EEG/ECoG/EMG publications

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.

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.

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.

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.

Psychedelics lead to profound changes in subjective experience and behaviour, which are typically conceptualised in psychological terms rather than corresponding to an altered brain state or a distinct state of vigilance. Here, we performed chronic electrophysiological recordings from the neocortex concomitant with pupillometry in freely moving adult male mice following an injection of a short-acting psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). We report an acute induction of a dissociated state, characterised by prominent slow oscillations in the cortex and marked pupil dilation in behaviourally awake, moving animals. REM sleep was initially markedly suppressed, but was overcompensated in the subsequent 48 hours, while administration of 5-MeO-DMT immediately after sleep deprivation attenuated the subsequent rebound of sleep slow-wave activity. We argue that the occurrence of a dissociated state combining features of waking and sleep may fundamentally underpin the known and hypothesised effects of psychedelics — from dream-like hallucinations to reopening of the critical period for plasticity.

Speech production entails several processing steps that encode linguistic and articulatory structure, but whether these computations correspond to spatiotemporally discrete patterns of neural activity is unclear. To address this issue, we use electrocorticography to directly measure the brains of neurosurgical participants performing an interactive speech paradigm. We observe a broad range of cortical modulation profiles, and subsequent clustering analyses establish that responses comprised distinct classes associated with sensory perception, planning, motor execution, and task-related suppression. These activity classes are also localized to separate neural substrates, indicating their status as specialized networks. We then parse dynamics in the planning and motor networks using unsupervised dimensionality reduction, which reveals subnetworks that are sequentially active throughout preparation and articulation. These results therefore support and extend a localizationist model of speech production where cortical activity "flows" within and across discrete pathways during language use.

Context‐dependent sensory processing within the predictive coding framework relies on detecting mismatches between incoming stimuli and internal predictive models. Sensory deviants elicit prediction errors, seen as enhanced neural responses, that update these models and influence attention and behaviour. Although prediction errors have been widely observed across brain regions, the downstream processes remain poorly understood. In this study, we recorded electrocorticography in five urethane‐anaesthetised rats and identified cortical slow oscillations, characterised by spontaneous transitions between ‘Up’ and ‘Down’ states. Deviant stimuli in an auditory oddball paradigm evoked an initial positive prediction error, followed by a prolonged, all‐or‐nothing response which spread in a travelling wave across the cortex. Identified as putative evoked cortical Up states, these responses were not evoked by standards, omissions or a many‐standards control. Up states following deviants occurred more recently after a previous Up state when compared to spontaneous Up states. In preliminary data from an awake rat, long‐latency Up states were not present spontaneously or evoked. In a different rat, anaesthetic depth was key to spontaneous and evoked Up states, with more robust Up/Down states and more reliable triggering of Up states under deeper anaesthesia. These results suggest that sensory deviants may cause shifts in cortical state under anaesthesia, explaining the long‐latency mismatch response under anaesthesia and sleep.

As part of a deep brain stimulation (DBS) procedure, direct electrophysiological recordings from thalamic and basal ganglia circuits were obtained from a pediatric participant with secondary dystonia to examine the neural mechanisms of motor timing. The participant performed a two-phase repetitive timing task that began with synchronization to a series of externally presented auditory cues, followed by a continuation phase in which the participant maintained the movement rhythm without external guidance. Simultaneous recordings from stereoelectroencephalography (sEEG) leads implanted in the globus pallidus internus (GPi), subthalamic nucleus (STN), ventral oralis (Vo), centromedian nucleus (CM), and thalamic nuclei receiving projections from the cerebellum (ventral intermediate nucleus (VIM) and centrolateral nucleus (CL)) revealed behaviorally relevant neural dynamics. Local field potentials (LFPs) from recorded nuclei exhibited strong, time-locked responses during the synchronization phase, with reduced amplitudes during the continuation phase. Time-frequency analysis showed consistent power increases around the corresponding mean of the inter-response intervals (IRIs) in both behavioral output and neural signals, suggesting frequency-specific entrainment across circuits. These findings suggest of cerebellar-thalamic and basal ganglia contributions to temporal coordination.

Background: Optimizing deep brain stimulation (DBS) parameter settings requires postoperative adjustments through a time-consuming trial-and-error process. As such, researchers have been developing computational models to guide DBS programming. Despite growing interest in image-guided DBS technology, and recent adoption into clinical practice, the direct validation of the prediction accuracy remains limited. Objective: The objective of this study was to establish a comparative framework for validating the accuracy of various DBS computational modeling methodologies in predicting the activation of clinically relevant pathways using in vivo measurements from PD patients undergoing subthalamic (STN) DBS surgery. Methods: In this study, we compared the accuracy of six computational modeling variations for predicting the activation of the corticospinal/bulbar tract (CSBT) and cortico-subthalamic hyperdirect pathway (HDP) using very short- (<2 ms) and short-latency (2-4 ms) cortical evoked potentials (cEPs). We constructed the variations using three key factors: modeling method (Driving Force [DF] vs. Volume of Tissue Activated [VTA]), imaging space (native vs. normative), and anatomical representation (pathway vs. structure). The model performances were quantified using the coefficient of determination (R2) between the cEP amplitudes and percent pathway or structure activation. Results: We compared model accuracy for 11 PD patients. The DF-Native-Pathway model was the most accurate method for quantitatively predicting experimental subcortical pathway activations. Additionally, our analysis showed that using normative brain space significantly diminished the accuracy of model predictions. Conclusion: The choice of methodology should depend on the specific application and the required level of precision for the intended analysis. However, model parameters should be optimized to accurately predict known experimental activation measures.

Purpose: We aim to develop a robust method to improve the estimation accuracy of motor-evoked potential (MEP) recruitment curves (RCs), including motor threshold, in small-sample settings which typically involve fewer than 40 stimuli. Methods: We present a hierarchical Bayesian (HB) method to model MEP size as a rectified-logistic function of stimulation intensity. This method is designed to account for small samples, handle outliers without discarding data, quantify estimation uncertainty, and simulate synthetic data that closely matches real observations, useful for optimizing experimental design. We validate its performance on transcranial magnetic stimulation (TMS), epidural spinal cord stimulation (SCS), and synthetic TMS datasets, and provide an open-source library for Python, called hbMEP, for diverse applications. Results: The rectified-logistic outperformed sigmoidal functions in predictive accuracy on TMS and SCS datasets, as demonstrated through cross-validation. A mixture extension of the HB model improved robustness to outliers by further increasing its predictive accuracy. The HB model reduced threshold estimation error by up to 70% on sparse synthetic TMS data compared to non-hierarchical models. Bayesian estimation with the HB model reduced the required number of participants by at least 23% to detect a shift in threshold with 80% power, compared to frequentist testing. Empirical results on human SCS data further validated its applicability to real data. Conclusion: By improving accuracy on sparse data, our method minimizes the number of stimuli needed to probe each individual's neuromuscular parameters across multiple muscles simultaneously, thereby reducing session duration and the risk of inadvertent neuromodulation. Our approach provides a more statistically powerful and conclusive framework for inferring changes in threshold, and therefore corticospinal excitability. The hbMEP library streamlines and unifies the analysis of RCs across stimulation modalities and experimental paradigms.

The locus coeruleus–norepinephrine (LC-NE) system regulates arousal and awakening; however, it remains unclear whether the LC does this in a global or circuit-specific manner. We hypothesized that sensory-evoked awakenings are predominantly regulated by specific LC-NE efferent pathways. Anatomical, physiological, and functional modularities of LC-NE pathways involving the mouse basal forebrain (BF) and pontine reticular nucleus (PRN) were tested. We found partial anatomical segregation between the LC → PRN and LC → BF circuits. Extracellular NE dynamics in BF and PRN exhibited distinct sound-evoked activation during sleep, including a fast sound-evoked NE peak specific to PRN. Causal optogenetic interrogation of LC efferent pathways, by retro-channelrhodopsin (ChR2) activation or Platynereis dumerilii ciliary opsin (PdCO) silencing of synapses in target regions, revealed a role for early LC → PRN activity in driving arousal and sound-evoked awakenings. Together, our results uncover a role for early LC-NE PRN activity in connecting sensory and arousal pathways and establish LC heterogeneity in regulating arousal.

Target engagement determines therapeutic efficacy. In spinal cord stimulation (SCS), efficacy depends on the attributes of the electrodes used to deliver stimulation, particularly their position, interelectrode distance, size, and current orientation. We tested the effects of these electrode parameters using cervical stimulation to elicit forelimb muscle responses in the rat. We implanted devices over the C6 dorsal root entry zone (DREZ) in eight rats and measured responses in six forelimb muscles. We used custom designed electrode arrays to systematically vary position, distance, and size with linear arrays, and current orientation with circular arrays. Stimulation consisted of biphasic and pseudomonophasic pulse shapes with bipolar or distant return, and a high-definition montage with four returns surrounding a central contact to increase local current density. Efficacy was calculated from the motor thresholds of recruitment curves, and parameters were compared using linear mixed models. For position, stimulation over the DREZ was most effective, reducing thresholds by 25.9% ( p = 0.0002) relative to the midline; efficacy decreased as the electrode was positioned medial or lateral to the DREZ. For distance, placing the electrodes farther apart significantly improved efficacy ( p = 0.0022). For size, large electrodes increased SCS efficacy, reducing thresholds by 21.5% ( p = 0.0026) relative to small electrodes. After accounting for position and distance, current orientation did not affect SCS efficacy. Lastly, the high-definition montage decreased efficacy, increasing thresholds by 16.7% ( p = 0.003) relative to monopolar stimulation with a distant return. In conclusion, electrode position, distance, and size had the greatest effect on SCS efficacy, with the optimal parameters combining large electrodes at the DREZ position with a distant return. These results have the potential to lower the current needed to engage cervical spinal circuitry and to inform the design of SCS systems to improve dexterity in people with neurological injury or disease.

Gastrointestinal (GI) dysmotility and associated conditions affect over 20% of population, yet pharmacological, behavioural, and surgical interventions offer limited therapeutic efficacy. Targeted electrical stimulation addressing underlying neuromuscular pathology stands to transform our ability to treat dysmotility. Here, we developed a closed-loop GI neuroprosthesis which activates or relaxes GI tract musculature through electrochemical stimulation in response to sensed food stimuli. We additionally describe a tool supporting minimally invasive endoscopically guided implantation that can penetrate the mucosa, accurately localize the submucosa, and safely deploy this device to directly interface with the enteric nervous system. The neuroprosthesis enables generation of coordinated peristaltic waves, significantly increasing the motility rate in a swine model of oesophageal and stomach dysmotility (p < 0.05, student's t-test). Further, by directly modulating the myenteric plexus and thus mimicking meal ingestion, we induce peristalsis in a fasted state and achieve a metabolic response commensurate with a fed or satiated state. This neuroprosthesis and implantation platform expand opportunities in fundamental studies and treatments of metabolic and neuromuscular pathologies affecting the GI tract.

The central nervous system controls movement by combining neuromotor modules, known as muscle synergies. Previous studies suggest that spinal premotor interneurons (PreM‐INs) contribute to the encoding of stable muscle synergies for voluntary movement. But descending and sensory inputs also influence motor outputs through the spinal interneuronal network, which may be configured by its inputs to encode different sets of muscle synergies depending on the network state, thereby recruiting different selections of synergies. Here we tested this possibility of state‐dependent synergy encoding by examining the muscle synergies represented by the same upstream spinal interneurons under different activity states induced by various optogenetic stimulation patterns. Lumbosacral spinal units and electromyographic (EMG) activities of hindlimb muscles were simultaneously recorded from anaesthetized Thy1‐ChR2 mice as the spinal cord was stimulated by one or two optic fibres at different intensities. The synergy encoded by each unit was revealed as a ‘muscle field’ derived from spike‐triggered averages of EMG, whereas the entire muscle synergy set was factorized from the EMG. We found that although the muscle synergy set remained stable across stimulation conditions, the muscle fields of the same units were matched to different synergies within the set in different states. Thus the interneurons may flexibly adjust their connectivity with the motoneurons of the muscles as descending and sensory afferents impose different states on the spinal network. State‐dependent encoding of muscle synergies may allow different synergies to be selected for producing stable movement in an ever‐changing workspace environment. image Key points Muscle synergies for locomotion can be represented by spinal interneurons, as revealed by the interneurons’ muscle fields derived from spike‐triggered averages of EMG. The muscle field of a single spinal interneuron may vary under different stimulation conditions, as demonstrated by optogenetic stimulation. Encoding of muscle synergies is dependent on the state of spinal activities, thus facilitating the selection of appropriate synergies in different dynamic environments.

The discrete events of our narrative experience are organized by the neural substrate that underlies episodic memory. This narrative process is segmented into distinct units by event boundaries, which facilitate a replay process that acts to consolidate each event into a narrative memory. High-frequency oscillations (HFOs) may synchronize neural activity during these processes. We use intracranial recordings from participants viewing and freely recalling a continuous, audiovisual stimulus. We find that hippocampal HFOs increase following event boundaries and hippocampal-cortical coincident HFOs (co-HFOs) occur in cortical regions that underlie event segmentation (inferior parietal, precuneus, lateral occipital, and inferior frontal cortices). Event-specific co-HFO patterns that occur during event viewing reoccur following event boundaries for the subsequent three events and during recall. This is consistent with models that support replay as a mechanism for memory consolidation. Therefore, HFOs may coordinate activity across brain regions that facilitate event segmentation, encode memory of discrete events, and bind representations to assemble memory of a coherent, continuous experience.

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.

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.

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.