamics in quasi-real time (10 ns precision) is presented.

Subtle random deviations from perfect symmetry in bilateral traits are suggested to signal reduced phenotypic and genetic quality of a sender, but only little is known about the related receiver mechanisms for discriminating symmetrical from asymmetrical traits. Here we investigate these mechanisms in behavioural and neurophysiological experiments in the Mediterranean field cricket, Gryllus bimaculatus. A downward frequency modulation at the end of each syllable in the calling song has been suggested to indicate morphological asymmetry in sound radiating structures between left and right forewings. Even under ideal laboratory conditions on a trackball system female crickets only discriminated between songs of symmetrical and asymmetrical males in two-choice experiments at carrier frequencies of 4.4 kHz and large modulation depth of 600 and 800 Hz. Under these conditions they preferred the pure tone calling songs over the modulated (asymmetrical) alternative, whereas no preference was observed at carrier frequencies of 4.9 and 5.2 kHz. These preferences correlate well with responses of a pair of identified auditory interneuron (AN1), known for its importance in female phonotaxis. The interneuron is tuned to an average frequency of 4.9 kHz, and the roll-off towards lower and higher frequencies determines the magnitude of responses to pure tone and frequency modulated calling songs. The difference in response magnitude between the two neurons appears to drive the decision of females towards the song alternatives. We discuss the relevance of song differences based on asymmetry in the morphology of song producing structures under natural conditions.

Axons from the nucleus magnocellularis (NM) and their targets in nucleus laminaris (NL) form the circuit responsible for encoding interaural time differences (ITDs). In barn owls, NL receives bilateral inputs from NM such that axons from the ipsilateral NM enter NL dorsally, while contralateral axons enter from the ventral side. These afferents and their synapses on NL neurons generate a tone-induced local field potential, or neurophonic, that varies systematically with position in NL. From dorsal to ventral within the nucleus, the best interaural time difference (ITD) of the neurophonic shifts from contralateral space to best ITDs around 0 µs. Earlier recordings suggested that in NL, iso-delay contours ran parallel to the dorsal and ventral borders of NL (Sullivan WE, Konishi M. Proc Natl Acad Sci U S A 83:8400-8404, 1986). This axis is orthogonal to that seen in chicken NL, where a single map of ITD runs from around 0 µs ITD medially to contralateral space laterally (Köppl C, Carr CE. Biol Cyber 98:541-559, 2008). Yet the trajectories of the NM axons are similar in owl and chicken (Seidl AH, Rubel EW, Harris DM, J Neurosci 30:70-80, 2010). We therefore used clicks to measure conduction time in NL and made lesions to mark the 0 µs iso-delay contour in multiple penetrations along an isofrequency slab. Iso-delay contours were not parallel to the dorsal and ventral borders of NL; instead the 0 µs iso-delay contour shifted systematically from a dorsal position in medial NL to a ventral position in lateral NL. Could different conduction delays account for the mediolateral shift in the representation of 0 µs ITD? We measured conduction delays using the neurophonic potential and developed a simple linear model of the delay-line conduction velocity. We then raised young owls with time-delaying earplugs in one ear (Gold JI, Knudsen EI, J Neurophysiol 82:2197-2209, 1999) to examine map plasticity.

The nonsteroidal antiinflammatory drug (NSAID) ketorolac is a candidate for use as a supplemental analgesic during major surgery in anesthetized rodents. The use of ketorolac during surgery is believed to reduce the anesthetic dose required to achieve and maintain an adequate surgical plane, thus improving the physiologic condition and survival of animals during long experimental procedures. Ketorolac has reported side effects that include dizziness, ear pain, hearing loss, tinnitus, and vertigo in humans, but ketorolac has not been reported to affect the vestibular system in animals. To investigate this possibility, we evaluated the acute effects of ketorolac on vestibular compound action potentials in C57BL/6 mice. Linear vestibular sensory-evoked potentials (VsEP) were recorded during the administration of ketorolac at doses 3 to 14 times the effective analgesic dose. VsEP results for ketorolac were compared with those from a control group maintained under anesthesia for the same period. Ketorolac did not significantly affect the temporal profiles of response latencies and amplitudes or the rate of change in response measures over time between controls and ketorolac-treated mice. These findings demonstrate that ketorolac can be used as an analgesic to supplement anesthesia in mice without concerns of modifying the amplitudes and latencies of the linear VsEP.

Descending projections from the cortex to subcortical structures are critical for auditory plasticity, including the ability for central neurons to adjust their frequency tuning to relevant and meaningful stimuli. We show that focal electrical stimulation of primary auditory cortex in guinea pigs produces excitatory responses in the central nucleus of the inferior colliculus (CNIC) with two tonotopic patterns: a narrow tuned pattern that is consistent with previous findings showing direct frequency-aligned projections; and a broad tuned pattern in which the auditory cortex can influence multiple frequency regions. Moreover, excitatory responses could be elicited in the caudomedial portion along the isofrequency laminae of the CNIC but not in the rostrolateral portion. This descending organization may underlie or contribute to the ability of the auditory cortex to induce changes in frequency tuning of subcortical neurons as shown extensively in previous studies.

The encoding of auditory spatial acuity (measured as the precision to distinguish between two spatially distinct stimuli) by neural circuits in both auditory cortices is a matter of ongoing research. Here, the event-related potential (ERP) mismatch negativity (MMN), a sensitive indicator of preattentive auditory change detection, was used to tap into the underlying mechanism of cortical representation of auditory spatial information. We characterized the MMN response affected by the degree of spatial deviance in lateral acoustic space using a passive oddball paradigm. Two stimulation conditions (SCs)-specifically focusing on the investigation of the mid- and far-lateral acoustic space-were considered: (1) 65° left standard position with deviant positions at 70, 75, and 80°; and (2) 95° left standard position with deviant positions at 90, 85, and 80°. Additionally, behavioral data on the minimum audible angle (MAA) were acquired for the respective standard positions (65, 95° left) to quantify spatial discrimination in separating distinct sound sources. The two measurements disclosed the linkage between the (preattentive) MMN response and the (attentive) behavioral threshold. At 65° spatial deviations as small as 5° reliably elicited MMNs. Thereby, the MMN amplitudes monotonously increased as a function of spatial deviation. At 95°, spatial deviations of 15° were necessary to elicit a valid MMN. The behavioral data, however, yielded no difference in mean MAA thresholds for position 65 and 95°. The different effects of laterality on MMN responses and MAA thresholds suggest a role of spatial selective attention mechanisms particularly relevant in active discrimination of neighboring sound sources, especially in the lateral acoustic space.

Auditory neurons in bats that use frequency modulated (FM) sweeps for echolocation are selective for the behaviorally-relevant rates and direction of frequency change. Such selectivity arises through spectrotemporal interactions between excitatory and inhibitory components of the receptive field. In the pallid bat auditory system, the relationship between FM sweep direction/rate selectivity and spectral and temporal properties of sideband inhibition have been characterized. Of note is the temporal asymmetry in sideband inhibition, with low-frequency inhibition (LFI) exhibiting faster arrival times compared to high-frequency inhibition (HFI). Using the two-tone inhibition over time (TTI) stimulus paradigm, this study investigated the interactions between two sound parameters in shaping sideband inhibition: intensity and time. Specifically, the impact of changing relative intensities of the excitatory and inhibitory tones on arrival time of inhibition was studied. Using this stimulation paradigm, single unit data from the auditory cortex of pentobarbital-anesthetized cortex show that the threshold for LFI is on average ~8 dB lower than HFI. For equal intensity tones near threshold, LFI is stronger than HFI. When the inhibitory tone intensity is increased further from threshold, the strength asymmetry decreased. The temporal asymmetry in LFI vs. HFI arrival time is strongest when the excitatory and inhibitory tones are of equal intensities or if excitatory tone is louder. As inhibitory tone intensity is increased, temporal asymmetry decreased suggesting that the relative magnitude of excitatory and inhibitory inputs shape arrival time of inhibition and FM sweep rate and direction selectivity. Given that most FM bats use downward sweeps as echolocation calls, a similar asymmetry in threshold and strength of LFI vs. HFI may be a general adaptation to enhance direction selectivity while maintaining sweep-rate selective responses to downward sweeps.

Cerebellar granule cells (GrCs) convey information from mossy fibers (MFs) to Purkinje cells (PCs) via their parallel fibers (PFs). MF to GrC signaling allows transmission of frequencies up to 1 kHz and GrCs themselves can also fire bursts of action potentials with instantaneous frequencies up to 1 kHz. So far, in the scientific literature no evidence has been shown that these high-frequency bursts also exist in awake, behaving animals. More so, it remains to be shown whether such high-frequency bursts can transmit temporally coded information from MFs to PCs and/or whether these patterns of activity contribute to the spatiotemporal filtering properties of the GrC layer. Here, we show that, upon sensory stimulation in both un-anesthetized rabbits and mice, GrCs can show bursts that consist of tens of spikes at instantaneous frequencies over 800 Hz. In vitro recordings from individual GrC-PC pairs following high-frequency stimulation revealed an overall low initial release probability of ~0.17. Nevertheless, high-frequency burst activity induced a short-lived facilitation to ensure signaling within the first few spikes, which was rapidly followed by a reduction in transmitter release. The facilitation rate among individual GrC-PC pairs was heterogeneously distributed and could be classified as either "reluctant" or "responsive" according to their release characteristics. Despite the variety of efficacy at individual connections, grouped activity in GrCs resulted in a linear relationship between PC response and PF burst duration at frequencies up to 300 Hz allowing rate coding to persist at the network level. Together, these findings support the hypothesis that the cerebellar granular layer acts as a spatiotemporal filter between MF input and PC output (D'Angelo and De Zeeuw, 2009).