Electrophysiology publications

Objective. To develop and validate a machine learning framework for the classification of distinct seizure onset patterns using intracranial EEG (iEEG) recordings in a non-human primate (NHP) model of penicillin-induced seizures. Approach. iEEG data were collected from six NHPs, comprising 1, 496 frontal and 549 temporal lobe seizures. Seizure onset patterns were manually categorized into five types: Sharp Activity (5–15 Hz), Low Amplitude Fast Activity (15–30 Hz), Delta Brush (1–3 Hz with bursts), High Amplitude Spike (2–5 Hz), and Polyspike. A Random Forest classifier was trained using features extracted from optimized seizure onset segments. Feature selection and seizure segment length optimization were performed using nested cross-validation to enhance classification accuracy and generalizability. Main results. The classifier achieved strong performance with F1-scores exceeding 79% for Sharp Activity, Low Amplitude Fast Activity, and High Amplitude Spike patterns. When validated on an independent temporal lobe seizure dataset, the model demonstrated robust generalizability, achieving precision and sensitivity above 80% for Sharp Activity and High Amplitude Spike. Significance. These findings demonstrate that the suggested spectral and dynamic features can effectively distinguish seizure onset patterns and generalize in distinct brain regions. Although there are limitations due to use of manual annotations and the sample size of certain categories, the proposed approach provides a framework for automatic classification of seizure onset patterns. Further, the framework has a potential use for epilepsy research and clinical applications in future.

Animals continuously adapt their behavior to balance survival and fulfilling essential needs. This balancing act involves prioritization of safety over the pursuit of other needs. However, the specific deep brain circuits that regulate safety-seeking behaviors in conjunction with motor circuits remain poorly understood. Here, we identify a class of glutamatergic neurons in the mouse lateral hypothalamic area (LHA) that target the midbrain locomotor-promoting pedunculopontine nucleus (PPN). Following activation, this LHA-PPN pathway orchestrates context-dependent locomotion, prioritizing safety-directed movement over other essential needs such as foraging or social contact. Remarkably, the neuronal activity of this circuit correlates directly with safety-seeking behavior. The circuit may respond to both intrinsic and extrinsic cues, having a pivotal role in ensuring survival. Our findings uncover a circuit motif within the lateral hypothalamus that, when recruited, prioritizes critical needs through the recruitment of an appropriate motor action.

Advancements in the field of implantable neurotechnologies have enabled the integration of hundreds of microelectrodes on ultra-thin and flexible substrates. Besides implantable components, also connectors, headstages and cables have to comply with the high-count demand, resulting in a complex and compact chain with reduced line spacing and smaller safety margins. Here, we show that epicortical recordings acquired from anesthetized rat brains with a state-of-art neural acquisition system are undoubtedly compromised by crosstalk, with signal coherence maps exhibiting a strong dependency to the routing layout. A crosstalk back-correction algorithm is developed, allowing to infer on how signals would look like under a zero-crosstalk scenario. We found that signal coherence between closely routed channels effectively drops after correction, corroborating crosstalk contamination. Our work stresses the importance of validating recorded data against the routing layout as a crucial step of data quality control, helping to come closer to ground truth data.

Purpose Present-day cochlear-implant (CI) users can achieve high levels of speech reception in quiet surroundings. Nevertheless, sensitivity to the temporal pitch of sounds is limited, which contributes to deficits in speech reception amid multiple talkers and in appreciation of musical melodies. Short-term, invasive neurophysiological studies in animals have demonstrated limitations in neural phase locking in the tonotopic range of the auditory pathway that is activated by CIs. It remains an open question, however, whether those neural limitations can account for perceptual deficits in those animal species, let alone in human CI users. For that reason, we have evaluated non-invasive recordings of phase locking from cats chronically implanted with a CI. Methods Ten deafened cats (eight female) were implanted with an animal version of a clinical CI array. The electrically evoked frequency following response (eFFRs) was recorded from the scalps of sedated animals at ≥ 10 weeks post-implantation. Stimuli consisted of constant-amplitude electrical pulse trains at rates from ~ 40 to 640 pulses per second. Results Recordings of the eFFR demonstrated robust responses synchronized to electrical pulse trains across all stimulus rates. Analyses of eFFR amplitude and phase transfer functions confirmed that the eFFR, as with its normal-hearing counterpart, originates from multiple subcortical and cortical generators. The slopes of segments of eFFR phase transfer functions revealed stimulus-to-response latencies of generators that dominated the eFFR across restricted ranges of pulse rates. Those rate ranges must coincide with the limits of phase locking by putative generators at successive levels of the auditory neuroaxis and could inform our understanding of the limits to perceptual temporal acuity. Conclusion The eFFR demonstrated here in an animal model provides a valuable non-invasive measure of temporal processing in electric cochlear stimulation that can be related to ongoing perceptual measures in the same animals and is well-suited to evaluate novel modes of auditory prosthesis for enhancing temporal acuity.

Many animal training paradigms rely on head-fixation. Head-fixation training is typically laborious and can benefit from automation to relieve the workload and reduce the variability in the training outcome. Several groups have reported successful implementations of such systems, but throughput varied greatly across groups. In addition, most studies relied on brief periods of head-fixation sessions (≤ 1 minute) to reduce the potential stress on the animal. Here, we report the design of a new system that could achieve head-fixation sessions on the order of minutes with a high participation rate from the animal (100%). Throughout the training period, each mouse performed a total of close to 40 minutes of head-fixation training on average each day and learned common psychoacoustic tasks, i.e., tone detection and tone discrimination. Our system can achieve highly efficient training with minimum idling time, allowing combinations with high-end neural recording equipment to achieve maximum training and data collection efficiency.

Animals have evolved complex auditory systems to extract acoustic information from natural environmental noise, yet they are challenged by rising levels of novel anthropogenic noise. Songbirds adjust their vocal production in response to increasing noise, but auditory processing of signals in noise remains understudied. Auditory processing characteristics, including auditory filter bandwidth, filter efficiency and critical ratios (level-independent signal-to-noise ratios at threshold), likely influence auditory and behavioral responses to noise. Here, we investigated the effects of noise on auditory processing in three songbird species (black-capped chickadees, tufted titmice and white-breasted nuthatches) that live in mixed-species flocks and rely on heterospecific communication to coordinate mobbing behaviors. We determined masked thresholds and critical ratios from 1 to 4 kHz using auditory evoked potentials. We predicted that nuthatches would have the lowest critical ratios given that they have narrowest filters, followed by titmice and then chickadees. We found that nuthatches had the greatest sensitivity in quiet conditions, but the highest critical ratios, suggesting their auditory sensitivity is highly susceptible to noise. Titmice had the lowest critical ratios, suggesting relatively minor impacts of noise on their auditory processing. This is not consistent with predictions based on auditory filter bandwidth, but is consistent with both recent behavioral findings and predictions made by auditory filter efficiency measures. Detrimental effects of noise were most prevalent in the 2–4 kHz range, frequencies produced in vocalizations. Our results using the critical ratio as a measure of processing in noise suggest that low levels of anthropogenic noise may influence these three species differently.

The posterior medial (POm) thalamus is heavily interconnected with sensory and motor circuitry and is likely involved in behavioral modulation and sensorimotor integration. POm provides axonal projections to the dorsal striatum, a hotspot of sensorimotor processing, yet the role of POm-striatal projections has remained undetermined. Using optogenetics with mouse brain slice electrophysiology, we found that POm provides robust synaptic input to direct and indirect pathway striatal spiny projection neurons (D1- and D2-SPNs, respectively) and parvalbumin-expressing fast spiking interneurons (PVs). During the performance of a whisker-based tactile discrimination task in head-restrained mice, POm-striatal projections displayed learning-related activation correlating with anticipatory, but not reward-related, pupil dilation. Inhibition of POm-striatal axons across learning caused slower reaction times and an increase in the number of training sessions for expert performance. Our data indicate that POm-striatal inputs provide a behaviorally relevant arousal-related signal, which may prime striatal circuitry for efficient integration of subsequent choice-related inputs.

Transcranial focused ultrasound stimulation (tFUS) is a promising neuromodulation technique capable of noninvasively modulating focal neuronal activities and neural circuits in both animals and humans. The cell-type selectivity of tFUS within targeted areas such as the somatosensory cortex (S1) during sonication has been shown to be parameter related. However, it remains unclear how tFUS affects neural circuits by changing the correlation between neurons and how to optimize the tFUS parameters to modulate neural pathways. In this study, multisite intracranial recordings are used in anesthetized male rats to quantify the neuronal responses to tFUS stimulation recorded from S1 and posterior medial thalamic nucleus (POm) of cortico-thalamo-cortical (CTC) pathway. Different tFUS parameters including ranges of pulse repetition frequencies (PRFs) and duty cycles (DCs) are tested. We find that when targeting at S1, only regular-spiking units (RSUs) respond to specific tFUS parameters during sonication (DC, 6−60%; PRF, 1,500, 3,000 and 4,500 Hz), and RSUs from the POm exhibit a synchronized response. The changes of directional correlation between S1 RSUs and POm RSUs indicate the activation of feedback modulation. Delayed responses and correlation changes were further observed at ∼200 ms postsonication from the neurons in S1 and POm, indicating feedforward modulation. Our results reveal that tFUS can modulate the feedback and feedforward CTC pathways by selectively activating cortical RSUs and adjusting the tFUS parameters, particularly the PRF, to maximize cortical RSU activity could enhance the modulation of the CTC pathway.

Phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, is a common cause of intellectual disability. However, the mechanisms by which elevated Phe levels cause cognitive impairment remain unclear. Here, we show that submillimolar Phe perturbs synaptic plasticity through the hyperactivation of GluN2B-containing NMDARs. Pah Enu2 PKU model mice exhibited submillimolar and supramillimolar concentrations of Phe in the cerebrospinal fluid (CSF) and serum, respectively. l-Phe produced concentration-dependent bidirectional effects on NMDA-induced currents, without affecting synaptic NMDA receptors (NMDARs) in hippocampal CA1 neurons. l-Phe-induced hyperactivation of extrasynaptic GluN2B resulted in activity-dependent downregulation of AMPA receptors during burst or sustained synaptic activity. Administration of l-Phe in mice decreased neural activity and impaired memory, which were blocked by pretreatment with GluN2B inhibitors. Furthermore, pharmacological and virus-mediated suppression of GluN2B reversed the impaired learning in Pah Enu2 mice. Collectively, these results suggest the concentration of Phe in the CSF of patients with PKU perturbs extrasynaptic NMDARs and synaptic plasticity and that suppression of GluN2B may have the potential to improve cognitive function in patients with PKU.

Flexible behaviour requires decision-making that integrates both perceptual and mnemonic-related information. While the dorsal premotor cortex (PMd) is known to support decision-making based on perceptual computations, its contributions to decisions based on mnemonic information for motor planning are underexplored. Here, investigating local field potential (LFP) oscillations in PMd of monkeys performing a transitive inference task required the formation and retrieval of mnemonic representations of an arbitrarily defined rank order among perceptual items. Our results highlight that a dynamic interplay between lower frequencies (Theta, Alpha, Beta) and high-Gamma oscillatory activity of LFP reflects a mechanism for accessing and manipulating memory-related information underlying decision-making. These findings provide evidence that the PMd plays a role in multiplexing both perceptual and mnemonic information, extending its competence beyond the association of perceptual input with motor decisions.

To build in vitro tissues for therapeutic applications, it is essential to replicate the spatial distribution of cells that occurs during morphogenesis in vivo. However, it remains technically challenging to simultaneously regulate the geometric alignment and aggregation of cells during tissue fabrication. Here, we introduce the acoustofluidic bioassembly induced morphogenesis, which is the combination of precise arrangement of cells by the mechanical forces produced by acoustofluidic cues, and the morphological and functional changes of cells in the following in vitro and in vivo cultures. The acoustofluidic bioassembly can be used to create tissues with regulated nano-, micro-, and macro-structures. We demonstrate that the neuromuscular tissue fabricated with the acoustofluidic bioassembly exhibits enhanced contraction dynamics, electrophysiology, and therapeutic efficacy. The potential of the acoustofluidic bioassembly as an in situ application is demonstrated by fabricating artificial tissues at the defect sites of living tissues. The acoustofluidic bioassembly induced morphogenesis can provide a pioneering platform to fabricate tissues for biomedical applications.

In utero nicotine exposure from maternal smoking is linked to increased risk of auditory processing deficits. This study investigated the impact of developmental nicotine exposure during the critical period on nicotinic acetylcholine receptor (nAChR) functional expression, glutamatergic synaptic transmission and auditory processing in the mouse auditory brainstem. We assessed nAChR function at a central synapse and the consequences of perinatal nicotine exposure (PNE) on synaptic currents and auditory brainstem responses (ABRs) in mice. Our results indicate developmentally regulated changes in nAChR expression in medial nucleus of the trapezoid body (MNTB) neurons and presynaptic calyx of Held terminals. PNE led to increased ACh‐evoked postsynaptic currents and impaired glutamatergic neurotransmission, underscoring the importance of nAChR activity in early auditory synaptic development. PNE also increased ABR thresholds and reduced ABR peak amplitudes, indicating impaired central auditory processing without cochlear dysfunction. Our study provides new insights into the synaptic disruptions underlying auditory deficits from prenatal nicotine exposure. image Key points In utero nicotine exposure leads to increased risk of sensory processing deficits and elevated expression of nicotinic acetylcholine receptors (nAChRs). nAChRs are essential for auditory processing and are present in the auditory brainstem. Within the medial nucleus of the trapezoid body in the auditory brainstem, the patterning of nicotinic receptor expression during development and how nicotine exposure might affect this are unknown. Nicotinic receptors are expressed postsynaptically before hearing onset and switch to presynaptic expression after hearing onset. Perinatal nicotine exposure disrupts physiological nicotinic receptor patterning and impairs synaptic transmission at the calyx of Held.

The control of speech and vocal production involves the calculation of error between the intended vocal output and the resulting auditory feedback. This model has been supported by evidence that the auditory cortex (AC) is suppressed immediately before and during vocal production yet remains sensitive to differences between vocal output and altered auditory feedback. This suppression has been suggested to be the result of top-down signals about the intended vocal output, potentially originating from frontal cortical (FC) areas. However, whether FC is the source of suppressive and predictive signaling to AC during vocalization remains unknown. Here, we simultaneously recorded neural activity from both AC and FC of marmoset monkeys during self-initiated vocalizations. We found increases in neural activity in both brain areas from 1 to 0.5 s before vocal production (early pre-vocal period), specifically changes in both multi-unit activity and theta-band power. Connectivity analysis using Granger causality demonstrated that FC sends directed signaling to AC during this early pre-vocal period. Importantly, early pre-vocal activity correlated with both vocalization-induced suppression in AC as well as the structure and acoustics of subsequent calls, such as fundamental frequency. Furthermore, bidirectional auditory-frontal interactions emerged during experimentally altered vocal feedback and predicted subsequent compensatory vocal behavior. These results suggest that FC communicates with AC during vocal production, with frontal-to-auditory signals that may reflect the transmission of sensory prediction information before vocalization and bidirectional signaling during vocalization suggestive of error detection that could drive feedback-dependent vocal control.

Accurate perception of objects within the environment independent of context is essential for the survival of an organism. While neurons that respond in an invariant manner to different stimulus waveforms resulting from identitypreserving transformations of objects are thought to provide a neural correlate of context-independent perception, how such responses emerge in the brain remains poorly understood. Here, we demonstrate that burst firing in neural populations can give rise to an invariant representation of highly heterogeneous natural communication stimuli. Multi-unit recordings from central sensory neural populations showed that considering burst spike trains led to invariant representations at the population but not the single neuron level. Computational modeling further revealed that optimal invariance is achieved at burst firing levels seen experimentally. Taken together, our results demonstrate an important function for burst firing toward establishing invariant representations of sensory input in neural populations.

Epidural electrical stimulation of the spinal cord (ES) is used to restore/improve locomotor movements in patients. However, the neuronal mechanisms underlying activation of locomotor networks by ES are unknown. Here, we analyzed the effects of ES on the activity of individual spinal neurons of different functional locomotor groups. Neuronal activity was recorded in decerebrate cats before and during ES that evoked locomotion. During ES initial period (NW-period, before the locomotion onset), the activity was increased in most neurons as compared to that before ES. We found that ES-caused activation of neurons of locomotor network to the average level similar to that observed during locomotion is not sufficient for initiation of locomotion. We demonstrated that the onset of ES-evoked locomotion was associated with specific changes in the activity of individual neurons within functional locomotor groups and in their responses to epidural stimuli. With the locomotion onset, there was a trend for individual neurons with extremely high activity during NW-period to decrease their activity, while for neurons with extremely low activity to become more active. Also, in neurons contributing to generation of a specific mode of locomotion, peaks and troughs in responses to individual epidural stimuli were significantly less pronounced as compared with those observed during NW-period. We suggest that these changes allow ES to maintain the high level of excitability of the locomotor network necessary for its operation without distortion of the locomotor rhythm. The obtained results advance our understanding of the neuronal mechanisms underlying activation of locomotor network by ES.

Fragile X syndrome (FXS) is a leading genetic form of autism and intellectual disability that is associated with a loss-of-function mutation in the Fragile X messenger ribonucleoprotein 1 (Fmr1) gene. The Fmr1 knockout (KO) mouse model displays many aspects of FXS-related phenotypes and is used to study FXS pathophysiology. Sensory manipulations, such as sound exposure, are considered as a non-invasive approach to alleviate FXS phenotypes. However, it is unclear what specific sound attributes may have beneficial effects. In this study, we examined the effects of sound repetition rate on auditory cortex development and FXS-associated behaviors in a mouse model of FXS. KO and wild-type (WT) male littermates were exposed to 14 kHz pure tone trains with 1 Hz or 5 Hz repetition rates during postnatal day (P)9-P21 developmental period. We analyzed the effects of developmental sound exposure on PV cell development, cortical activity and exploratory behaviors in sound-exposed WT and KO mice. We found that parvalbumin (PV) cell density was lower in the auditory cortex (AuC) of KO compared to WT mice raised in sound-attenuated environment, but was increased following the exposure to both 1 Hz and 5 Hz sound trains. However, PV protein levels were upregulated only in AuC of 5 Hz rate exposed KO mice. Interestingly, analysis of baseline cortical activity using electroencephalography (EEG) recordings showed that sound attenuation or exposure to sound trains with 5 Hz, but not 1 Hz, repetition rates corrected enhanced resting state gamma power in AuC of KO mice to WT levels. In addition, sound attenuation and exposure to 5 Hz showed some beneficial effects on the synchronization to frequency-modulated chirp in the frontal cortex (FC) of both WT and KO mice. Analysis of event-related potentials (ERP) in response to broadband sound showed increased ongoing responses and decreased habituation to noise stimuli in the AuC and FC of naive KO mice. While sound-attenuation and exposure to 5 Hz showed no significant effects on the power of onset and ongoing responses, exposure to 1 Hz further enhanced ongoing responses and decreased habituation to sound in both WT and KO mice. Finally, developmental exposure to sound trains with 5 Hz, but not 1 Hz, repetition rates normalized exploratory behaviors and improved social novelty preference but not hyperactivity in KO mice. Summarizing, our results show that developmental exposure of mice to sound trains with 5 Hz, but not 1 Hz, repetition rate had beneficial effects on PV cell development, overall cortical activity and behaviors in KO mice. While sound attenuation alone normalized some EEG phenotypes, it did not improve PV development or behaviors. These findings may have a significant impact on developing new approaches to alleviate FXS phenotypes and open possibilities for a combination of sound exposure with drug treatment which may offer highly novel therapeutic approaches.

Although control of movement involves many cortical association areas, bidirectional brain-machine interfaces (BMIs) typically decode movement intent from the motor cortex and deliver feedback information to the primary somatosensory cortex (S1). Compared to the S1, the parietal and premotor areas encode more complex information about object properties, hand pre-shaping, and reach trajectories. BMIs therefore might deliver richer information to those cortical association areas than to primary areas. Here, we investigated whether instructions for a center-out task could be delivered via intracortical microstimulation (ICMS) in the anterior intraparietal area (AIP), dorsal posterior parietal cortex (dPPC), or dorsal premotor cortex (PMd) as well as the ventral premotor cortex (PMv) and S1. Two monkeys successfully learned to use AIP, PMv, or S1-ICMS instructions, but neither learned to use dPPC- or PMd-ICMS instructions. The AIP, PMv, and S1 may thus be effective cortical territory for delivering information to the brain, whereas the dPPC or PMd may be comparatively ineffective.

Understanding how downstream brain areas decode sensory information represented by neural populations remains a central problem in neuroscience. While decoders that are optimized to extract the maximum amount of information have been extensively used in research, whether these are physiologically realistic remains at best unclear. Here we show that a physiologically realistic decoding scheme based on correlations between neural activities in the absence of stimulation can predict downstream neural responses as well as the optimal decoder. Simultaneous recordings were made from primary sensory neural populations and their downstream midbrain targets in the electrosensory system of Apteronotus leptorhynchus . We found that neural populations exhibited significant correlations in the absence of stimulation (i.e. ‘baseline’), with downstream neural activity lagging primary sensory neural activity with a short latency. We then investigated how primary sensory neural activities were combined downstream. Overall, a decoder that assigned weights to each primary sensory neuron and was trained solely on baseline correlations performed as well as the optimal decoder trained on neural responses to stimulation. Interestingly, both decoders greatly outperformed schemes for which every neuron was assigned the same weight or when the weights were shuffled, indicating that neural identity is critical. Taken together, our results suggest that the brain uses decoding strategies that perform at optimal levels but are qualitatively different from those predicted from optimal solutions. image Key points How neural signals are decoded to give rise to perception remains poorly understood. We recorded from primary sensory neural populations and their downstream targets. A physiologically realistic decoder performed as well as the optimal solution to predict downstream responses. We found important qualitative differences between how information is decoded and the optimal solution. Our results demonstrate that the brain can do as well as an optimal decoder but uses a different strategy.

The ability to evaluate valence of a social agent based on social experience is essential for an animal's survival in its social group1. Although hippocampal circuits have been implicated in distinguishing novel and familiar conspecifics2-7, it remains unclear how social valence is constructed on the basis of social history and what mechanisms underlie the heightened valence versatility in dynamic relationships. Here we demonstrate that the ventral (v)CA1 integrates serotonin (5-HT) inputs from the dorsal raphe and neurotensin inputs from the paraventricular nucleus of the thalamus (PVT) to determine positive or negative valence of conspecific representations. Specifically, during an appetitive social interaction 5-HT is released into the vCA1 and disinhibits pyramidal neurons through 5-HT1B receptors, whereas neurotensin is released during an aversive social interaction and potentiates vCA1 neurons directly through NTR1s. Optogenetic silencing of dorsal raphe 5-HT and PVT neurotensin inputs into the vCA1 impairs positive and negative social valence, respectively, and excitation flexibly switches valence assignment. These results show how aversive and rewarding social experiences are linked to conspecific identity through converging dorsal raphe 5-HT and PVT neurotensin signals in the vCA1 that instruct opposing valence, and represent a synaptic switch for flexible social valence computation.

Autologous nerve grafting remains the gold standard for treating peripheral nerve injuries; however, it is constrained by limited donor nerve availability, the need for secondary surgeries, and sensory loss at the donor site. Biodegradable material‐based nerve conduits have emerged as a promising alternative to address these limitations and enhance nerve regeneration. Among these materials, magnesium stands out due to its exceptional biocompatibility, biofunctionality, and neuroprotective properties. Despite its potential, magnesium's rapid corrosion rate and the need for controlled ion release necessitate advanced modifications, such as the development of Mg alloys. However, these approaches often face challenges, including viability concerns and material hardness, which can hinder nerve repair and damage surrounding tissues. In this study, a novel solution is introduced by sputtering magnesium onto a soft collagen sheet, achieving controlled magnesium ion release while preserving the material's nerve‐like softness. This Mg‐sputtered collagen sheet demonstrates excellent biocompatibility and significantly improves axon regeneration, muscle reinnervation, and functional recovery in a sciatic nerve defect model. These findings highlight the potential of an innovative Mg‐based biodegradable nerve conduit, offering transformative applications across various medical fields.