EEG/ECoG/EMG publications

A hallmark of intelligence is proficiency in solving new problems, including those that substantially differ from previously seen problems. Problem solving in turn depends on the goal-directed generation of novel ideas and behaviours 1 , which has been proposed to involve internal representations of discrete units (or symbols) that can be recombined into numerous possible composite representations 1–7 . Although this view has been influential in cognitive-level explanations of behaviour, definitive evidence for a neuronal substrate of symbols has remained elusive. Here we identify a neural population that encodes action symbols—recombinable representations of discrete units of motor behaviour—in a specific area of the frontal cortex. In macaque monkeys performing a drawing-like task, we found behavioural evidence that action elements (strokes) exhibit three crucial features that indicate an underlying symbolic representation: (1) invariance over low-level motor parameters; (2) categorical structure, which reflects discrete action types; and (3) recombination into novel sequences. Based on simultaneous neural recordings across eight regions of the motor, premotor and prefrontal cortex, we identified population activity specifically in the ventral premotor cortex that encodes planned actions in a manner that also reflects invariance, categorical structure and recombination. These findings reveal a neural representation of action symbols localized to the ventral premotor cortex and a putative neural substrate for symbolic operations.

Cognitive impairments are common in absence epilepsy, yet the neural basis of these deficits remains largely unknown. Communication between the thalamic reuniens nucleus and the prefrontal cortex is critical for flexible behavior. Here, we identify a disruption of this pathway in mice with absence epilepsy. This dysfunction leads to impaired cognitive flexibility and altered cortical inhibition, linking seizure-related thalamic activity to prefrontal network imbalance. Notably, targeted stimulation of the thalamic-prefrontal pathway alleviates both seizure occurrence and cognitive deficits. These findings reveal a shared circuit mechanism underlying epileptic and cognitive symptoms, pointing to new strategies for intervention.

Understanding speech in noisy environments is difficult for many people, and current hearing aids often fail because they amplify all sounds rather than the talker of interest. Auditory attention decoding (AAD) offers a potential solution by using the listener's brain signals to identify and enhance the attended speaker, but it has been unclear whether this can provide real-time perceptual benefits. Here we used high-resolution intracranial electroencephalography in patients undergoing neurosurgical procedures to implement a closed-loop system that achieves the decoding fidelity necessary to dynamically amplify the attended talker. Across multiple experiments, the system improved speech intelligibility, reduced listening effort and was consistently preferred by subjects. It also tracked both instructed and self-initiated attention shifts. By providing direct evidence that a real-time, brain-controlled hearing system can enhance perception, this work establishes a key performance benchmark for future auditory brain-computer interfaces and advances AAD from a theoretical concept to a validated solution for personalized assistive hearing.

Objective Traumatic brain injury (TBI) significantly reduces the quality of life for millions of survivors worldwide, causing persistent brain tissue damage and cognitive impairments, with no established therapeutic interventions currently available. Slow‐wave activity, a hallmark of deep sleep, has been implicated in recovery after TBI, but pharmacological approaches to enhance it lack specificity and scalability, complicating efforts to identify slow‐wave activity as a direct mechanistic contributor and severely limiting clinical translation. Methods To overcome these limitations, we developed a preclinical closed‐loop auditory stimulation (CLAS) paradigm that targets sleep's slow waves, enabling highly specific and temporally precise enhancement of slow‐wave activity. Therefore, we delivered 30‐ms sound triggers targeting the up‐phase of real‐time detected slow‐waves (upCLAS: TBI n = 8), or no sound stimulation (mockCLAS: non‐TBI n = 8, TBI n = 7) during sleep to healthy controls (non‐TBI) or brain injured (TBI) rats. Concomitantly, we assessed the ability of upCLAS‐enhanced sleep to counteract brain tissue damage (primary outcome) and symptomatic sequelae (secondary outcome) of TBI. Results Bayesian analysis revealed that sound‐mediated slow‐wave activity enhancement: (1) reduces diffuse axonal injury, with TBI mockCLAS posterior estimates falling outside the 95% confidence intervals of both other groups, whereas the posterior distributions of TBI upCLAS and non‐TBI groups largely overlapped (~13% posterior differences >0), consistent with a negligible effect size between groups; (2) decreases demyelination, with approximately 97% posterior differences >0 between TBI mockCLAS and TBI upCLAS groups, compared to approximately 60% between non‐TBI and TBI upCLAS groups; and (3) preserves cognitive ability, with recognition indexes in the novel object recognition test significantly above chance level in non‐TBI (* p = 0.031) and TBI upCLAS (* p = 0.026) groups, in contrast to mockCLAS‐treated TBI rats ( p = 0.156), presenting pronounced cognitive deficit. Furthermore, microglial response to brain injury was increased by deep sleep enhancement, with reduced ionized calcium‐binding adaptor molecule 1+ area coverage in TBI upCLAS rats (* p = 0.0445) compared to non‐TBI ones. Interpretation These results unambiguously demonstrate slow‐wave activity enhancement confers robust disease modification following TBI while overcoming major limitations of other preclinical approaches. Our findings constitute proof‐of‐concept that boosted sleep intensity mitigates histopathological and cognitive sequelae of brain trauma, suggesting that a clinically relevant, nonobtrusive, sleep‐based therapy may represent a novel therapeutic intervention for TBI survivors. ANN NEUROL 2026;100:242–254

Post-stroke spasticity (PSS), characterized by hyperreflexia and spastic hypertonia, is a common and debilitating consequence of cerebrovascular injury that impedes motor recovery. Despite its prevalence, the neurophysiological mechanisms underlying PSS remain poorly understood, partly due to the lack of reliable animal models. A known clinical correlate of spasticity is weakened rate-dependent depression (RDD) of the Hoffman reflex (H-reflex), particularly in the upper limbs of chronic stroke patients. However, the mechanistic basis of RDD impairment and its relationship to brain lesion characteristics remain unclear. Here, we characterized the longitudinal progression of H-reflex RDD in a wrist flexor muscle following photothrombotic stroke in mice and examined its association with lesion volume across cortical and subcortical regions using magnetic resonance imaging. RDD was significantly reduced 2-3 weeks after stroke, indicating hyperreflexia. Approximately 60% of stroke mice exhibited weakened RDD. Notably, lesion volumes in contralateral primary (M1) and secondary (M2) motor cortices correlated positively with RDD impairment, linking greater cortical damage to more severe reflex hyperexcitability. These results suggest that damage to motor cortical regions disrupts central reflex-modulating pathways, contributing to post-stroke hyperreflexia. The presented stroke model provides a valuable platform for mechanistic investigations of PSS and for evaluating potential therapeutic interventions.

Interictal epileptiform discharges (IEDs) are pathological bursts of brain activity between seizures in people with epilepsy. Despite their importance in diagnosis, cognitive comorbidities and therapeutic implications as biomarkers for neurostimulation, it is unknown how IEDs arise from structured large-scale neuronal firing across human cortical lamina. We used high-density Neuropixels probes to record from epileptogenic tissue in patients undergoing resective surgery, sampling 1,152 neurons during 1,094 IEDs across nine neocortical sites. We identified microcircuits for IEDs organized by firing pattern, neocortical depth and putative cell type. Regular-spiking cells, concentrated in superficial cortical lamina, initiated and coded the amplitude of the sharp discharge and excitatory–inhibitory imbalances across neocortical lamina preceded IEDs, enabling IED prediction up to 1,000 ms in advance. Most neurons that were modulated during IEDs also encoded cognitive information and adhered to physiological rhythms at baseline. Thus, neocortical IEDs are generated from predictable laminar–cellular interactions, providing the groundwork for new neurostimulation therapies that harness the granularity of single neurons.

The cortex generates diverse neural dynamics, ranging from broadband fluctuations to narrowband oscillations at specific frequencies. Here, we investigated whether broadband and oscillatory dynamics play different roles in the encoding and transmission of visual information. We used information-theoretical measures to dissociate neural signals sharing common information (i.e., redundancy) from signals encoding complementary information (i.e., synergy). We analyzed electrocorticography (ECoG) and local field potentials (LFP) in the visual cortex of human and non-human primates (macaque) to investigate the extent to which broadband signals (BB) and narrowband gamma (NBG) oscillations conveyed synergistic or redundant information about images. In both species, the information conveyed by BB signals was highly synergistic within and between visual areas. By contrast, the information carried by NBG was primarily redundant within and between the same visual areas. Finally, the information conveyed by BB signals emerged early after stimulus onset, while NBG sustained information at later time points. These results suggest a potential dual role of BB and NBG cortical dynamics in visual processing, with broadband dynamics supporting nonlinear pattern recognition and oscillations facilitating information maintenance across the cortex.

Background Transcranial electrical stimulation (TES) has limited spatial focus and depth penetration, constraining its therapeutic efficacy. Intersectional Short-Pulse (ISP) stimulation was developed to overcome these limitations by delivering rapidly switching pulses that can be temporally integrated by neuronal membranes. Here, we aimed to establish the biophysical basis of ISP-induced temporal summation and to test whether this mechanism enables effective brain modulation in vivo. Methods We combined finite-element modeling, cadaver measurements ( n = 2 human cadavers), and biophysically realistic NEURON simulations to characterize the spatial and temporal properties of ISP-induced electric fields. In vivo whole-cell patch-clamp recordings were performed in the rat somatosensory cortex (female Wistar rat) to test the membrane-level integration of sequential electric field pulses. Functional efficacy was evaluated using closed-loop ISP stimulation in a hippocampal kindling model of temporal lobe epilepsy in male Long–Evans rats ( n = 11 animals, >500 induced seizures analyzed across conditions). Results Here we show that neurons integrate sequential ISP pulses in a non-vectorial, temporally accumulative manner, consistent with membrane-level charge integration rather than extracellular field superposition. ISP and conventional TES simulations produced similar instantaneous field magnitudes, but ISP stimulation resulted in more uniform neuronal excitability across brain depths. Closed-loop ISP stimulation significantly outperformed conventional TES in reducing seizure duration and severity. ISP reduced hippocampal seizure duration by 45% and 35% compared to SHAM stimulation and conventional TES, and significantly reduced motor seizure severity. Conclusions ISP stimulation provides a non-invasive neuromodulation approach that enhances deep brain engagement through rapid, temporally structured pulse sequences. These findings demonstrate effective seizure suppression in a rodent model and support the translational potential of ISP for disorders involving pathological neural dynamics.

Non-rapid eye movement (NREM) sleep is not uniform but characterized by brief intrusions of wake-like brain activity and increased muscle tonus known as micro-arousals or brief awakenings. Although micro-arousals are an inherent feature of human and animal sleep, knowledge about the neural correlates of micro-arousals is sparse. We here developed an algorithm for automatic detection of micro-arousals based on EMG activity and used it to analyse the associated laminar neural activity in the motor cortex in mice. Our analysis showed that short micro-arousals with a duration below 5 s were associated with decreased cortical firing, while longer micro-arousals with a duration of 5–10 s were associated with increased firing in a similar manner to transitions to wakefulness. Analysis of single-channel firing showed that some channels exhibited increased activity immediately prior to micro-arousals, while others exhibited decreased activity. Slow wave activity (SWA, 1–4 Hz) immediately after micro-arousals was tightly correlated with sleep pressure and even surpassed average SWA levels during NREM sleep in sleep deprived animals. This study provides new insights into the neural mechanisms associated with micro-arousals and identifies a new link between sleep architecture and sleep homeostasis.

Objective. Low-intensity transcranial focused ultrasound (tFUS) offers high spatial specificity and deep brain penetration, representing a promising non-invasive approach for modulating brain activity and behavior. Although emerging studies indicate that tFUS can modulate pain-related behaviors in rodents and humans, the underlying network-level and cellular mechanisms remain unknown. This study investigates the effects of tFUS neuromodulation on inhibitory neural circuits in a humanized mouse model of chronic pain, integrating electrophysiological, molecular, and histological analyses across a cohort of 50 animals, including wild-type controls. Approach. A 128-element random array transducer was used to precisely target the pain-processing brain circuit, while a non-invasive and flexible 30-channel electroencephalography electrode was applied to record local evoked responses, topographical activity, and global excitation and inhibition dynamics, which were further validated by optogenetics experiments. Cellular-level modulation and safety outcomes were evaluated through blinded histological examination. Main results. We found that tFUS produced robust modulation of local and global brain activity, characterized by suppression of local theta oscillations and enhancement of network-level inhibitory dynamics. These electrophysiological patterns aligned with those observed during optogenetic activation of parvalbumin (PV) interneurons. Immunohistochemistry further showed significant increases in inhibitory neuronal markers, including elevated expressions of glutamate decarboxylase 67 and PV. Blinded histological assessment confirmed the absence of tissue damage, supporting the safety of the stimulation paradigm. Significance. These findings demonstrated that tFUS stimulation non-invasively engages PV GABAergic inhibitory circuits in a chronic pain mouse model, providing mechanistic insight and supporting its development as a precise and safe neuromodulation technology for clinical translation.

The development of motor control in primary motor cortex (M1) requires both movements and neural activity. In rats, cortical motor control first appears around postnatal day (P) 25, prior to which movements are generated by subcortical motor nuclei such as the red nucleus (RN). While these subcortically generated movements are thought to provide the activity that guides the development of M1, the specific movements associated with M1 activity and their somatotopic and temporal precision remain unknown. Here, we performed acute electrophysiological recordings of neural activity in the forelimb region of M1 of P12–24 rats as they cycled between sleep and wake and compared M1 and RN activity in P24 rats. At every age, M1 neurons exhibited somatopically precise activity during REM sleep twitches, along with strong activity during wake movements. From P12 to P24, the proportion of neurons exhibiting twitch-related activity decreased, twitch-related activity became more temporally refined, and a larger fraction of spikes occurred before movement onset. At P24, M1 showed less premovement activity than RN. Further, in contrast to the non-selective activity seen in M1, some RN neurons showed movement-selective activity patterns during wake, firing only during particular wake movements. These findings reveal that movement-related activity in M1 is somatotopically precise by P12 and temporally precise by P24. But M1 still lacks the strong premovement activity and selectivity characteristic of RN, suggesting that at P24, subcortical outputs remain the main drivers of M1’s movement-related activity.

The unique gyral patterns of the human brain demand patient‐specific neural interfaces to achieve precise neuromodulation, mitigate adverse tissue responses, and optimize therapeutic efficacy and safety. One‐size‐fits‐all, conventional rigid electrocorticography (ECoG) electrodes, standardized for mass production through lithographic techniques, exhibit limited conformability to the brain's heterogeneous cortical topography. This mechanical mismatch results in poor electrode‐tissue contact, signal loss, and foreign body responses. To address these limitations, we present an integrated novel platform, synergizing MRI‐based anatomical mapping, finite element analysis (FEA)—optimized mechanical design, and direct ink writing (DIW) 3D printing to fabricate electrodes customized to individual gyral patterns. The resulting honeycomb‐inspired printable gel electrode (HiPGE) employs a bioinspired honeycomb architecture with ultra‐soft hydrogels, engineered to match the bending stiffness of brain tissue (0.1–10 kPa) while maintaining cost‐efficiency and long‐term durability. This mechanical congruence ensures exceptional cortical conformability and adaptive interfacing, circumventing the geometric and material limitations of traditional rigid electrodes. By combining patient‐specific design with scalable fabrication, our platform establishes a transformative framework for neural interface engineering, enhancing precision, biocompatibility, and functional performance in neuromodulation therapies and neuroprosthetic applications.

Reconstructing speech from neural recordings is crucial for understanding human speech coding and developing brain-computer interfaces (BCIs). However, existing methods trade off acoustic richness (pitch, prosody) for linguistic intelligibility (words, phonemes). To overcome this limitation, we propose a dual-path framework to concurrently decode acoustic and linguistic representations. The acoustic pathway uses a long-short term memory (LSTM) decoder and a high-fidelity generative adversarial network (HiFi-GAN) to reconstruct spectrotemporal features. The linguistic pathway employs a transformer adaptor and text-to-speech (TTS) generator for word tokens. These two pathways merge via voice cloning to combine both acoustic and linguistic validity. Using only 20 min of electrocorticography (ECoG) data per human subject, our approach achieves highly intelligible synthesized speech (mean opinion score = 4.0/5.0, word error rate = 18.9%). Our dual-path framework reconstructs natural and intelligible speech from ECoG, resolving the acoustic-linguistic trade-off.

The clinical manifestations of mood and psychotic disorders encompass phasic and transdiagnostic features. The complexity of these symptoms may hamper the development of biomarkers for these diagnostic categories. In the present study, machine learning was employed to cluster their transdiagnostic clinical manifestations as a means of developing state-dependent biomarkers with electroencephalography (EEG). This data-driven clustering classified the items of multiple symptom scales into three symptom domains, which subsequently stratified patients with major depressive, bipolar, and schizophrenia spectrum disorders into distinct symptom state groups. The specific brain activity profiles of each stratum were then characterized by resting-state and auditory steady-state EEG paradigms. The resting-state readings of patients in manic states revealed significantly increased gamma and beta oscillations, whereas 40-Hz and 20-Hz auditory steady-state responses (ASSRs) showed no significant differences. These findings suggest that manic states are associated with heightened high-frequency oscillatory activity, represented by gamma and beta oscillations, without a concomitant increase in sensory-evoked information processing precision. Further investigations of excessive gamma and beta oscillations may facilitate the development of state-dependent biomarkers for the assessment, diagnosis, and treatment of manic state symptomatology in clinical psychiatry.

Auditory areas on the superior temporal plane and lateral convexity are key initial stages of speech processing in the human cortex, representing acoustic and phonetic attributes in a temporally precise manner. More complex representations in auditory-related cortex along the ventral and dorsal processing streams and prefrontal cortex are associated with perception and action. In this study, we used intracranial electroencephalography (iEEG) to clarify where and how activity leading to perceptually driven behavioral events emerges. Participants were patients undergoing iEEG monitoring for medically intractable epilepsy. Stimuli were monosyllabic words, and participants pressed a button in response to a semantic target category. Significant high gamma activity after stimulus onset and immediately prior to motor response defined stimulus- and behavior-related activity patterns, respectively. The stimulus-related pattern was more common than behavior-related throughout the cortical auditory hierarchy as well as sensorimotor cortex. Behavior-related activity was sparsely represented, with the highest prevalence in the prefrontal cortex and a more limited representation in anterior temporal and parieto-occipital cortex. Hemispheric asymmetries included a higher prevalence of stimulus-related activity in the right sensorimotor cortex and a higher prevalence of the behavior-related pattern in the left prefrontal cortex. Faster behavioral responses were associated with greater stimulus-locked high gamma power in non-core auditory, prefrontal, and premotor cortex. Results reveal the cortical distribution of sensory stimulus-driven responses and activity time-locked to behavior and provide insights into neural substrates of speech perception.

Stimulation of sensory vagal pathways is typically delivered via invasive, cervical vagus nerve stimulation (cVNS) or noninvasive, trans-auricular nerve stimulation (taNS). While both methods are investigated therapeutically, their effects on brain physiology remain poorly understood, hindering mechanistic insights and stimulus optimization. In 6 awake nonhuman primates, we recorded cortical vagal-evoked potentials (VEPs) from subdural electrodes placed in prefrontal, sensorimotor and parietal cortical areas, in response to cVNS or taNS. Across 478 different taNS and cVNS protocols, we varied stimulation side, intensity, frequency, pulse count, and pulse width and assessed independent effects on amplitude and latency of early (EC; 30-100 ms), intermediate (IC; 101-200 ms) and late components (LC; 201-500 ms) of VEPs. Fixed and random effects of stimulation parameters and subjects, respectively, on VEPs were assessed using a linear mixed-effects model. Overall, cVNS elicits more robust VEPs than taNS, with larger EC, IC and LC amplitudes, in both hemispheres. cVNS-elicited ECs and LCs are largest in PFC and PC areas, whereas ICs are largest in SM areas. On the other hand, taNS generally does not elicit area-specific responses. cVNS-elicited ECs have slower latency than ta-NS elicited ECs. Higher stimulation frequencies and intensities and a longer pulse width elicit larger ECs and ICs for cVNS, and to some extent for taNS. Both short and long cVNS trains elicit stronger ECs, and long trains elicit slower ICs. Earlobe stimulation elicits VEPs that partially overlap with those from taNS. In conclusion, cVNS and taNS elicit cortical VEPs in a manner consistent with distinct engagement of ascending vagal pathways, with both similarities and differences in the effects of stimulation parameters on evoked responses.

Cytokines and their receptors play important roles in brain development and aging-related disease, but their functions within the healthy adult brain remain poorly understood. Here, we show that pyramidal neurons in hippocampal CA1 induce Fn14 expression in response to activity and environmental enrichment. Once expressed, Fn14 dampens the activity of these neurons most prominently at the daily transition between light and dark. Fn14 expression in CA1 neurons is regulated by the circadian transcription factor Bmal1, and mice lacking Fn14 exhibit disrupted sleep-wake patterns in vivo. At the cellular level, microglia contact fewer excitatory synapses in the absence of Fn14, while neuronal overexpression of Fn14 induces rod-like microglia and recruits them to excitatory synapses. Beyond a homeostatic context, mice lacking Fn14 exhibit heightened susceptibility to chemically induced seizures. These findings reveal that pro-inflammatory cytokine receptors such as Fn14 can play major roles in healthy neurological function in the adult brain.

Neurotransmitters and neuromodulators regulate brain states through diverse mechanisms, yet how their activities are coordinated during sleep remains unresolved. Using in vivo fiber photometry in adult mice expressing genetically encoded fluorescent biosensors, combined with EEG/EMG recordings, we investigated the temporal organization of multiple neuromodulators during sleep in barrel cortex, with norepinephrine (NE) as a reference signal. All five neuromodulators examined, acetylcholine, serotonin, dopamine, histamine, and NE, exhibited synchronized infraslow cortical oscillations during NREM sleep. Optogenetic suppression of locus coeruleus (LC) neurons abolished NE oscillations and selectively reduced acetylcholine fluctuations in barrel cortex, whereas targeted inhibition of basal forebrain cholinergic neurons attenuated REM-associated acetylcholine elevations without disrupting NREM-related oscillations or NE dynamics. The synchronized infraslow cortical oscillations spanning multiple neuromodulators reveal a previously unrecognized mechanism for organizing sleep architecture.

Astrocytes control neural communications by influencing GABAergic transmission through uptake and synthesis of GABA. Impaired GABAergic signaling is thought to underlie cortical hyperexcitability in autism. Here we show that dysregulation of astrocyte GABA transport in Fragile X syndrome (FXS), a leading genetic cause of autism, contributes to circuit hyperexcitability. Human FXS astrocytes derived from patient-specific induced pluripotent stem cells and mouse Fmr1 knockout (KO) astrocytes display a significant increase in levels of GABA and GABA-synthesizing enzyme GAD65/67. Our astrocyte-specific Fmr1 KO (cKO) mouse model reveals reduced inhibitory connectivity and impaired cortical responses to sound. Abnormal GABA transport in cortical astrocytes contributes to impaired fidelity of temporal processing and abnormal behaviors in cKO mice. Blocking astrocyte GABA transport enables higher PV expression, improves EEG responses to frequency-modulated sound, and corrects aberrant exploratory behavior. Our findings suggest astrocyte GABA transport plays a key role in regulating cortical inhibition, and contributes to autism-associated phenotypes.

Reduction in neuronal firing from wake to sleep, i.e., sleep firing rate homeostasis (sFRH), is essential for restorative sleep. Sleep dysfunction is common in Parkinson's disease (PD), but sFRH has not been investigated. Here, using a within-subject design in the nonhuman primate model of PD, we report that thalamocortical sFRH is disrupted in parkinsonism. These findings can inform therapeutic approaches tailored to normalize sFRH and reestablish restorative sleep in PD.