Electrophysiology publications

Neurons in sensory cortex are tuned to diverse features in natural scenes. But what determines which features neurons become selective to? Here we explore the idea that neuronal selectivity is optimized to represent features in the recent sensory past that best predict immediate future inputs. We tested this hypothesis using simple feedforward neural networks, which were trained to predict the next few moments of video or audio in clips of natural scenes. The networks developed receptive fields that closely matched those of real cortical neurons in different mammalian species, including the oriented spatial tuning of primary visual cortex, the frequency selectivity of primary auditory cortex and, most notably, their temporal tuning properties. Furthermore, the better a network predicted future inputs the more closely its receptive fields resembled those in the brain. This suggests that sensory processing is optimized to extract those features with the most capacity to predict future input.

The paraventricular nucleus of the thalamus (PVT) is increasingly being recognized as a critical node linking stress detection to the emergence of adaptive behavioral responses to stress. However, despite growing evidence implicating the PVT in stress processing, the neural mechanisms by which stress impacts PVT neurocircuitry and promotes stressed states remain unknown. Here we show that stress exposure drives a rapid and persistent reduction of inhibitory transmission onto projection neurons of the posterior PVT (pPVT). This stress-induced disinhibition of the pPVT was associated with a locus coeruleus-mediated rise in the extracellular concentration of dopamine in the midline thalamus, required the function of dopamine D2 receptors on PVT neurons, and increased sensitivity to stress. Our findings define the locus coeruleus as an important modulator of PVT function: by controlling the inhibitory tone of the pPVT, it modulates the excitability of pPVT projection neurons and controls stress responsivity.

Recent work has highlighted the importance of transient low-frequency oscillatory (LFO; <4 Hz) activity in the healthy primary motor cortex during skilled upper-limb tasks. These brief bouts of oscillatory activity may establish the timing or sequencing of motor actions. Here, we show that LFOs track motor recovery post-stroke and can be a physiological target for neuromodulation. In rodents, we found that reach-related LFOs, as measured in both the local field potential and the related spiking activity, were diminished after stroke and that spontaneous recovery was closely correlated with their restoration in the perilesional cortex. Sensorimotor LFOs were also diminished in a human subject with chronic disability after stroke in contrast to two non-stroke subjects who demonstrated robust LFOs. Therapeutic delivery of electrical stimulation time-locked to the expected onset of LFOs was found to significantly improve skilled reaching in stroke animals. Together, our results suggest that restoration or modulation of cortical oscillatory dynamics is important for the recovery of upper-limb function and that they may serve as a novel target for clinical neuromodulation.

Loudness dependence of auditory evoked potentials (LDAEP) is a widely used EEG-based biomarker for central serotonergic activity. Serotonin has been shown to be associated with different psychiatric disorders such as depression and schizophrenia. Despite its clinical significance, the underlying neurochemical mechanism of this promising marker is not fully understood, and further research is needed to improve its validity. Other neurotransmitters might have a significant impact on this measure. Thus, we assessed the inhibitory action through individual GABA/H20 concentrations and GABA/glutamate ratios by means of magnetic resonance spectroscopy at 3T in healthy subjects. The measurements were assessed in the primary auditory cortex to investigate the association with the LDAEP, whose generators are mainly in the primary auditory cortex. For the first time, this study examines the link between GABAergic neurotransmission and LDAEP, and the data preliminary show that GABA may not contribute to the generation of EEG-based LDAEP.

The brainstem’s lateral superior olive (LSO) is thought to be crucial for localizing high-frequency sounds by coding interaural sound level differences (ILD). Its neurons weigh contralateral inhibition against ipsilateral excitation, making their firing rate a function of the azimuthal position of a sound source. Since the very first in vivo recordings, LSO principal neurons have been reported to give sustained and temporally integrating ‘chopper’ responses to sustained sounds. Neurons with transient responses were observed but largely ignored and even considered a sign of pathology. Using the Mongolian gerbil as a model system, we have obtained the first in vivo patch clamp recordings from labeled LSO neurons and find that principal LSO neurons, the most numerous projection neurons of this nucleus, only respond at sound onset and show fast membrane features suggesting an importance for timing. These results provide a new framework to interpret previously puzzling features of this circuit.

Background: High-frequency Deep Brain Stimulation (DBS) of the subcallosal cingulate (SCC) region is an emerging strategy for treatment-resistant depression (TRD). This study examined changes in SCC local field potentials (LFPs). The LFPs were recorded from the DBS leads following transient, unilateral stimulation at the neuroimaging-defined optimal electrode contact. The goal was identifying a putative electrophysiological measure of target engagement during implantation. Methods: Fourteen consecutive patients underwent bilateral SCC DBS lead implantation. LFP recordings were collected from all electrodes during randomized testing of stimulation on each DBS contact (eight total). Analyses evaluated changes in spectral power before and after 3 min of unilateral stimulation at the contacts that later facilitated antidepressant response, as a potential biomarker of optimal contact selection in each hemisphere. Results: Lateralized and asymmetric power spectral density changes were detected in the SCC with acute unilateral SCC stimulation at those contacts subsequently selected for chronic, therapeutic stimulation. Left stimulation induced broadband ipsilateral decreases in theta, alpha, beta and gamma bands. Right stimulation effects were restricted to ipsilateral beta and gamma decreases. These asymmetric effects contrasted with identical white matter stimulation maps used in each hemisphere. More variable ipsilateral decreases were seen with stimulation at the adjacent "suboptimal" contacts, but changes were not statistically different from the "optimal" contact in either hemisphere despite obvious differences in impacted white matter bundles. Change in theta power was, however, most robust and specific with left-sided optimal stimulation, which suggested a putative functional biomarker on the left with no such specificity inferred on the right. Conclusion: Hemisphere-specific oscillatory changes can be detected from the DBS lead with acute intraoperative testing at contacts that later engender antidepressant effects. Our approach defined potential target engagement signals for further investigation, particularly left-sided theta decreases following initial exposure to stimulation. More refined models combining tractography, bilateral SCC LFP, and cortical recordings may further improve the precision and specificity of these putative biomarkers. It may also optimize and standardize the lead implantation procedure and provide input signals for next generation closed-loop therapy and/or monitoring technologies for TRD.

Objective . To compare responses of retinal ganglion cells (RGCs) to intracellular and extracellular electrical stimulation of varying frequency and amplitude. Approach. In vitro patch clamp was used to record the responses of RGCs to sinusoidal current stimulation of varying frequency and amplitude. The results were simulated using the Neuron software package. Main results . The stimulation frequency yielding the greatest response was higher for extracellular stimulation compared to intracellular stimulation in the same cells (256 Hz versus 64 Hz). In fact, at the high end of the frequency range, where extracellular stimulation was highly efficacious, no responses could be generated using intracellular stimulation. A region in the amplitude-frequency stimulation space was identified where OFF-RGCs could be preferentially stimulated over ON-RGCs. We found that the inability of RGCs to respond at high frequencies of intracellular stimulation is likely the result of the axon acting as a low pass filter. Significance . There is no direct translation of the results obtained with intracellular stimulation to those that employ extracellular stimulation.

Two synchronous sounds at different locations in the midsagittal plane induce a fused percept at a weighted-average position, with weights depending on relative sound intensities. In the horizontal plane, sound fusion (stereophony) disappears with a small onset asynchrony of 1–4 ms. The leading sound then fully determines the spatial percept (the precedence effect). Given that accurate localisation in the median plane requires an analysis of pinna-related spectral-shape cues, which takes ~25–30 ms of sound input to complete, we wondered at what time scale a precedence effect for elevation would manifest. Listeners localised the first of two sounds, with spatial disparities between 10–80 deg, and inter-stimulus delays between 0–320 ms. We demonstrate full fusion (averaging), and largest response variability, for onset asynchronies up to at least 40 ms for all spatial disparities. Weighted averaging persisted, and gradually decayed, for delays >160 ms, suggesting considerable backward masking. Moreover, response variability decreased with increasing delays. These results demonstrate that localisation undergoes substantial spatial blurring in the median plane by lagging sounds. Thus, the human auditory system, despite its high temporal resolution, is unable to spatially dissociate sounds in the midsagittal plane that co-occur within a time window of at least 160 ms.

Sensory deprivation during development induces lifelong changes to central nervous system function that are associated with perceptual impairments. However, the relationship between neural and behavioral deficits is uncertain due to a lack of simultaneous measurements during task performance. Therefore, we telemetrically recorded from auditory cortex neurons in gerbils reared with developmental conductive hearing loss as they performed an auditory task in which rapid fluctuations in amplitude are detected. These data were compared to a measure of auditory brainstem temporal processing from each animal. We found that developmental HL diminished behavioral performance, but did not alter brainstem temporal processing. However, the simultaneous assessment of neural and behavioral processing revealed that perceptual deficits were associated with a degraded cortical population code that could be explained by greater trial-to-trial response variability. Our findings suggest that the perceptual limitations that attend early hearing loss are best explained by an encoding deficit in auditory cortex.

Deviance sensitivity is the specific response to a surprising stimulus, one that violates expectations set by the past stimulation stream. In audition, deviance sensitivity is often conflated with stimulus-specific adaptation (SSA), the decrease in responses to a common stimulus that only partially generalizes to other, rare stimuli. SSA is usually measured using oddball sequences, where a common (standard) tone and a rare (deviant) tone are randomly intermixed. However, the larger responses to a tone when deviant does not necessarily represent deviance sensitivity. Deviance sensitivity is commonly tested using a control sequence in which many different tones serve as the standard, eliminating the expectations set by the standard ('deviant among many standards'). When the response to a tone when deviant (against a single standard) is larger than the responses to the same tone in the control sequence, it is concluded that true deviance sensitivity occurs. In primary auditory cortex of anesthetized rats, responses to deviants and to the same tones in the control condition are comparable in size. We recorded local field potentials and multiunit activity from the auditory cortex of awake, freely moving rats, implanted with 32-channel drivable microelectrode arrays and using telemetry. We observed highly significant SSA in the awake state. Moreover, the responses to a tone when deviant were significantly larger than the responses to the same tone in the control condition. These results establish the presence of true deviance sensitivity in primary auditory cortex in awake rats.

Background: It is becoming increasingly important to understand the mechanisms of spinal cord stimulation (SCS) in alleviating neuropathic pain as novel stimulation paradigms arise. Purpose: Additionally, the small anatomic scale of current SCS animal models is a barrier to more translational research. Methods: Using chronic constriction injury (CCI) of the common peroneal nerve (CPN) in sheep (ovine), we have created a chronic model of neuropathic pain that avoids motor deficits present in prior large animal models. This large animal model has allowed us to implant clinical grade SCS hardware, which enables both acute and chronic testing using von Frey filament thresholds and gait analysis. Furthermore, the larger anatomic scale of the sheep allows for simultaneous single-unit recordings from the dorsal horn and SCS with minimal electrical artifact. Results: Detectable tactile hypersensitivity occurred 21 days after nerve injury, with preliminary indications that chronic SCS may reverse it in the painful limb. Gait analysis revealed no hoof drop in the CCI model. Single neurons were identified and discriminated in the dorsal horn, and their activity was modulated via SCS. Unlike previous large animal models that employed a complete transection of the nerve, no motor deficit was observed in the sheep with CCI. Conclusion: To our knowledge, this is the first reported large animal model of chronic neuropathic pain which facilitates the study of both acute and chronic SCS using complementary behavioral and electrophysiologic measures. As demonstrated by our successful establishment of these techniques, an ovine model of neuropathic pain is suitable for testing the mechanisms of SCS.

A vast array of motor skills can be maintained throughout life. Do these behaviors require stability of individual neuron tuning or can the output of a given circuit remain constant despite fluctuations in single cells? This question is difficult to address due to the variability inherent in most motor actions studied in the laboratory. A notable exception, however, is the courtship song of the adult zebra finch, which is a learned, highly precise motor act mediated by orderly dynamics within premotor neurons of the forebrain. By longitudinally tracking the activity of excitatory projection neurons during singing using two-photon calcium imaging, we find that both the number and the precise timing of song-related spiking events remain nearly identical over the span of several weeks to months. These findings demonstrate that learned, complex behaviors can be stabilized by maintaining precise and invariant tuning at the level of single neurons.

Ultrasound (US) can noninvasively activate intact brain circuits, making it a promising neuromodulation technique. However, little is known about the underlying mechanism. Here, we apply transcranial US and perform brain mapping studies in guinea pigs using extracellular electrophysiology. We find that US elicits extensive activation across cortical and subcortical brain regions. However, transection of the auditory nerves or removal of cochlear fluids eliminates the US-induced activity, revealing an indirect auditory mechanism for US neural activation. Our findings indicate that US activates the ascending auditory system through a cochlear pathway, which can activate other non-auditory regions through cross-modal projections. This cochlear pathway mechanism challenges the idea that US can directly activate neurons in the intact brain, suggesting that future US stimulation studies will need to control for this effect to reach reliable conclusions.

When speaking, we dynamically coordinate movements of our jaw, tongue, lips, and larynx. To investigate the neural mechanisms underlying articulation, we used direct cortical recordings from human sensorimotor cortex while participants spoke natural sentences that included sounds spanning the entire English phonetic inventory. We used deep neural networks to infer speakers' articulator movements from produced speech acoustics. Individual electrodes encoded a diversity of articulatory kinematic trajectories (AKTs), each revealing coordinated articulator movements toward specific vocal tract shapes. AKTs captured a wide range of movement types, yet they could be differentiated by the place of vocal tract constriction. Additionally, AKTs manifested out-and-back trajectories with harmonic oscillator dynamics. While AKTs were functionally stereotyped across different sentences, context-dependent encoding of preceding and following movements during production of the same phoneme demonstrated the cortical representation of coarticulation. Articulatory movements encoded in sensorimotor cortex give rise to the complex kinematics underlying continuous speech production. VIDEO ABSTRACT.

Introduction It is known that an interruption of acoustic input in early life will result in abnormal development of the auditory system. Here, we further show that this negative impact actually spans beyond the auditory system to the hippocampus, a system critical for spatial memory. Methods We induced a temporary conductive hearing loss (TCHL) in P14 rats by perforating the eardrum and allowing it to heal. The Morris water maze and Y‐maze tests were deployed to evaluate spatial memory of the rats. Electrophysiological recordings and anatomical analysis were made to evaluate functional and structural changes in the hippocampus following TCHL. Results The rats with the TCHL had nearly normal hearing at P42, but had a decreased performance with the Morris water maze and Y‐maze tests compared with the control group. A functional deficit in the hippocampus of the rats with the TCHL was found as revealed by the depressed long‐term potentiation and the reduced NMDA receptor‐mediated postsynaptic current. A structural deficit in the hippocampus of those animals was also found as revealed the abnormal expression of the NMDA receptors, the decreased number of dendritic spines, the reduced postsynaptic density and the reduced level of neurogenesis. Conclusions Our study demonstrates that even temporary auditory sensory deprivation in early life of rats results in abnormal development of the hippocampus and consequently impairs spatial memory in adulthood.

It is well known that auditory experience during early development shapes response properties of auditory cortex (AC) neurons, influencing, for example, tonotopical arrangement, response thresholds and strength, or frequency selectivity. Here, we show that rearing rat pups in a complex acoustically enriched environment leads to an increased reliability of responses of AC neurons, affecting both the rate and the temporal codes. For a repetitive stimulus, the neurons exhibit a lower spike count variance, indicating a more stable rate coding. At the level of individual spikes, the discharge patterns of individual neurons show a higher degree of similarity across stimulus repetitions. Furthermore, the neurons follow more precisely the temporal course of the stimulus, as manifested by improved phase-locking to temporally modulated sounds. The changes are persistent and present up to adulthood. The results document that besides basic alterations of receptive fields presented in our previous study, the acoustic environment during the critical period of postnatal development also leads to a decreased stochasticity and a higher reproducibility of neuronal spiking patterns.

The “non-specific” ventromedial thalamic nucleus (VM) has long been considered a candidate for mediating cortical arousal due to its diffuse, superficial projections, but direct evidence was lacking. Here, we show in mice that the activity of VM calbindin1-positive matrix cells is high in wake and REM sleep and low in NREM sleep, and increases before cortical activity at the sleep-to-wake transition. Optogenetic stimulation of VM cells rapidly awoke all mice from NREM sleep and consistently caused EEG activation during slow wave anesthesia, while arousal did not occur from REM sleep. Conversely, chemogenetic inhibition of VM decreased wake duration. Optogenetic activation of the “specific” ventral posteromedial nucleus (VPM) did not cause arousal from either NREM or REM sleep. Thus, matrix cells in VM produce arousal and broad cortical activation during NREM sleep and slow wave anesthesia in a way that accounts for the effects classically attributed to “non-specific” thalamic nuclei.

Brain stimulation modulates the excitability of neural circuits and drives neuroplasticity. While the local effects of stimulation have been an active area of investigation, the effects on large-scale networks remain largely unexplored. We studied stimulation-induced changes in network dynamics in two macaques. A large-scale optogenetic interface enabled simultaneous stimulation of excitatory neurons and electrocorticographic recording across primary somatosensory (S1) and motor (M1) cortex (Yazdan-Shahmorad et al., 2016). We tracked two measures of network connectivity, the network response to focal stimulation and the baseline coherence between pairs of electrodes; these were strongly correlated before stimulation. Within minutes, stimulation in S1 or M1 significantly strengthened the gross functional connectivity between these areas. At a finer scale, stimulation led to heterogeneous connectivity changes across the network. These changes reflected the correlations introduced by stimulation-evoked activity, consistent with Hebbian plasticity models. This work extends Hebbian plasticity models to large-scale circuits, with significant implications for stimulation-based neurorehabilitation.

Neurons in the auditory cortex exhibit distinct frequency tuning to the onset and offset of sounds, but the cause and significance of ON and OFF receptive field (RF) organisation are not understood. Here we demonstrate that distinct ON and OFF frequency tuning is largely absent in immature mouse auditory cortex and is thus a consequence of cortical development. Simulations using a novel implementation of a standard Hebbian plasticity model show that the natural alternation of sound onset and offset is sufficient for the formation of non-overlapping adjacent ON and OFF RFs in cortical neurons. Our model predicts that ON/OFF RF arrangement contributes towards direction selectivity to frequency-modulated tone sweeps, which we confirm by neuronal recordings. These data reveal that a simple and universally accepted learning rule can explain the organisation of ON and OFF RFs and direction selectivity in the developing auditory cortex.

Current clinical practice in focal epilepsy involves brain source imaging (BSI) to localize brain areas where from interictal epileptiform discharges (IEDs) emerge. These areas, named irritative zones, have been useful to define candidate seizures-onset zones during pre-surgical workup. Since human histological data are mostly available from final resected zones, systematic studies characterizing pathophysiological mechanisms and abnormal molecular/cellular substrates in irritative zones-independent of them being epileptogenic-are challenging. Combining BSI and histological analysis from all types of irritative zones is only possible through the use of preclinical animal models. Here, we recorded 32-channel spontaneous electroencephalographic data from rats that have focal cortical dysplasia (FCD) and chronic seizures. BSI for different IED subtypes was performed using the methodology presented in Bae et al. (2015). Post-mortem brain sections containing irritative zones were stained to quantify anatomical, functional, and inflammatory biomarkers specific for epileptogenesis, and the results were compared with those obtained using the contralateral healthy brain tissue. We found abnormal anatomical structures in all irritative zones (i.e., larger neuronal processes, glioreactivity, and vascular cuffing) and larger expressions for neurotransmission (i.e., NR2B) and inflammation (i.e., ILβ1, TNFα and HMGB1). We conclude that irritative zones in this rat preclinical model of FCD comprise abnormal tissues disregarding whether they are actually involved in icto-genesis or not. We hypothesize that seizure perpetuation happens gradually; hence, our results could support the use of IED-based BSI for the early diagnosis and preventive treatment of potential epileptic foci. Further verifications in humans are yet needed.