EEG/ECoG/EMG publications

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

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

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

Objective Cortical delta band (1–4 Hz) activity is considered a biomarker for states of altered consciousness, with increased delta power observed during anesthesia, sleep, coma, and delirium. The current study sought to characterize delta power following electrode implantation with respect to patient demographics and clinical characteristics as well as type and duration of surgery. Methods Participants were 25 adult neurosurgical patients implanted with intracranial electrodes for clinical monitoring of their epilepsy. Resting state cortical activity was recorded at multiple occasions over the course of the monitoring period. The initial time point was defined as the first recording within 72 h following surgery. Analyses of cortical activity were conducted using a linear mixed effects modeling approach to account for within‐participant correlations and between‐participant heterogeneity. Results Throughout the monitoring period, delta power decreased in frontal, occipital, parietal, and temporal regions, indicating a global phenomenon. By contrast, beta (14–30 Hz) power remained stable. Delta power was higher following surgical cases that required craniotomy compared to stereoelectroencephalography cases. Surgery duration and anesthesia emergence duration were associated with higher delta power. Recordings from depth electrodes showed higher delta power compared to subdural electrodes. No significant effects of patients' age, sex, white blood cell count, antiseizure medication, and opioid medication dosage on postoperative delta power were found. Significance The results are consistent with a postoperative elevation in delta power that resolves over the course of the monitoring period and indicate an association between increased delta power and craniotomy surgery, as well as longer surgery and emergence durations. The current work provides a comprehensive analysis of surgical, clinical, and physiological factors, suggests risk factors, and lays fundamental groundwork for future studies.

Presbycusis or age-related hearing loss (ARHL) affects millions of people worldwide, increasing their risk of cognitive decline and poor quality of life. However, ARHL remains an irreversible condition due to our inability to induce inner-ear hair cell regeneration. Nevertheless, multisession epidural stimulation of the auditory cortex (AC) at the onset of ARHL prevents hearing threshold elevation in naturally aging Wistar rats. Accordingly, we hypothesized that anodal direct current (DC) stimulation of the AC may also compensate for age-related maladaptive, activity-dependent changes. Here, we examined immunocytochemical markers in the AC, including early genes (c-fos and Arc), AMPA receptors (GluR2/3), parvalbumin (PV), and GAD67, along with auditory-evoked potentials (CAEPs) recorded in both auditory and visual (VC) cortices. When comparing 6 and 18.13-month-old rats without AC simulation, we observed loss of c-fos and Arc-positive neurons and decreased GluR2/3 expression, confirming altered AC neuronal network plasticity and activation. In addition, we noted changes in PV and decreased GAD67 immunoreactivity suggesting disrupted inhibition and significantly increased wave amplitudes in CAEPs, altered AC latencies, and decreased VC responses. By contrast, electrically stimulated rats showed no significant variations in early gene markers, GluR2/3, PV, or GAD67 with age, and the amplitudes and latencies of CAEPs recorded in their AC and VC resembled those of young rat. These findings indicate that anodal DC stimulation at the onset of ARHL delays AC aging by minimizing the loss of inhibition and preventing increases in cortical excitability in Wistar rats.

The auditory brainstem response (ABR) is an acoustically evoked EEG potential that is an important diagnostic tool for hearing loss, especially in newborns. The ABR originates from the response sequence of auditory nerve and brainstem nuclei, and a click-evoked ABR typically shows three positive peaks (“waves”) within the first six milliseconds. However, an assignment of the waves of the ABR to specific sources is difficult, and a quantification of contributions to the ABR waves is not available. Here, we exploit the large size and physical separation of the barn owl first-order cochlear nucleus magnocellularis (NM) to estimate single-cell contributions to the ABR. We simultaneously recorded NM neurons’ spikes and the EEG in owls of both sexes, and found that ≳ 5000 spontaneous single-cell spikes are necessary to isolate a significant spike-triggered average (STA) response at the EEG electrode. An average single-neuron contribution to the ABR was predicted by convolving the STA with the cell’s peri-stimulus time histogram. Amplitudes of predicted contributions of single NM cells typically reached 32.9 ± 1.1 nV (mean ± SE, range: 2.5–162.7 nV), or 0.07 ± 0.02 % (median ± SE; range from 0.01% to 1%) of the ABR amplitude. The time of the predicted peak coincided best with the peak of the ABR wave II, independent of the click sound level. Our results suggest that individual neurons’ contributions to an EEG can vary widely, and that wave II of the ABR is shaped by NM units.

Effective regulation of energy metabolism is critical for survival. Metabolic control involves various nuclei within the hypothalamus, which receive information about the body’s energy state and coordinate appropriate responses to maintain homeostasis, such as thermogenesis, pancreatic insulin secretion, and food-seeking behaviors. It has recently been found that the hippocampus, a brain region traditionally associated with memory and spatial navigation, is also involved in metabolic regulation. Specifically, hippocampal sharp wave-ripples (SWRs), which are high-frequency neural oscillations supporting memory consolidation and foraging decisions, have been shown to reduce peripheral glucose levels. However, whether SWRs are enhanced by recent feeding—when the need for glucose metabolism increases, and if so, whether feeding-dependent modulation of SWRs is communicated to other brain regions involved in metabolic regulation—remains unknown. To address these gaps, we recorded SWRs from the dorsal CA1 region of the hippocampus of mice during sleep sessions before and after consumption of meals of varying caloric values. We found that SWRs occurring during sleep are significantly enhanced following food intake, with the magnitude of enhancement being dependent on the caloric content of the meal. This pattern occurred under both food-deprived and ad libitum feeding conditions. Moreover, we demonstrate that GABAergic neurons in the lateral hypothalamus, which are known to regulate food intake, exhibit a robust SWR-triggered increase in activity. These findings identify the satiety state as a factor modulating SWRs and suggest that hippocampal-lateral hypothalamic communication is a potential mechanism by which SWRs could modulate peripheral metabolism and food intake.

While evolutionary cortical expansion is thought to underlie the evolution of human cognitive capabilities, excessive developmental expansion can lead to megalencephaly, often found in neurodevelopmental disorders. Still, little is known about how the overproduction of cortical neurons during development affects cortical processing and behavior in later life. Here we show that developmental overproduction of cortical superficial neurons impairs auditory processing in adult mice. We applied XAV939 to overproduce cortical superficial excitatory neurons during development. XAV939-treated adult mice exhibited auditory behavioral deficits and abnormal auditory cortical processing. Furthermore, we found fewer functional monosynaptic connections between cortical putative excitatory neurons. Altogether, our results suggest that abnormal auditory cortical processing contributes to the atypical auditory detectability in XAV939-treated mice. Although the expansion of cortical size is evolutionarily advantageous, an abnormal expansion during development can result in detrimental effects on cortical processing and perceptual behavior in adulthood.

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.

Maladaptive fear generalization is one of the hallmarks of trauma-related disorders. The endocannabinoid 2-arachidonoylglycerol (2-AG) is crucial for modulating anxiety, fear, and stress adaptation, but its role in balancing fear discrimination versus generalization is not known. To address this, we used a combination of plasma endocannabinoid measurement and neuroimaging in a childhood maltreatment–exposed and –nonexposed mixed population, combined with human and rodent fear-conditioning models. Here we show that 2-AG levels were inversely associated with fear generalization at the behavioral level in both mice and humans. In mice, 2-AG depletion increased the proportion of neurons that respond to, and the similarity of neuronal representations for, both threat-predictive and neutral stimuli within prelimbic prefrontal cortex neuronal ensembles. In humans, increased dorsolateral prefrontal cortical–amygdala resting-state connectivity was inversely correlated with fear generalization. These data provide convergent cross-species evidence that 2-AG is a key regulator of fear generalization and further support the notion that 2-AG deficiency could represent a trauma-related disorder-susceptibility endophenotype.

Restoring upper limb function is critical in individuals with central paralysis, and hand control is a priority in patients with neurological impairments. Functional electrical stimulation with implantable electrodes targeting the peripheral nervous system has the potential to selectively recruit hand muscles and generate multiple functional hand movements. However, the implantation of electrodes in the forearm or elbow areas requires multiple incisions for surgery, and elbow joint movements cannot be performed. In this study, we designed and implanted two epineural cuffs on the median and radial nerves in the distal brachial plexus of a single Japanese macaque ( Macaca fuscata ) monkey. The cuffs were successfully placed via an axillary approach using a single incision. Electrical stimuli were applied to innervate the contraction patterns of the hand, forearm, and triceps muscles relevant to the median and radial nerves. The evoked potentials of the target muscles electrically stimulated the distal brachial plexus to reliably and selectively innervate the upper limb muscles at the functional group level. Our results demonstrated that the distal brachial plexus can be a useful stimulation site for upper limb muscle contraction and that the axillary approach enables electrode placement to peripheral nerves required for upper limb control.

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.

Here, we present a protocol to decode Mandarin sentences from invasive neural recordings using a brain-to-text framework. We describe steps for preparing materials, including designing the sentence corpus and setting up electrocorticography (ECoG) recording systems. We then detail procedures for decoding, such as data preprocessing, selection of speech-responsive electrodes, speech detection, syllable and tone decoding, and language modeling. We also outline performance evaluation metrics. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.

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.

Closed-loop neural control is a powerful tool for both the scientific exploration of neural function and for mitigating deficiencies found in open-loop deep brain stimulation (DBS). Here, we present a protocol for artificial intelligence-guided neural control in rats using deep reinforcement learning (RL) and infrared neural stimulation (INS). We describe steps for integrating RL closed-loop control into neuroscience and neuromodulation studies. We then detail procedures for using and deploying infrared INS in chronic DBS applications. For complete details on the use and execution of this protocol, please refer to Coventry et al.1 and Coventry and Bartlett.2.

Background: Successful seizure onset zone (SOZ) localisation for epilepsy surgery often relies upon intracranial recordings. Accurate delineation requires anatomical detail yet influences of intracranial electrode density on clinical variables have not been systematically studied. Methods: In this experimental study we compared SOZ localisation between spontaneously captured seizures on higher-density depth and grid electrode arrays (4-5 mm inter-electrode spacing) vs. lower-density resampled versions of those same seizures (8-10 mm spacing). Since traditional review of channel traces would reveal density conditions, we instead projected seizure activity data as heatmaps on patient brain reconstructions and hid electrode locations. Using a single-blinded randomised crossover design, six attending-level epileptologists viewed these visualisations from ten patients under both higher-density and lower-density conditions (n = 120 observations) and digitally annotated SOZs. Findings: Inter-rater agreement between epileptologists on annotated margins was moderate (average Cohen's kappa: 0.47) and lower for the lower-density condition (p = 0.021, mixed effects model). Scorer confidence ratings did not differ between higher- and lower-density conditions (p = 0.410). The spatial extents of annotated SOZs for higher-density recordings were 25.4% larger on average (p = 0.011) and always closer to true SOZ extents in computer simulations, relative to lower-density. Interpretation: Epileptologists using higher-density depth and subdural intracranial EEG recordings had higher inter-rater agreement and identified larger extents of SOZs compared to lower-density recordings. While further studies assessing surgical outcomes in more patients are needed, these results suggest higher densities of electrodes on already-implanted hardware may reveal sub-centimetre extensions and clearer functional contiguity of the SOZ(s) for better appraisals of pathophysiological margins in epilepsy surgery. Funding: This work was supported by the National Institutes of Health through NINDS grant K23NS110920 and through a UCSF Weill Institute for Neurosciences Pilot Award.

Episodic memory relies on the formation and retrieval of content-specific memory traces. In addition to their veridical reactivation, previous studies have indicated that traces may undergo substantial transformations. However, the exact time course and regional distribution of reinstatement and transformation during recognition memory have remained unclear. We applied representational similarity analysis to human intracranial electroencephalography to track the spatiotemporal dynamics underlying the reinstatement and transformation of memory traces. Specifically, we examined how reinstatement and transformation of item-specific representations across occipital, ventral visual, and lateral parietal cortices contribute to successful memory formation and recognition. Our findings suggest that reinstatement in temporal cortex and transformation in parietal cortex coexist and provide complementary strategies for recognition. Further, we find that generalization and differentiation of neural representations contribute to memory and probe memory-specific correspondence with deep neural network (DNN) model features. Our results suggest that memory formation is particularly supported by generalized and mnemonic representational formats beyond the visual features of a DNN.

Auditory neuropathies affect the spiral ganglion neurons of the auditory nerve or their synapses with the sensory hair cells, distorting the sound information transmitted from the ear to the brain. Deciphering the underlying pathophysiological mechanisms remains challenging owing to the diversity of spiral ganglion neuron subtypes and associated central auditory circuits. An auditory neuropathy mechanism is unraveled by investigating the origin of auditory hyperexcitability in a mouse model for hereditary congenital deafness. Otogl encodes the large Otogelin‐like protein, which is related to secreted epithelial mucins and is implicated in the mechanical stimulation of cochlear outer hair cells. Heterozygous Otogl +/− mutant mice display auditory hyperexcitability, highlighted by their susceptibility to audiogenic seizures induced by loud sounds. It is shown that Otogl is transiently expressed in a subpopulation of spiral ganglion neurons during cochlear development. Despite their apparently normal hearing, Otogl +/− mice display poor activation of the spiral ganglion neurons processing loud sounds and an elevation of the activation threshold of the middle the ear muscle reflex that attenuates loud sounds. The findings reveal how a neuropathy affecting spiral ganglion neurons specialized in loud sound processing and associated with the middle the ear muscle reflex can manifest itself as auditory hyperexcitability.

Sound‐evoked wakefulness from sleep is crucial in daily life, yet its neural mechanisms remain poorly understood. It is found that CaMKIIα+ neurons in the temporal association cortex (TeA) of mice are not essential for natural awakening from sleep. However, optogenetic activation of these neurons reliably induces wakefulness from non‐rapid eye movement (NREM) sleep but not from rapid eye movement (REM) sleep. In vivo electrophysiological and calcium recordings further demonstrated that TeA neurons are monotonically tuned to sound intensity but not frequency. More importantly, it is found that the activity of CaMKIIα+ neurons in TeA can gate sound‐evoked arousal from NREM sleep, which is further confirmed by optogenetic manipulations. Further investigation reveals that the baseline excitability of TeA CaMKIIα+ neurons and the delta oscillations in the electroencephalogram are particularly important in regulating the evoked activity of TeA neurons. Anatomical and functional screening of downstream targets of TeA reveals that excitatory projections from TeA glutamatergic neurons to glutamatergic neurons in the basolateral/lateral amygdala are critical for modulating sound‐evoked arousal from NREM sleep. These findings uncover a top‐down regulatory circuit that selectively governs sound‐evoked arousal from NREM sleep, with the TeA functioning as a key connecting cortex to subcortical regions.

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.