Electrophysiology publications

Episodic memory requires the precise coordination between the hippocampus and distributed cortical regions. This may be facilitated by bursts of brain activity called high-frequency oscillations (HFOs). We hypothesized that HFOs activate specific networks during memory retrieval and aimed to describe the electrophysiological properties of HFO-associated activity. To study this, we recorded intracranial electroencephalography while human participants performed a list learning task. Hippocampal HFOs (hHFOs) increased during encoding and retrieval, and these increases correlated with memory performance. During retrieval, hHFOs demonstrated activation of semantic processing regions that were previously active during encoding. This consisted of broadband high-frequency activity (HFA) and cortical HFOs. HFOs in the anterior temporal lobe, a major semantic hub, co-occurred with hHFOs, particularly during retrieval. These coincident HFOs were associated with greater cortical HFA and cortical theta bursts. Hence, HFOs may support synchronization of activity across distributed nodes of the hippocampal-cortical memory network.

The medial prefrontal cortex (mPFC) and hippocampus are critical for memory retrieval, decision making, and emotional regulation. While ventral CA1 (vCA1) shows direct and reciprocal connections with mPFC, dorsal CA1 (dCA1) forms indirect pathways to mPFC, notably via the thalamic reuniens nucleus (Re). Neuroanatomical tracing has documented structural connectivity of this indirect pathway through Re however, its functional operation is largely unexplored. Here, we used in vivo and in vitro electrophysiology along with optogenetics to address this question. Whole-cell patch-clamp recordings in acute mouse brain slices revealed both monosynaptic excitatory responses and disynaptic feedforward inhibition at Re–mPFC synapses. However, we also identified a prolonged excitation of mPFC by Re. These early monosynaptic and late recurrent components are in marked contrast to the primarily feedforward inhibition characteristic of thalamic inputs to the neocortex. Local field potential recordings in mPFC brain slices revealed prolonged synaptic activity throughout all cortical lamina upon Re activation, with the late excitation enhanced by blockade of parvalbumin neurons and GABA A Rs. In vivo Neuropixels recordings in head-fixed awake mice revealed a similar prolonged excitation of mPFC units by Re activation. In summary, Re output produces recurrent feedforward excitation within mPFC suggesting a potent amplification system in the Re–mPFC network. This may facilitate amplification of dCA1->mPFC signals for which Re acts as the primary conduit, as there is little direct connectivity. In addition, the capacity of mPFC neurons to fire bursts of action potentials in response to Re input suggests that these synapses have a high gain.

Dopamine (DA) signals to the striatum play critical roles in shaping and sustaining stimulus-reward associations. In primates, however, the dynamics of the DA signals remain unknown since conventional methods are not necessarily appropriate in terms of the spatiotemporal resolution or chemical specificity sufficient for detecting the DA signals. In our study, fiber photometry with a fluorescent DA sensor was employed to identify reward-related DA transients in the monkey striatum. This technique, which directly monitors local DA release, reveals a reward prediction error signal in the anterior putamen originating from midbrain DA neurons. Further, DA transients in the head of the caudate nucleus exhibit a value-based response to reward-predicting stimuli. These signals have been found to arise from two separate groups of DA neurons in the substantia nigra pars compacta. The present results demonstrate that fluorescence DA monitoring is applicable to detect DA signals in the primate striatum for investigating their roles.

Although recent work has made headway in understanding the neural temporospatial dynamics of conscious perception, much of that work has focused on visual paradigms. To determine whether there are shared mechanisms for perceptual consciousness across sensory modalities, here we test within the auditory domain. Participants completed an auditory threshold task while undergoing intracranial electroencephalography. Recordings from >2,800 grey matter electrodes were analyzed for broadband gamma power (a range which reflects local neural activity). For perceived trials, we find nearly simultaneous activity in early auditory regions, the right caudal middle frontal gyrus, and the non-auditory thalamus; followed by a wave of activity that sweeps through auditory association regions into parietal and frontal cortices. For not perceived trials, significant activity is restricted to early auditory regions. These findings show the cortical and subcortical networks involved in auditory perception are similar to those observed with vision, suggesting shared mechanisms for conscious perception.

Face processing models propose gradually more complex receptive field properties culminating in invariant representations in anterior inferotemporal cortex (aITC), leading to late socio-emotionally relevant encoding in pre- and orbitofrontal cortex (POC). Top-down facilitation models, however, predict that some lower-level POC neurons respond faster than aITC. To resolve this discrepancy, we recorded from 2,459 neurons in fMRI-defined POC and aITC face patches. POC patches are more heterogeneous, containing smaller fractions of face-selective neurons than aITC and a mixture of responses to faces and non-faces. In one POC patch, face responses are surprisingly fast, outpacing those in aITC. Moreover, its responses correlate inversely with stimulus spatial frequency. Hence, our extensive data, with a large diversity of POC neurons, support both models and suggest one POC face patch might be specialized in fast, low-level face processing, which may enable (partially) invariant face representations during subsequent processing stages in inferotemporal cortex (ITC).

To comprehend the volumetric neural connectivity of a brain organoid, it is crucial to monitor the spatiotemporal electrophysiological signals within the organoid, known as intra-organoid signals. However, previous methods risked damaging the three-dimensional (3D) cytoarchitecture of organoids, either through sectioning or inserting rigid needle-like electrodes. Also, the limited numbers of electrodes in fixed positions with non-adjustable electrode shapes were insufficient for examining the complex neural activity throughout the organoid. Herein, we present a magnetically reshapable 3D multi-electrode array (MEA) using direct printing of liquid metals for electrophysiological analysis of brain organoids. The adaptable distribution and the softness of these printed electrodes facilitate the spatiotemporal recording of intra-organoid signals. Furthermore, the unique capability to reshape these soft electrodes within the organoid using magnetic fields allows a single electrode in the MEA to record from multiple points, effectively increasing the recording site density without the need for additional electrodes.

Homeostatic sleep regulation is essential for optimizing the amount and timing of sleep for its revitalizing function, but the mechanism underlying sleep homeostasis remains poorly understood. Here, we show that optogenetic activation of locus coeruleus (LC) noradrenergic neurons immediately increased sleep propensity following a transient wakefulness, contrasting with many other arousal-promoting neurons whose activation induces sustained wakefulness. Fiber photometry showed that repeated optogenetic or sensory stimulation caused a rapid reduction of calcium activity in LC neurons and steep declines in noradrenaline/norepinephrine (NE) release in both the LC and medial prefrontal cortex (mPFC). Knockdown of α 2 A adrenergic receptors in LC neurons mitigated the decline of NE release induced by repetitive stimulation and extended wakefulness, demonstrating an important role of α 2 A receptor–mediated auto-suppression of NE release. Together, these results suggest that functional fatigue of LC noradrenergic neurons, which reduces their wake-promoting capacity, contributes to sleep pressure.

In this paper we aim to examine the correlation between diffusion tensor imaging parameters of anatomical connectivity and characteristics of signal transmission obtained from patient-specific transfer function models. Here, we focused on elucidating the correlation between structural and functional neural connectivity within a cohort of pediatric patients diagnosed with dystonia. Diffusion tractography images were obtained from 12 patients with dystonia prior to the deep brain stimulation surgery. For each patient, we processed the imaging data to estimate anatomical measures including fractional anisotropy, axial diffusivity, number of fibre tracts per unit area, and fibre tract length. After the implantation of temporary depth leads for each patient as part of their treatment plan, intracranial signals were recorded. Transfer function models of local field potential recordings and the corresponding measures of functional connectivity were computed for each patient. Linear mixed effect analysis was then employed to determine the relationship between transfer function measures and diffusion tractography parameters. Our results illustrate a positive correlation between fractional anisotropy, AD, and intrinsic neural transmission measures, representing amplification and spread of intrinsic neural oscillations, obtained from the transfer functions models. However, no significant correlation was found between the functional connectivity and number of fibre tracts or fibre lengths. Our findings suggest that white matter integrity, as measured by fractional anisotropy and AD, can potentially reflect the amplification and spread of intrinsic brain signals throughout the network. This study underscores the significant relationship between structural and functional connectivity, offering valuable insights into propagation of neural activity in the brain network and potential implications for optimizing non-invasive treatments and planning for neurological disorders.

The ability of the brain to process auditory information across multiple temporal scales is crucial for perception. This study introduces an innovative experimental approach using nonlinguistic structured stimuli composed of click trains that alternate at different rates to investigate auditory processing across 3 distinct temporal scales: individual clicks (tens of milliseconds), click trains forming auditory objects (hundreds of milliseconds), and higher-order click trains in neuronal novelty detection (seconds) in both rhesus monkeys and humans. Electrocorticography recordings in the auditory cortex of rhesus monkeys unveil the primate brain’s remarkable ability to process intricate auditory temporal patterns at timescales of tens and hundreds of milliseconds. Furthermore, extracellular recordings in monkeys demonstrate pronounced responsiveness to deviant click trains at longer temporal scales in the primary auditory cortex (A1), accompanied by synchronization with both individual clicks and click trains. By contrast, neurons in the auditory thalamus prefer individual clicks only. Notably, neurons in A1 exhibit the ability to synchronize with individual clicks while simultaneously integrating these clicks into cohesive train objects, a phenomenon we term “temporal integration during synchronization”. Additional human electroencephalography recordings complement and support these findings, highlighting the paradigm’s potential for clinical applications. Our research offers novel insights into the neural mechanisms underpinning auditory information processing across various temporal scales at the neuronal level.

Closed-loop strategies offer advanced therapeutic potential through intelligent disease management. Here, we develop a hydrogel-based, single-component, organic electronic device for closed-loop neurotherapy. Fabricated out of conductive hydrogels, the device consists of a flexible array of microneedle electrodes, each of which can be individually addressed to perform electrical recording and control chemical release with sophisticated spatiotemporal control, thus pioneering a smart antiseizure therapeutic system by combining electrical and pharmacological interventions. The recorded neural signal acts as the trigger for a voltage-driven drug release in detected pathological conditions predicted by real-time electrophysiology analysis. When implanted into epileptic animals, the device enables autonomous antiseizure management, where the dosing of antiepileptic drug is controlled in a time-sensitive, region-selective, and dose-adaptive manner, allowing the inhibition of seizure outbursts through the delivery of just-necessary drug dosages. The side effects are minimized with dosages three orders of magnitude lower than the usage in approaches simulating existing clinical treatments.

How consciousness is lost in states such as sleep or anesthesia remains a mystery. To gain insight into this phenomenon, concurrent recordings of electrophysiology signals in the anterior cingulate cortex and whole‐brain functional magnetic resonance imaging (fMRI) are conducted in rats exposed to graded propofol, undergoing the transition from consciousness to unconsciousness. The results reveal that upon the loss of consciousness (LOC), there is a sharp increase in low‐frequency power of the electrophysiological signal. Additionally, fMRI signals exhibit a cascade of deactivation across a pathway including the hippocampus, thalamus, and medial prefrontal cortex (mPFC) surrounding the moment of LOC, followed by a broader increase in brain activity across the cortex during sustained unconsciousness. Furthermore, sliding window analysis demonstrates a temporary increase in synchrony of fMRI signals across the hippocampus‐thalamus‐mPFC pathway preceding LOC. These data suggest that LOC may be triggered by sequential activities in the hippocampus, thalamus, and mPFC, while wide‐spread activity increases in other cortical regions commonly observed during anesthesia‐induced unconsciousness may be a consequence, rather than a cause of LOC. Taken together, the study identifies a cascade of neural events unfolding as the brain transitions into unconsciousness, offering insight into the systems‐level neural mechanisms underpinning LOC.

Here, we characterized the dynamics of sleep spindles, focusing on their damping, which we estimated using a metric called oscillatory-Quality (o-Quality), derived by fitting an autoregressive model to electrophysiological signals, recorded from the cortex in mice. The o-Quality of sleep spindles correlates weakly with their amplitude, shows marked laminar differences and regional topography across cortical regions, reflects the level of synchrony within and between cortical networks, is strongly modulated by sleep-wake history, reflects the degree of sensory disconnection, and correlates with the strength of coupling between spindles and slow waves. As most spindle events are highly localized and not detectable with conventional low-density recording approaches, o-Quality thus emerges as a valuable metric that allows us to infer the spread and dynamics of spindle activity across the brain and directly links their spatiotemporal dynamics with local and global regulation of brain states, sleep regulation, and function.

Resting-state brain networks (RSNs) have been widely applied in health and disease, but the interpretation of RSNs in terms of the underlying neural activity is unclear. To address this fundamental question, we conducted simultaneous recordings of whole-brain resting-state functional magnetic resonance imaging (rsfMRI) and electrophysiology signals in two separate brain regions of rats. Our data reveal that for both recording sites, spatial maps derived from band-specific local field potential (LFP) power can account for up to 90% of the spatial variability in RSNs derived from rsfMRI signals. Surprisingly, the time series of LFP band power can only explain to a maximum of 35% of the temporal variance of the local rsfMRI time course from the same site. In addition, regressing out time series of LFP power from rsfMRI signals has minimal impact on the spatial patterns of rsfMRI-based RSNs. This disparity in the spatial and temporal relationships between resting-state electrophysiology and rsfMRI signals suggests that electrophysiological activity alone does not fully explain the effects observed in the rsfMRI signal, implying the existence of an rsfMRI component contributed by ‘electrophysiology-invisible’ signals. These findings offer a novel perspective on our understanding of RSN interpretation.

Visual object memory is a fundamental element of various cognitive abilities, and the underlying neural mechanisms have been extensively examined especially in the anterior temporal cortex of primates. However, both macroscopic large-scale functional network in which this region is embedded and microscopic neuron-level dynamics of top-down regulation it receives for object memory remains elusive. Here, we identified the orbitofrontal node as a critical partner of the anterior temporal node for object memory by combining whole-brain functional imaging during rest and a short-term object memory task in male macaques. Focal chemogenetic silencing of the identified orbitofrontal node downregulated both the local orbitofrontal and remote anterior temporal nodes during the task, in association with deteriorated mnemonic, but not perceptual, performance. Furthermore, imaging-guided neuronal recordings in the same monkeys during the same task causally revealed that orbitofrontal top-down modulation enhanced stimulus-selective mnemonic signal in individual anterior temporal neurons while leaving bottom-up perceptual signal unchanged. Furthermore, similar activity difference was also observed between correct and mnemonic error trials before silencing, suggesting its behavioral relevance. These multifaceted but convergent results provide a multiscale causal understanding of dynamic top-down regulation of the anterior temporal cortex along the ventral fronto-temporal network underpinning short-term object memory in primates.

Converging electrophysiological, molecular and ultrastructural evidence supports the hypothesis that sleep promotes a net decrease in excitatory synaptic strength, counteracting the net synaptic potentiation caused by ongoing learning during waking. However, several outstanding questions about sleep‐dependent synaptic weakening remain. Here, we address some of these questions by using two established molecular markers of synaptic strength, the levels of the AMPA (alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid) receptors containing the GluA1 subunit and the phosphorylation of GluA1 at serine 845 (p‐GluA1(845)). We previously found that, in the rat cortex and hippocampus, these markers are lower after 6–8 h of sleep than after the same time spent awake. Here, we measure GluA1 and p‐GluA1(845) levels in synaptosomes of mouse cortex after 5 h of either sleep, sleep deprivation, recovery sleep after sleep deprivation or selective REM sleep deprivation (32 C57BL/B6 adult mice, 16 females). We find that relative to after sleep deprivation, these synaptic markers are lower after sleep independent of whether the mice were allowed to enter REM sleep. Moreover, 5 h of recovery sleep following acute sleep deprivation is enough to renormalize their expression. Thus, the renormalization of GluA1 and p‐GluA1(845) expression crucially relies on NREM sleep and can occur in a few hours of sleep after acute sleep deprivation.

The cerebral cortex is widely considered part of the neural substrate of consciousness, but direct causal evidence is missing. Here, we tested in mice whether optogenetic activation of cortical neurons in posterior parietal cortex (PtA) or medial prefrontal cortex (mPFC) is sufficient for arousal from three behavioral states characterized by progressively deeper unresponsiveness: sleep, a coma-like state induced by muscimol injection in the midbrain, and deep sevoflurane-dexmedetomidine anesthesia. We find that cortical stimulation always awakens the mice from both NREM sleep and REM sleep, with PtA requiring weaker/shorter light pulses than mPFC. Moreover, in most cases light pulses produce both cortical activation (decrease in low frequencies) and behavioral arousal (recovery of the righting reflex) from brainstem coma, as well as cortical activation from anesthesia. These findings provide evidence that direct activation of cortical neurons is sufficient for behavioral and/or cortical arousal from sleep, brainstem coma, and anesthesia.

Objective. This study aims to reveal longitudinal changes in functional network connectivity within and across different brain structures near chronically implanted microelectrodes. While it is well established that the foreign-body response (FBR) contributes to the gradual decline of the signals recorded from brain implants over time, how the FBR affects the functional stability of neural circuits near implanted brain–computer interfaces (BCIs) remains unknown. This research aims to illuminate how the chronic FBR can alter local neural circuit function and the implications for BCI decoders. Approach. This study utilized single-shank, 16-channel,100 µ m site-spacing Michigan-style microelectrodes (3 mm length, 703 µ m2 site area) that span all cortical layers and the hippocampal CA1 region. Sex balanced C57BL6 wildtype mice (11–13 weeks old) received perpendicularly implanted microelectrode in left primary visual cortex. Electrophysiological recordings were performed during both spontaneous activity and visual sensory stimulation. Alterations in neuronal activity near the microelectrode were tested assessing cross-frequency synchronization of local field potential (LFP) and spike entrainment to LFP oscillatory activity throughout 16 weeks after microelectrode implantation. Main results . The study found that cortical layer 4, the input-receiving layer, maintained activity over the implantation time. However, layers 2/3 rapidly experienced severe impairment, leading to a loss of proper intralaminar connectivity in the downstream output layers 5/6. Furthermore, the impairment of interlaminar connectivity near the microelectrode was unidirectional, showing decreased connectivity from Layers 2/3 to Layers 5/6 but not the reverse direction. In the hippocampus, CA1 neurons gradually became unable to properly entrain to the surrounding LFP oscillations. Significance . This study provides a detailed characterization of network connectivity dysfunction over long-term microelectrode implantation periods. This new knowledge could contribute to the development of targeted therapeutic strategies aimed at improving the health of the tissue surrounding brain implants and potentially inform engineering of adaptive decoders as the FBR progresses. Our study’s understanding of the dynamic changes in the functional network over time opens the door to developing interventions for improving the long-term stability and performance of intracortical microelectrodes.

Dopamine neurons in the ventral tegmental area support intracranial self-stimulation (ICSS), yet the cognitive representations underlying this phenomenon remain unclear. Here, 20-Hz stimulation of dopamine neurons, which approximates a physiologically relevant prediction error, was not sufficient to support ICSS beyond a continuously reinforced schedule and did not endow cues with a general or specific value. However, 50-Hz stimulation of dopamine neurons was sufficient to drive robust ICSS and was represented as a specific reward to motivate behavior. The frequency dependence of this effect is due to the rate (not the number) of action potentials produced by dopamine neurons, which differently modulates dopamine release downstream.

Objective This study investigated the relationship between DBS evoked potentials (EPs) and diffusion tensor imaging (DTI) in a group of patients with dystonia who underwent DBS treatment. EPs and DTI are both useful methods for studying neural connectivity in the brain but measure different aspects of brain function. EPs provide information on electrical connectivity, while DTI provides information on anatomical pathways connecting regions. Methods This study focused on the pallidum and motor thalamus nuclei, which are common targets for DBS in dystonia. Prior to DBS implantation, DTI images were acquired for each patient, and were processed to obtain DTI coefficients such as length (L), volume (V), and fractional anisotropy (FA) of the fiber tracts. The relationship between the fiber tracts and electrophysiology was examined using a generalized linear model (GLM). Results We showed that the amplitude of EPs correlated with FA and tract volume, while delay correlated with tract length. These findings suggest that DBS signals travel across tracts to affect both local and distant brain regions, and the magnitude of the effect of DBS is determined by the integrity of the white matter tract, while DBS signal delay is affected by the tract length. Our results further suggest that the magnitude and delay of the spread of the DBS signal may be predicted by the DTI connectivity. This provides strong supporting evidence for other studies that have assumed, but have been unable to test, such a relationship. Conclusion Overall, this study suggests that the electrical effects of DBS can be at least partially predicted by noninvasive DTI imaging in patients with dystonia. By combining EPs with DTI, we could investigate the propagation of stimulation pulses through brain regions. While this relationship has been previously hypothesized by the neuroscience community, this is the first study in humans to demonstrate this relationship between DBS EPs and DTI, thereby advancing the field of human brain mapping and enhancing the precision of neurosurgical targeting.

Hearing is an active process in which listeners must detect and identify sounds, segregate and discriminate stimulus features, and extract their behavioral relevance. Adaptive changes in sound detection can emerge rapidly, during sudden shifts in acoustic or environmental context, or more slowly as a result of practice. Although we know that context- and learning-dependent changes in the spectral and temporal sensitivity of auditory cortical neurons support many aspects of flexible listening, the contribution of subcortical auditory regions to this process is less understood. Here, we recorded single- and multi-unit activity from the central nucleus of the inferior colliculus (ICC) and the ventral subdivision of the medial geniculate nucleus (MGV) of Mongolian gerbils under two different behavioral contexts: as animals performed an amplitude modulation (AM) detection task and as they were passively exposed to AM sounds. Using a signal detection framework to estimate neurometric sensitivity, we found that neural thresholds in both regions improved during task performance, and this improvement was driven by changes in firing rate rather than phase locking. We also found that ICC and MGV neurometric thresholds improved and correlated with behavioral performance as animals learn to detect small AM depths during a multi-day perceptual training paradigm. Finally, we reveal that in the MGV, but not the ICC, context-dependent enhancements in AM sensitivity grow stronger during perceptual training, mirroring prior observations in the auditory cortex. Together, our results suggest that the auditory midbrain and thalamus contribute to flexible sound processing and perception over rapid and slow timescales. Significance statement What a listener hears depends on several factors, such as whether the listener is attentive or distracted, and whether the sound is meaningful or irrelevant. Practice can also shape hearing by improving the detection of particular sound features, as occurs during language or musical learning. Understanding how changes in sound perception are implemented in the brain is important for developing strategies to optimize healthy hearing, and for treating disorders in which these processes go awry. We report that neurons in auditory midbrain and thalamus exhibit rapid shifts in sound sensitivity that depend on the sound’s behavioral relevance, and slower improvements that emerge over several days of training. Our results suggest that subcortical areas make an important contribution to flexible hearing.