Electrophysiology publications

First ever in vivo sensor for directly measuring cocaine concentration in the brain via electrochemical detection at DNA aptamer functionalized single shank, silicon-based neural recording probes.

The interlaminar connections in the primate primary visual cortex (V1) are well described, as is the presence of ongoing alpha-range (7-14 Hz) fluctuations in this area. Less well understood is how these interlaminar connections and ongoing fluctuations contribute to the regulation of visual spiking responses. Here, we investigate the relationship between alpha fluctuations and spiking responses to visual stimuli across cortical layers. Using laminar probes in macaque V1, we show that neural firing couples with the phase of alpha fluctuations, and that magnitude of this coupling is particularly pronounced during visual stimulation. The strongest modulation of spiking activity was observed in layers 2/3. Alpha-spike coupling and current source density analysis pointed to an infragranular origin of the alpha fluctuations. Taken together, these results indicate that ongoing infragranular alpha-range fluctuations in V1 play a role in regulating columnar visual activity.

We develop a framework to uncover and analyse dynamical anomalies from massive, nonlinear and non-stationary time series data. The framework consists of three steps: preprocessing of massive datasets to eliminate erroneous data segments, application of the empirical mode decomposition and Hilbert transform paradigm to obtain the fundamental components embedded in the time series at distinct time scales, and statistical/scaling analysis of the components. As a case study, we apply our framework to detecting and characterizing high-frequency oscillations (HFOs) from a big database of rat electroencephalogram recordings. We find a striking phenomenon: HFOs exhibit on–off intermittency that can be quantified by algebraic scaling laws. Our framework can be generalized to big data-related problems in other fields such as large-scale sensor data and seismic data analysis.

In active sensing, animals make motor adjustments to match sensory inputs to specialized neural circuitry. Here, we describe an active sensing system for sound level processing. The pallid bat uses downward frequency-modulated (FM) sweeps as echolocation calls for general orientation and obstacle avoidance. The bat’s auditory cortex contains a region selective for these FM sweeps (FM sweep-selective region, FMSR). We show that the vast majority of FMSR neurons are sensitive and strongly selective for relatively low levels (30-60 dB SPL). Behavioral testing shows that when a flying bat approaches a target, it reduces output call levels to keep echo levels between ∼30 and 55 dB SPL. Thus, the pallid bat behaviorally matches echo levels to an optimized neural representation of sound levels. FMSR neurons are more selective for sound levels of FM sweeps than tones, suggesting that across-frequency integration enhances level tuning. Level-dependent timing of high-frequency sideband inhibition in the receptive field shapes increased level selectivity for FM sweeps. Together with previous studies, these data indicate that the same receptive field properties shape multiple filters (sweep direction, rate, and level) for FM sweeps, a sound common in multiple vocalizations, including human speech. The matched behavioral and neural adaptations for low-intensity echolocation in the pallid bat will facilitate foraging with reduced probability of acoustic detection by prey.

Visual cortical neurons are tuned to similar orientations through the two eyes. The binocularly-matched orientation preference is established during a critical period in early life, but the underlying circuit mechanisms remain unknown. Here, we optogenetically isolated the thalamocortical and intracortical excitatory inputs to individual layer 4 neurons and studied their binocular matching. In adult mice, the thalamic and cortical inputs representing the same eyes are similarly tuned and both are matched binocularly. In mice before the critical period, the thalamic input is already slightly matched, but the weak matching is not manifested due to random connections in the cortex, especially those serving the ipsilateral eye. Binocular matching is thus mediated by orientation-specific changes in intracortical connections and further improvement of thalamic matching. Together, our results suggest that the feed-forward thalamic input may play a key role in initiating and guiding the functional refinement of cortical circuits in critical period development.

Cochlear hair cells and the stria vascularis are critical for normal hearing. Hair cells transduce mechanical stimuli into electrical signals, whereas the stria is responsible for generating the endocochlear potential (EP), which is the driving force for hair cell mechanotransduction. We questioned whether hair cells and the stria interdepend for survival by using two mouse models. Atoh1 conditional knockout mice, which lose all hair cells within four weeks after birth, were used to determine whether the absence of hair cells would affect function and survival of stria. We showed that stria morphology and EP remained normal for long time despite a complete loss of all hair cells. We then used a mouse model that has an abnormal stria morphology and function due to mutation of the Mitf gene to determine whether hair cells are able to survive and transduce sound signals without a normal electrochemical environment in the endolymph. A strial defect, reflected by missing intermediate cells in the stria and by reduction of EP, led to systematic outer hair cell death from the base to the apex after postnatal day 18. However, an 18-mV EP was sufficient for outer hair cell survival. Surprisingly, inner hair cell survival was less vulnerable to reduction of the EP. Our studies show that normal function of the stria is essential for adult outer hair cell survival, while the survival and normal function of the stria vascularis do not depend on functional hair cells.

Respiration plays an essential role in odor processing. Even in the absence of odors, oscillating excitatory and inhibitory activity in the olfactory bulb synchronizes with respiration, commonly resulting in a burst of action potentials in mammalian mitral/tufted cells (MTCs) during the transition from inhalation to exhalation. This excitation is followed by inhibition that quiets MTC activity in both the glomerular and granule cell layers. Odor processing is hypothesized to be modulated by and may even rely on respiration-mediated activity, yet exactly how respiration influences sensory processing by MTCs is still not well understood. By using optogenetics to stimulate discrete sensory inputs in vivo, it was possible to temporally vary the stimulus to occur at unique phases of each respiration. Single unit recordings obtained from the mitral cell layer were used to map spatiotemporal patterns of glomerular evoked responses that were unique to stimulations occurring during periods of inhalation or exhalation. Sensory evoked activity in MTCs was gated to periods outside phasic respiratory mediated firing, causing net shifts in MTC activity across the cycle. In contrast, odor evoked inhibitory responses appear to be permitted throughout the respiratory cycle. Computational models were used to further explore mechanisms of inhibition that can be activated by respiratory activity and influence MTC responses. In silico results indicate that both periglomerular and granule cell inhibition can be activated by respiration to internally gate sensory responses in the olfactory bulb. Both the respiration rate and strength of lateral connectivity influenced inhibitory mechanisms that gate sensory evoked responses.

The analysis of cross-frequency coupling (CFC) has become popular in studies involving intracranial and scalp EEG recordings in humans. It has been argued that some cases where CFC is mathematically present may not reflect an interaction of two distinct yet functionally coupled neural sources with different frequencies. Here we provide two empirical examples from intracranial recordings where CFC can be shown to be driven by the shape of a periodic waveform rather than by a functional interaction between distinct sources. Using simulations, we also present a generalized and realistic scenario where such coupling may arise. This scenario, which we term waveform-dependent CFC, arises when sharp waveforms (e.g., cortical potentials) occur throughout parts of the data, in particular if they occur rhythmically. Since the waveforms contain both low- and high-frequency components, these components can be inherently phase-aligned as long as the waveforms are spaced with appropriate intervals. We submit that such behavior of the data, which seems to be present in various cortical signals, cannot be interpreted as reflecting functional modulation between distinct neural sources without additional evidence. In addition, we show that even low amplitude periodic potentials that cannot be readily observed or controlled for, are sufficient for significant CFC to occur.

Bidirectional brain-machine interfaces (BMIs) establish a two-way direct communication link between the brain and the external world. A decoder translates recorded neural activity into motor commands and an encoder delivers sensory information collected from the environment directly to the brain creating a closed-loop system. These two modules are typically integrated in bulky external devices. However, the clinical support of patients with severe motor and sensory deficits requires compact, low-power, and fully implantable systems that can decode neural signals to control external devices. As a first step toward this goal, we developed a modular bidirectional BMI setup that uses a compact neuromorphic processor as a decoder. On this chip we implemented a network of spiking neurons built using its ultra-low-power mixed-signal analog/digital circuits. On-chip on-line spike-timing-dependent plasticity synapse circuits enabled the network to learn to decode neural signals recorded from the brain into motor outputs controlling the movements of an external device. The modularity of the BMI allowed us to tune the individual components of the setup without modifying the whole system. In this paper, we present the features of this modular BMI and describe how we configured the network of spiking neuron circuits to implement the decoder and to coordinate it with the encoder in an experimental BMI paradigm that connects bidirectionally the brain of an anesthetized rat with an external object. We show that the chip learned the decoding task correctly, allowing the interfaced brain to control the object's trajectories robustly. Based on our demonstration, we propose that neuromorphic technology is mature enough for the development of BMI modules that are sufficiently low-power and compact, while being highly computationally powerful and adaptive.

Acoustic environments are composed of complex overlapping sounds that the auditory system is required to segregate into discrete perceptual objects. The functions of distinct auditory processing stations in this challenging task are poorly understood. Here we show a direct role for mouse auditory cortex in detection and segregation of acoustic information. We measured the sensitivity of auditory cortical neurons to brief tones embedded in masking noise. By altering spectrotemporal characteristics of the masker, we reveal that sensitivity to pure tone stimuli is strongly enhanced in coherently modulated broadband noise, corresponding to the psychoacoustic phenomenon comodulation masking release. Improvements in detection were largest following priming periods of noise alone, indicating that cortical segregation is enhanced over time. Transient opsin-mediated silencing of auditory cortex during the priming period almost completely abolished these improvements, suggesting that cortical processing may play a direct and significant role in detection of quiet sounds in noisy environments. SIGNIFICANCE STATEMENT Auditory systems are adept at detecting and segregating competing sound sources, but there is little direct evidence of how this process occurs in the mammalian auditory pathway. We demonstrate that coherent broadband noise enhances signal representation in auditory cortex, and that prolonged exposure to noise is necessary to produce this enhancement. Using optogenetic perturbation to selectively silence auditory cortex during early noise processing, we show that cortical processing plays a crucial role in the segregation of competing sounds.

During non-rapid eye movement (NREM) sleep, cortical neurons alternate between ON periods of firing and OFF periods of silence. This bi-stability, which is largely synchronous across neurons, is reflected in the EEG as slow waves. Slow-wave activity (SWA) increases with wake duration and declines homeostatically during sleep, but the underlying mechanisms remain unclear. One possibility is neuronal “fatigue”: high, sustained firing in wake would force neurons to recover with more frequent and longer OFF periods during sleep. Another possibility is net synaptic potentiation during wake: stronger coupling among neurons would lead to greater synchrony and therefore higher SWA. Here, we obtained a comparable increase in sustained firing (6 h) in cortex by: (1) keeping mice awake by exposure to novel objects to promote plasticity and (2) optogenetically activating a local population of cortical neurons at wake-like levels during sleep. Sleep after extended wake led to increased SWA, higher synchrony, and more time spent OFF, with a positive correlation between SWA, synchrony, and OFF periods. Moreover, time spent OFF was correlated with cortical firing during prior wake. After local optogenetic stimulation, SWA and cortical synchrony decreased locally, time spent OFF did not change, and local SWA was not correlated with either measure. Moreover, laser-induced cortical firing was not correlated with time spent OFF afterward. Overall, these results suggest that high sustained firing per se may not be the primary determinant of SWA increases observed after extended wake. SIGNIFICANCE STATEMENT A long-standing hypothesis is that neurons fire less during slow-wave sleep to recover from the “fatigue” accrued during wake, when overall synaptic activity is higher than in sleep. This idea, however, has rarely been tested and other factors, namely increased cortical synchrony, could explain why sleep slow-wave activity (SWA) is higher after extended wake. We forced neurons in the mouse cortex to fire at high levels for 6 h in 2 different conditions: during active wake with exploration and during sleep. We find that neurons need more time OFF only after sustained firing in wake, suggesting that fatigue due to sustained firing alone is unlikely to account for the increase in SWA that follows sleep deprivation.

Despite the success of cochlear implants (CIs) in human populations, most users perform poorly in noisy environments and music and tonal language perception. How CI devices engage the brain at the single neuron level has remained largely unknown, in particular in the primate brain. By comparing neuronal responses with acoustic and CI stimulation in marmoset monkeys unilaterally implanted with a CI electrode array, we discovered that CI stimulation was surprisingly ineffective at activating many neurons in auditory cortex, particularly in the hemisphere ipsilateral to the CI. Further analyses revealed that the CI-nonresponsive neurons were narrowly tuned to frequency and sound level when probed with acoustic stimuli; such neurons likely play a role in perceptual behaviors requiring fine frequency and level discrimination, tasks that CI users find especially challenging. These findings suggest potential deficits in central auditory processing of CI stimulation and provide important insights into factors responsible for poor CI user performance in a wide range of perceptual tasks. SIGNIFICANCE STATEMENT The cochlear implant (CI) is the most successful neural prosthetic device to date and has restored hearing in hundreds of thousands of deaf individuals worldwide. However, despite its huge successes, CI users still face many perceptual limitations, and the brain mechanisms involved in hearing through CI devices remain poorly understood. By directly comparing single-neuron responses to acoustic and CI stimulation in auditory cortex of awake marmoset monkeys, we discovered that neurons unresponsive to CI stimulation were sharply tuned to frequency and sound level. Our results point out a major deficit in central auditory processing of CI stimulation and provide important insights into mechanisms underlying the poor CI user performance in a wide range of perceptual tasks.

The addition of tactile and proprioceptive feedback to neuroprosthetic limbs is expected to significantly improve the control of these devices. Intracortical microstimulation (ICMS) of somatosensory cortex is a promising method of delivering this sensory feedback. To date, the main focus of somatosensory ICMS studies has been to deliver discriminable signals, corresponding to varying intensity, to a single location in cortex. However, multiple independent and simultaneous streams of sensory information will need to be encoded by ICMS to provide functionally relevant feedback for a neuroprosthetic limb (e.g., encoding contact events and pressure on multiple digits). In this study, we evaluated the ability of an awake, behaving non-human primate (Macaca mulatta) to discriminate ICMS stimuli delivered on multiple electrodes spaced within somatosensory cortex. We delivered serial stimulation on single electrodes to evaluate the discriminability of sensations corresponding to ICMS of distinct cortical locations. Additionally, we delivered trains of multichannel stimulation, derived from a tactile sensor, synchronously across multiple electrodes. Our results indicate that discrimination of multiple ICMS stimuli is a challenging task, but that discriminable sensory percepts can be elicited by both single and multichannel ICMS on electrodes spaced within somatosensory cortex.

Consciousness has been linked to the repertoire of brain states at various spatiotemporal scales. Anesthesia is thought to modify consciousness by altering information integration in cortical and thalamocortical circuits. At a mesoscopic scale, neuronal populations in the cortex form synchronized ensembles whose characteristics are presumably state-dependent but this has not been rigorously tested. In this study, spontaneous neuronal activity was recorded with 64-contact microelectrode arrays in primary visual cortex of chronically instrumented, unrestrained rats under stepwise decreasing levels of desflurane anesthesia (8%, 6%, 4%, and 2% inhaled concentrations) and wakefulness (0% concentration). Negative phases of the local field potentials formed compact, spatially contiguous activity patterns (CAPs) that were not due to chance. The number of CAPs was 120% higher in wakefulness and deep anesthesia associated with burst-suppression than at intermediate levels of consciousness. The frequency distribution of CAP sizes followed a power-law with slope -1.5 in relatively deep anesthesia (8-6%) but deviated from that at the lighter levels. Temporal variance and entropy of CAP sizes were lowest in wakefulness (76% and 24% lower at 0% than at 8% desflurane, respectively) but changed little during recovery of consciousness. CAPs categorized by K-means clustering were conserved at all anesthesia levels and wakefulness, although their proportion changed in a state-dependent manner. These observations yield new knowledge about the dynamic landscape of ongoing population activity in sensory cortex at graded levels of anesthesia. The repertoire of population activity and self-organized criticality at the mesoscopic scale do not appear to contribute to anesthetic suppression of consciousness, which may instead depend on large-scale effects, more subtle dynamic properties, or changes outside of primary sensory cortex.

Sensory neurons across sensory modalities and specific processing areas have diverse levels of spontaneous firing rates (SFRs) in the absence of sensory stimuli. However, the functional significance of this spontaneous activity is not well-understood. Previous studies in the auditory system have demonstrated that different levels of spontaneous activity are correlated with a variety of physiological and anatomic properties, suggesting that neurons with differing SFRs make unique contributions to the encoding of auditory stimuli. Additionally, altered SFRs are a correlate of tinnitus, arising in several auditory areas after exposure to ototoxic substances and noise trauma. In this study, we recorded single-unit activity from primary auditory cortex of awake marmoset monkeys while delivering wide-band random-spectrum stimuli and white Gaussian noise (WGN) to examine any divergences in stimulus encoding properties across SFR classes. We found that higher levels of spontaneous activity were associated with both higher levels of activation relative to suppression across a variety of wide-band stimuli and higher driven rates in response to WGN. Moreover, response latencies to WGN were negatively correlated with the level of activation in response to both stimulus types. These findings are consistent with a novel view of the role spontaneous spiking may play during normal stimulus processing in primary auditory cortex and how it may malfunction in cases of tinnitus.

Understanding how the brain processes sensory input to generate behavior remains an important problem in neuroscience. Towards this end, it is useful to compare results obtained across multiple species to gain understanding as to the general principles of neural coding. Here we investigated hindbrain pyramidal cell activity in the weakly electric fish Apteronotus albifrons. We found strong heterogeneities when looking at baseline activity. Additionally, ON- and OFF-type cells responded to increases and decreases of sinusoidal and noise stimuli, respectively. While both cell types displayed band-pass tuning, OFF-type cells were more broadly tuned than their ON-type counterparts. The observed heterogeneities in baseline activity as well as the greater broadband tuning of OFF-type cells were both similar to those previously reported in other weakly electric fish species, suggesting that they constitute general features of sensory processing. However, we found that peak tuning occurred at frequencies ∼15 Hz in A. albifrons, which is much lower than values reported in the closely related species Apteronotus leptorhynchus and the more distantly related species Eigenmannia virescens. In response to stimuli with time-varying amplitude (i.e., envelope), ON- and OFF-type cells displayed similar high-pass tuning curves characteristic of fractional differentiation and possibly indicate optimized coding. These tuning curves were qualitatively similar to those of pyramidal cells in the closely related species A. leptorhynchus. In conclusion, comparison between our and previous results reveals general and species-specific neural coding strategies. We hypothesize that differences in coding strategies, when observed, result from different stimulus distributions in the natural/social environment.

The coding of sound level by ensembles of neurons improves the accuracy with which listeners identify how loud a sound is. In the auditory system, the rate at which neurons fire in response to changes in sound level is shaped by local networks. Voltage-gated conductances alter local output by regulating neuronal firing, but their role in modulating responses to sound level is unclear. We tested the effects of L-type calcium channels (Ca L : Ca V 1.1–1.4) on sound-level coding in the central nucleus of the inferior colliculus (ICC) in the auditory midbrain. We characterized the contribution of Ca L to the total calcium current in brain slices and then examined its effects on rate-level functions (RLFs) in vivo using single-unit recordings in awake mice. Ca L is a high-threshold current and comprises ∼50% of the total calcium current in ICC neurons. In vivo, Ca L activates at sound levels that evoke high firing rates. In RLFs that increase monotonically with sound level, Ca L boosts spike rates at high sound levels and increases the maximum firing rate achieved. In different populations of RLFs that change nonmonotonically with sound level, Ca L either suppresses or enhances firing at sound levels that evoke maximum firing. Ca L multiplies the gain of monotonic RLFs with dynamic range and divides the gain of nonmonotonic RLFs with the width of the RLF. These results suggest that a single broad class of calcium channels activates enhancing and suppressing local circuits to regulate the sensitivity of neuronal populations to sound level.

Electrical brain stimulation (EBS) complements neural measurements by probing the causal relationship between brain and perception, cognition, and action. Many fundamental questions about EBS remain unanswered, including the spatial extent of cortex responsive to stimulation, and the relationship between the circuitry engaged by EBS and the types of neural responses elicited by sensory stimulation. Here, we measured neural responses and the effects of EBS in primary visual cortex in four patients implanted with intracranial electrodes. Using stimulation, behavior, and retinotopic mapping, we show the relationship between the size of affected cortical area and the magnitude of electrical charge. Furthermore, we show that the spatial location of electrically induced visual sensations is matched to the receptive field of the cortical site measured with broadband field potentials, and less so with event related potentials. Together, these findings broaden our knowledge about the mechanism of EBS and the neuromodulation of the human brain.

Objective . Restoring or replacing function in paralyzed individuals will one day be achieved through the use of brain–machine interfaces. Regaining hand function is a major goal for paralyzed patients. Two competing prerequisites for the widespread adoption of any hand neuroprosthesis are accurate control over the fine details of movement, and minimized invasiveness. Here, we explore the interplay between these two goals by comparing our ability to decode hand movements with subdural and epidural field potentials (EFPs). Approach. We measured the accuracy of decoding continuous hand and finger kinematics during naturalistic grasping motions in five human subjects. We recorded subdural surface potentials (electrocorticography; ECoG) as well as with EFPs, with both standard- and high-resolution electrode arrays. Main results. In all five subjects, decoding of continuous kinematics significantly exceeded chance, using either EGoG or EFPs. ECoG decoding accuracy compared favorably with prior investigations of grasp kinematics (mean ± SD grasp aperture variance accounted for was 0.54 ± 0.05 across all subjects, 0.75 ± 0.09 for the best subject). In general, EFP decoding performed comparably to ECoG decoding. The 7–20 Hz and 70–115 Hz spectral bands contained the most information about grasp kinematics, with the 70–115 Hz band containing greater information about more subtle movements. Higher-resolution recording arrays provided clearly superior performance compared to standard-resolution arrays. Significance . To approach the fine motor control achieved by an intact brain-body system, it will be necessary to execute motor intent on a continuous basis with high accuracy. The current results demonstrate that this level of accuracy might be achievable not just with ECoG, but with EFPs as well. Epidural placement of electrodes is less invasive, and therefore may incur less risk of encephalitis or stroke than subdural placement of electrodes. Accurately decoding motor commands at the epidural level may be an important step towards a clinically viable brain–machine interface.

This study examines how temporally patterned stimuli are transformed as they propagate from primary to secondary zones in the thalamorecipient auditory pallium in zebra finches. Using a new class of synthetic click stimuli, we find a robust mapping from temporal sequences in the primary zone to distinct population vectors in secondary auditory areas. We tested whether songbirds could discriminate synthetic click sequences in an operant setup and found that a robust behavioral discrimination is present for click sequences composed of intervals ranging from 11 ms to 40 ms, but breaks down for stimuli composed of longer inter-click intervals. This work suggests that the analog of the songbird auditory cortex transforms temporal patterns to sequence-selective population responses or ‘spatial codes', and that these distinct population responses contribute to behavioral discrimination of temporally complex sounds.