EEG/ECoG/EMG publications

The limitations of electrical neuromodulation are driving the development of neuroprosthetic systems enhanced with complementary modalities. A key technological challenge however remains the integration of the necessary hardware components (optical, thermal, fluidic, electrical) into miniaturized implants. Here we present a design framework, inspired by fast prototyping, that promises to reduce the complexity, fabrication time, and device bulk of multimodal neural interface systems. By combining extrusion‐based 3D printing of silicones and discrete electronic components, we integrated thermal neuromodulation and electrical recording capabilities in soft packages suitable for placement on the cortical surface of rodents. When linked to an autonomous auxiliary driver unit, these packages establish rapid, stable and localized hypothermia together with ElectroCorticoGraphy (ECoG) recording. In a rodent model of epilepsy (4‐aminopyridine), we demonstrate hypothermia‐induced suppression of seizure‐like activity. Our approach may advance the clinical translation of focal hypothermia as an alternative therapy for drug‐resistant focal epilepsies.

Background Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism spectrum disorder. Previous studies in the Fmr1 knockout (KO) mouse model of FXS and affected individuals have identified common electroencephalographic (EEG) abnormalities, which constitute biomarkers of cortical dysfunction for drug treatments. Methods We evaluated the effects of three different doses of oral blarcamesine, a Sigma-1 receptor agonist (S1R), on FXS-relevant EEG biomarkers in Fmr1 KO mice utilizing a multielectrode array (MEA) on resting-state power (from delta to gamma frequencies) and network synchronization (inter-trial phase coherence [ITPC]) using three auditory stimulation paradigms (chirp, auditory steady-state response [ASSR] at 40 Hz and at 80 Hz). Results Blarcamesine-treated Fmr1 KO mice showed dose-dependent modulation of EEG biomarkers across cortical regions. Resting-state EEG power was reduced across multiple frequency bands, including suppression of the FXS-distinctive elevation in the gamma band. Significant improvements in ITPC were observed in all cortical regions for chirp stimulation and 40 Hz ASSR, while modest improvements were seen for 80 Hz ASSR. Conclusion Altogether, these data demonstrate that blarcamesine modulates multiple EEG biomarkers of cortical dysfunction in Fmr1 KO mice. Given that these biomarkers are associated with fundamental neurophysiological mechanisms underlying cognitive and behavioral abnormalities, and are shared between FXS mouse models and affected individuals, these findings are consistent with previously characterized S1R-mediated pharmacological effects of blarcamesine. These data support further investigation of blarcamesine’s clinical potential in FXS and other neurodevelopmental disorders.

Auditory hypersensitivity or decreased sound tolerance is a common phenotype of Fragile X Syndrome (FXS). Impairments in adaptation, defined as the reduction in the neuronal responsiveness to repeating sounds, can contribute to this prevalent phenotype. Previous studies on event-related potential observed impairments in mismatch negativity (MMN) in both FXS individuals and in the FMR1 -knockout (KO) mouse model of FXS. Therefore, in the present study we characterized stimulus-specific adaptation (SSA), a neural correlate of MMN, at the auditory cortex (AC) of anesthetized (with ketamine/xylazine) female and male postnatal day 20 (P20) wild-type (WT) and FMR1 -KO mice, using the oddball paradigm with either 4 Hz or 1 Hz repetition rate. We observed robust SSA at the 4 Hz repetition rate of the oddball paradigm in the AC neurons of all four groups of animals. We also noted that the strength of SSA diminished between 4 to 1 Hz repetition rate. In addition, at both the 4 Hz and 1 Hz repetition rate, reduced SSA was observed particularly in the male FMR1 -KO mice compared to their WT counterparts, while female WT and FMR1 -KO mice displayed similar SSA. In terms of sex differences, male FMR1 -KO mice had lower SSA than female FMR1 -KO mice, while SSA was similar in male and female WT mice. Overall, our observation of reduced SSA in the male FMR1 -KO mice suggests that impairments in neuronal adaptation potentially contribute to the auditory hypersensitivity phenotype particularly within the male population.

One of the most distinctive features of the mammalian cerebral cortex is its laminar structure. Of all cortical layers, layer 6b (L6b) is by far the least studied, despite exhibiting direct sensitivity to orexin and having widespread connectivity, suggesting an important role in regulating cortical oscillations and brain state. We performed chronic electroencephalogram (EEG) recordings in mice in which a subset of L6b neurons was conditionally ‘silenced’, during undisturbed conditions, after sleep deprivation (SD), and after intracerebroventricular (ICV) administration of orexin. While the total amount of waking and sleep or the response to SD were not altered, L6b-silenced mice showed a slowing of theta frequency (6–9 Hz) during wake and rapid eye movement (REM) sleep, and a marked reduction of total EEG power, especially in non-rapid eye movement (NREM) sleep. The infusion of orexin A increased wakefulness in both genotypes, but subsequent levels of EEG slow-wave activity during NREM sleep were lower in L6b-silenced animals in the occipital derivation. In summary, these results demonstrate a role for cortical L6b in state-dependent brain oscillations and in the response to orexinergic neurotransmission. Our findings provide new insights in functions of L6b neurons and could inform the understanding of abnormal regulation of brain states in neurodevelopmental and psychiatric disorders.

Many species display mating-related sleep suppression to maximize reproductive success, yet the underlying neural mechanisms in mammals remain unclear. Here, we report that male mice exhibit delayed sleep onset and reduced sleep duration in periods following successful mating, while females are unaffected. Single-cell transcriptomics identifies a group of sleep-promoting Rxfp1-expressing neurons in the preoptic area of hypothalamus (POA Rxfp1 neurons), and fiber photometry reveals selective inhibition of them during and after mating in male mice. Lifting this inhibition via chemogenetic activation reverses sleep suppression in mated males. Monosynaptic retrograde tracing from these POA Rxfp1 neurons identifies male-biased γ-aminobutyric acid–releasing inputs from the principal nucleus of the bed nucleus of the stria terminalis (BNSTpr). Notably, optogenetic activation of these neurons induces immediate wakefulness specifically in male mice, and BNSTpr → POA Rxfp1 neurons are hyperactive after mating. Together, these findings establish a BNSTpr → POA Rxfp1 circuit that integrates reproductive signals for male-specific sleep suppression in mice.

Neuronal variability is a fundamental feature of neuronal coding. In spiking activity, across-trial variance (ATV) normalized by mean spike count (i.e., the Fano factor) shows stimulus-induced quenching. ATV has also been studied in electro/magneto-encephalography (E/MEG) without normalization, revealing effects of stimulation and cognition. Here we show that outside of event-related potentials (ERPs), ATV for both EEG and local field potential (LFP) is nearly identical to intra-trial variance (ITV), which equals signal power. ATV–ITV correlation decreases during ERPs, proportional to how much the ERP explains total power. While EEG ATV shows post-stimulus quenching, LFP ATV does not, particularly in the gamma band, where power increases after stimulus onset. To provide an independent variability measure, we introduce CV(power), the coefficient of variation of signal power, as a mean-normalized metric. CV(power) is the inverse of the signal-to-noise ratio of power and thus related to decodability, offering a variability measure applicable to E/MEG and LFP.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by CGG trinucleotide repeat expansion in the fragile X messenger ribonucleoprotein 1 (FMR1) gene and the resulting loss of fragile X messenger ribonucleoprotein (FMRP). Gene therapy using recombinant adeno-associated virus (AAV) to restore FMRP expression, particularly in the brain, is a promising therapeutic strategy targeting the underlying cause of FXS. We examined the impact of AAV serotype 9 (AAV9)-mediated expression of a brain-abundant human FMRP isoform (isoform 7) driven by a fragment of the human FMR1 promoter on circuit and behavioral dysfunctions in the male Fmr1 knockout (KO) mouse, FXS model. Following intracerebroventricular (i.c.v.) injection of AAV9-NG276 into neonatal KO mice at a low (1e11 vg/animal) or high (3e11 vg/animal) dose, we assessed cortical phenotypes using electroencephalography (EEG) recordings and behavioral testing. High-dose AAV9-NG276 normalized baseline gamma power, improved sound-evoked responses, and reduced background neural activity. Analysis of behavioral deficits in adult KO mice showed that high-dose neonatal AAV9-NG276 delivery normalized exploratory behaviors, social preference, and probabilistic reversal learning. Thus, early AAV-mediated delivery of human FMR1 isoform 7 ameliorates cortical dysfunction and behavioral deficits in a murine FXS model and suggests that widespread cortical biodistribution is required for therapeutic benefit.

Recent work shows that the brain’s arousal system remains active during sleep, with rhythmic locus coeruleus (LC) activity shaping sleep architecture and supporting memory consolidation. The LC releases norepinephrine (NE) in infraslow (~0.02 Hz) bouts that gate NREM sleep spindles. Here, we demonstrate that heart rate (HR) fluctuations during NREM are tightly phase-locked to these NE rhythms, identifying the LC as a key driver of very-low-frequency HR variability (VLF-HRV), an understudied autonomic signal. Using optogenetics, transient LC inhibition blunts HR slowing, whereas LC activation produces rapid HR acceleration, demonstrating a direct LC-HR relationship during sleep that is maintained across a defined range of LC activity levels but breaks down when LC activity becomes excessive. We further show that infraslow HR variability is a cross-species marker of spindle-dependent memory processing. In mice, the amplitude of HR decelerations during NREM correlates with spindle activity and subsequent memory performance. Remarkably, human sleepers show the same pattern: stronger VLF-HR fluctuations during NREM correspond to increased spindle expression and better overnight memory retention. These findings reveal a mechanistic pathway through which graded changes in LC activity, up to a critical level, modulates autonomic physiology during sleep and identify infraslow HR variability as a non-invasive marker of brainstem function and memory-promoting sleep. Because LC degeneration occurs early in neurodegenerative disease, sleep-derived HR metrics may provide a scalable indicator of emerging neuromodulatory dysfunction.

The ability to detect deviations from expected sensory input is fundamental for adaptive behavior. We recorded electrocorticographic activity from the auditory (AC) and prefrontal (PFC) cortices of behaving macaques during an auditory oddball task to probe the cortical dynamics of predictive processing. Repetition of standard stimuli evoked suppression and facilitation in AC and strong low-frequency (2 Hz) enhancement in PFC, accompanied by bidirectional delta-band GC-defined interactions indicative of a shared predictive state. Deviant stimuli triggered earlier AC responses followed by PFC activation and increased GC-defined directed interactions across theta, alpha, and conventional gamma bands. Behavioral engagement amplified both repetition-related and deviance-related ECoG responses, strengthening cortical network coordination. Together, these findings reveal behaviorally gated auditory–prefrontal dynamics that are consistent with hierarchical predictive-processing accounts, while also allowing for contributions from repetition-, novelty-, and salience-related mechanisms.

The detection of unexpected sounds, or auditory deviance detection, is thought to be achieved by comparing prediction signals and sensory inputs in the auditory cortex. This process is markedly impaired in patients with schizophrenia. However, the local circuit properties underlying deviance detection, together with their dysfunction in schizophrenia-related conditions, remain poorly understood. We used two-photon calcium imaging to monitor the population activity of cortical neurons during auditory deviance detection. The deviance-detecting component was predominant in layer 2/3 neurons of the higher-order auditory cortex. The deviance-detecting cells were spatially clustered, exhibited robust synchronization, and constitutively expressed immediate-early genes. In the Del(1.5 megabase)/+ mouse model of 22q11.2 deletion syndrome, a model of schizophrenia, deviance-detecting activity in the upper-layer network was disrupted, accompanied by dysregulated gene expression and selective loss of dendritic spines in immediate-early gene–positive neurons. Our findings support the hypothesis that ensemble activation of this neuronal subpopulation amplifies unexpected inputs, driving error signals that propagate to higher-order cortical areas.

Brain function relies on coordinated activity across spatial and temporal scales. Single neurons integrate local and long-range connectivity and reflect activity across brain-wide networks. Understanding integrated brain function requires tools capable of recording from anatomically connected populations in distributed brain areas to bridge local and global dynamics. Here, we present high-density, micro-electrocorticography arrays that facilitate multi-scale studies of brain activity. The hybrid arrays integrate the desirable features of silicone elastomers and polyimide films: silicone provides optical transparency and permits repeated penetration with intracortical arrays, while polyimide enables fine photolithographic feature definition. This combination facilitates high-throughput functional mapping to identify targets and insertion of intracortical arrays for dense local sampling. We demonstrate functional mapping in rats, cats, and marmosets, showing how functional maps guide multi-area laminar recordings. Finally, we demonstrate local and feedforward optogenetic stimulation to investigate cortico-cortical interactions. These capabilities establish the hybrid μECoG as a compelling tool for systems neuroscience.

How does the human brain detect and respond to disruptions in breathing? While animal studies have advanced our understanding of respiratory control, breathing distress in humans remains difficult to treat. It often arises not only from pulmonary lesions or brainstem dysfunction but also from how higher brain regions interpret breathing signals shaped by emotion and experience. We recorded intracranial cortical activity in neurosurgical patients during an interoceptive task involving transient breathing challenges. Conscious detection of these disruptions was predicted by early responses in the anterior insula, which routed signals to orbitofrontal and premotor cortices for appraisal and compensation. These cortical regions preferentially encoded inspiratory effort or airflow, revealing signal-specific processing that echoes functional segregation in brainstem centers. The present findings identify a dynamic insular-frontal circuit for sensing and adapting to respiratory challenges, offering insight into the neural basis of breathing awareness and its disruption in disease.

Background Direct current (DC) stimulation can modulate neuronal activity in ways that differ from pulsatile stimulation, but its intracranial use has been limited by concerns about tissue injury at the electrode/tissue interface. Quantitative safety limits for DC delivered through metal electrodes directly to the brain remain poorly defined. Objective To estimate histological safety boundaries for DC stimulation delivered through metal electrodes in a large-brain gyrencephalic animal model. Methods Cathodal DC stimulation was applied to the exposed cortical surface of ten anesthetized sheep using platinum–iridium disc electrodes typically used in clinical applications (surface area ≤ 4.15 mm 2 ). Currents of 5 to 1000 µA were delivered for 10 to 15 minutes at 36 cortical sites. Stimulation dose was quantified as charge density. Brains were removed shortly after stimulation and examined histologically for tissue damage, including necrosis, inflammation, gliosis, and demyelination. Lesion volumes were quantified and related to charge density. Results No lesions were observed at sites where no current or a low charge density (0.7 mC/mm 2 ) was delivered. With stimulation, lesion probability and volume increased with charge density, although variability was substantial. Lesions occurred in 3 of 18 sites at lower charge densities (1.4 to 10 mC/mm 2 ) and in 5 of 9 sites at higher charge densities (14.4 to 144.4 mC/mm 2 ). Linear regression of lesion volume against charge density yielded an estimated zero-lesion intercept of 2.3 mC/mm 2 , whereas alternative nonlinear models predicted thresholds up to 8.7 mC/mm 2 . Conclusion These findings suggest that it may be possible to apply cathodal DC stimulation directly to the cortical surface through metal electrodes without detectable histological damage when current intensity, duration, and electrode size are appropriately constrained. These findings provide quantitative guidance for the safe application of DC directly to neural tissue in experimental and translational neuromodulation studies.

Purpose: In anesthesia research and clinical practice, the level of consciousness is often assessed by stimulating subjects and observing their responses. It is possible that such stimulation alters the very state of consciousness being assessed. Whether this phenomenon is accompanied by specific cortical activities remains unknown. Here, we tested the effects of behavioral assessments on neuronal activity in the rat primary auditory cortex (A1) and perirhinal cortex (PrC). Methods: Neuronal spiking activity was recorded from microwire arrays targeting A1 and/or PrC in rats (n = 9), whilst presenting 40 Hz click-trains and gradually increasing infusion rates of propofol, remifentanil, ketamine or dexmedetomidine. We assessed righting reflex, pain withdrawal, whisking reflex, and corneal reflex every 12 minutes (every 360 auditory trials). We searched for significant changes in baseline firing rate and stimulus-evoked activities (where present) due to the behavioral assessments, by comparing 4 min intervals before and after the behavioral tests. Results: Out of 1004 units in 20 sessions, we found significantly elevated activity (p < 0.01) following behavioral tests in 32% and 20% of A1 auditory-responsive units and 8.6% and 5.3% of auditory-unresponsive units under propofol and dexmedetomidine, respectively, but not under remifentanil or ketamine. A higher proportion of units modulated their firing following behavioral tests in A1 compared to PrC, with median gains ranging from +0.23 to +1.06, depending on the specific response feature. Conclusion: Behavioral testing increases ongoing firing rate and responses to sounds in some cortical neurons. This increase is more prevalent in A1 than in PrC, mirroring clinical observations that patients exhibit basic responses under sedation, while complex processing, such as memory encoding, is impaired. The degree of neuronal modulation due to behavioral testing varies between anesthetic agents, mirroring their clinical phenotypes.

Mafb and c-Maf transcription factors (TFs) are expressed in medial ganglionic eminence (MGE) lineages, beginning in progenitors and continuing into mature GABAergic parvalbumin-positive (PV + ) and somatostatin-positive (SST + ) cortical interneurons (CINs). Deleting Mafb and c-Maf in MGE before SST versus PV fate specification causes developmental anomalies, including altered numbers of CINs and seizure phenotypes, but the specific contributions of these TFs in postmitotic SST + and PV + CINs to epilepsy remain unknown. To address this, we conditionally deleted Mafb or c-Maf in SST + or PV + interneurons after interneuron fate specification in female and male mice. Deletion of c-Maf, but not Mafb, in SST+ cells was associated with reduced synaptic excitation onto these cells and with spontaneous spike-and-wave discharges, consistent with absence-like seizures. In contrast, deletion of Mafb in SST + CINs reduced their density in superficial cortical layers but did not induce epilepsy. Neither c-Maf nor Mafb deletion in PV + CINs produced major electrophysiological or histological abnormalities in the somatosensory cortex. These findings identify a specific requirement for c-Maf in modulating synaptic excitation of SST + interneurons and show that its loss in SST + cells is associated with the development of absence-like epileptiform activity in vivo. Together, our results refine the understanding of how transcriptional programs shape interneuron function in the mature cortex and highlight c-Maf/MAF-dependent pathways as candidates for investigation in epilepsy genetics.

Pain management strategies have progressed beyond traditional pharmacologic and physical interventions, integrating advanced neuromodulation techniques such as deep brain stimulation, peripheral nerve stimulation, and high‐frequency spinal cord stimulation (hSCS). Despite its clinical efficacy, the supraspinal mechanisms underlying hSCS remain poorly understood. Prior work in sheep demonstrated that hSCS modulates gamma (γ) band (70–150 Hz) activity in the primary somatosensory and association cortices, implicating cortical involvement in pain modulation. Given the interaction between low‐ and high‐oscillations, we hypothesized that hSCS modulates γ activity in a region‐ and time‐dependent manner through specific coupling with theta rhythms (θ, 4–8 Hz). To test this, we quantified θ–γ phase‐amplitude coupling (PAC) during tibial nerve stimulation (TNS) before (TNS 0 ) and after (TNS 1 ) hSCS to assess cortical processing of TNS‐evoked activity, while recording cortical (association and somatosensory cortices) neural activity using 96‐channel subdural electrocorticography (ECoG). We then computed the corresponding modulation index (MI) to quantify PAC strength. While the preferred θ phase of γ activity remained consistent across conditions in both cortical areas, θ‐γ coupling was more robust and stable in the association than the somatosensory cortex. However, MI increased significantly post‐hSCS in both cortices, indicating enhanced θ‐γ coupling during TNS 1 . Temporally, both cortices showed distinct response patterns: the somatosensory cortex exhibited strongest coupling increase early post‐hSCS, followed by a progressive decline, whereas the association cortex showed a more delayed and temporally distributed enhancement. These findings indicate that hSCS modulates cortical cross‐frequency interactions during TNS‐evoked sensory processing, wherein somatosensory and association cortices show distinct temporal coupling dynamics that may contribute to supraspinal mechanisms of pain modulation.

Chronic sleep disruption and cognitive deficits are debilitating long-term consequences of traumatic brain injury (TBI), yet the endogenous mechanisms that drive network-level recovery remain poorly understood. Here, we demonstrate that during the chronic phase post-injury, network oscillations critical for memory, including slow oscillations, delta waves, and sleep spindles, undergo precise adaptive tuning that sustains sleep-dependent memory consolidation. This functional circuit resilience requires Semaphorin-3A (Sema3a); loss of Sema3a function prevents the protective reorganization of non-rapid eye movement (NREM) sleep architecture, impairs sleep-dependent memory consolidation, and exacerbates cortical lesion size. Together, these findings identify Sema3a as an innate protective mechanism that preserves sleep architecture and cognitive function following TBI.

Objective To evaluate the feasibility of using the acoustic change complex (ACC) as an objective cortical marker of continuous speech sound discrimination using connected Ling-six stimuli. Design Cortical auditory evoked potentials were recorded from 10 young adults with normal hearing using a continuous, pause-free sequence of the six Ling phonemes (/u-a-i-ʃ-s-m/). ACC responses were recorded in a passive listening paradigm with minimal electrodes. Reproducibility was assessed in a subset of participants retested 1 year later. Results Robust ACC responses were elicited for all six phonemic transitions in every participant, indicating reliable cortical discrimination within the continuous speech stream. Although response morphology varied across listeners, within-subject responses demonstrated strong reproducibility over a one-year interval (mean cross-correlation = 0.95). Conclusion Continuous Ling-six stimuli reliably evoke ACC responses reflecting cortical speech sound discrimination. This efficient and repeatable paradigm shows promise as an objective verification tool for auditory learning and sound discrimination, particularly in populations for whom behavioral assessment is unreliable.

In mammals, slow-wave sleep is characterized by synchronized neuronal activity that alternates between on and off periods. Slow-wave activity (SWA) and synchrony reflect sleep need, are correlated with synaptic strength in cortical circuits and promote synaptic downselection and memory consolidation. Here we assessed whether these core benefits of sleep can be obtained during waking. We locally induced alternating on/off periods during wakefulness using optogenetics in mice. This led to a local ipsilateral reduction in SWA and synchrony during subsequent sleep, and to reduced markers of synaptic strength. Moreover, bilateral induction of off periods over sensorimotor cortex during sleep deprivation restored memory consolidation. Thus, inducing on/off activity during wakefulness is sufficient to reduce local sleep need and fulfill core functions of sleep.

CLN3 disease, the most common form of the Neuronal Ceroid Lipofuscinoses (NCLs), causes progressive cognitive decline and language impairment in humans. A pathological hallmark is the accumulation of storage material within neuronal lysosomes resulting from mutations in the CLN3 gene. We previously identified parallel deficits in auditory duration mismatch negativity (MMN), an electroencephalography (EEG)-based marker of auditory change detection, in individuals with CLN3 disease and in Cln3 -/- mice. MMN-dependent auditory change detection relies on sensory-memory comparison mechanisms. However, the anatomical and neurophysiological substrates underlying this response in CLN3 disease remain unclear. Here, we investigated central auditory dysfunction in Cln3 -/- mice by integrating immunohistochemical mapping of lysosomal storage pathology, using the canonical marker Subunit C of Mitochondrial ATP Synthase (SCMAS), with EEG analysis of auditory evoked potentials (AEPs). Neuropathological analyses revealed age-dependent and sex-divergent SCMAS accumulation across the auditory thalamocortical circuit, including the excitatory auditory thalamus, the inhibitory thalamic reticular nucleus, and the primary auditory cortex. In parallel, Cln3 -/- mice exhibited age- and sex-dependent alterations in AEPs relative to wild-type controls. Importantly, an integrated measure of auditory thalamocortical SCMAS accumulation accounted for a substantial portion of age- and sex-matched variation in AEP responses, with stronger associations for the early N1 component than the later MMN component. Together, these findings link age-dependent and sex-divergent auditory neurophysiological deficits to region-specific lysosomal storage pathology within the auditory thalamocortical circuit in the Cln3 -/- mouse model. This integrated functional-anatomical framework provides insight into circuit vulnerability and supports the development of translational neurophysiological biomarkers for CLN3 disease. Graphical Abstract Highlights SCMAS accumulates across the auditory thalamocortical circuit in Cln3 -/- mice Accumulation shows distinct age- and sex-dependent regional trajectories Cln3 -/- mice exhibit progressive alterations in auditory evoked potentials Thalamic pathology is strongly associated with the early auditory N1 response Histology–EEG integration links circuit pathology to auditory dysfunction