LFP publications

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.

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

Neurons in the cerebral cortex and hippocampus discharge synchronously in a brain state-dependent manner to transfer information. Published studies have highlighted the temporal coordination of neuronal activities between the hippocampus and a neocortical area; however, how the spatial extent of neocortical activity relates to hippocampal activity remains partially unknown. We imaged mesoscopic neocortical activity while recording hippocampal local field potentials in anesthetized and unanesthetized GCaMP-expressing transgenic mice. We found that neocortical activity elevates around hippocampal sharp wave ripples (SWRs). SWR-associated neocortical activities occurred predominantly in vision-related regions including the visual, retrosplenial, and frontal cortex. While pre-SWR neocortical activities were frequently observed in awake and natural sleeping states, post-SWR neocortical activity decreased significantly in the latter. Urethane-anesthetized mice also exhibited SWR-correlated calcium elevation, but in longer timescale than observed in natural sleeping mice. During hippocampal theta oscillation states, phase-locked oscillations of calcium activity were observed throughout the entire neocortical areas. In addition, possible environmental effects on neocortico-hippocampal dynamics were assessed in this study by comparing mice reared in ISO (isolated condition) and ENR (enriched environment). In both SWR and theta oscillations, mice reared in ISO exhibited clearer brain state-dependent dynamics than those reared in ENR. Our data demonstrate that the neocortex and hippocampus exhibit heterogeneous activity patterns that characterize brain states, and postnatal experience plays a significant role in modulating these patterns.

High-frequency stimulation (HFS)-induced long–term potentiation (LTP) is generally regarded as a homosynaptic Hebbian-type LTP, where synaptic changes are thought to occur at the synapses that project from the stimulation site and terminate onto the neurons at the recording site. In this study, we first investigated HFS-induced LTP on urethane-anesthetized rats and found that cortical HFS enhances neural responses at the recording site through the strengthening of local connectivity with nearby neurons at the stimulation site rather than through synaptic strengthening at the recording site. This enhanced local connectivity at the stimulation site leads to increased output propagation, resulting in signal potentiation at the recording site. Additionally, we discovered that HFS can also nonspecifically strengthen distant afferent synapses at the HFS site, thereby expanding its impact beyond local neural connections. This form of plasticity exhibits a neo-Hebbian characteristic as it exclusively manifests in the presence of cholecystokinin release, induced by HFS. The cortical HFS-induced local LTP was further supported by a behavioral task, providing additional evidence. Our results unveil a previously overlooked mechanism underlying cortical plasticity: synaptic plasticity is more likely to occur around the soma site of strongly activated cortical neurons rather than solely at their projection terminals.

Noise exposure is one of the most common causes of hearing loss and hyperacusis. Studies have shown that noise exposure can induce a cortical gain to compensate for reduced input of the cochlea, which may contribute to the increased sound sensitivity. However, many people with hyperacusis have no measurable cochlear lesion after being exposed to loud sound. In this experiment, we studied the neurological alterations in the cortical and subcortical areas following a prolonged moderate level of noise exposure (84 dB SPL, 8 h/day for 4 weeks) in the laboratory mice. The cochlear function was monitored by auditory brainstem responses (ABRs). The behavioral auditory sensitivity and temporal processing were evaluated using the acoustic startle response (ASR) and gap‐induced prepulse inhibition (gap‐PPI). The central auditory functions were determined by electrophysiological recordings of the inferior colliculus (IC) and the auditory cortex (AC). Our results showed that although there was no significant difference in the ABR thresholds, the noise group showed enhanced ASR and gap‐PPI compared to the control group. Increased neural activity in both the IC and the AC was recorded in the noise‐exposed mice compared to the control group, suggesting a central gain in both the subcortical and cortical regions. The current source density (CSD) analysis of the AC response revealed an increased columnar excitation and reduced corticocortical projection in the noise group, different from the central gain model of noise‐induced hearing loss. Our results suggest that chronic “nondestructive” noise can increase the gain of the central auditory system by altering the balance of auditory thalamocortical and intracortical inputs, which may contribute to the increased sound sensitivity in people with normal hearing.

Allogeneic modified bone marrow-derived human mesenchymal stromal/stem cells (hMSC-SB623 cells) are in clinical development for the treatment of chronic motor deficits after traumatic brain injury and cerebral ischemic stroke. However, their exact mechanisms of action remain unclear. Here, we investigated the effects of this cell therapy on cortical network excitability, brain tissue, and peripheral blood at a chronic stage after ischemic stroke in a rat model. One month after focal cortical ischemic stroke, hMSC-SB623 cells or the vehicle solution were injected into the peri-stroke cortex. Starting one week after treatment, cortical excitability was assessed ex vivo. hMSC-SB623 cell transplants reduced stroke-induced cortical hyperexcitability, restoring cortical excitability to control levels. The histology of brain tissue revealed an increase of factors relevant to neuroregeneration, and synaptic and cellular plasticity. Whole-blood RNA sequencing and serum protein analyses showed that intra-cortical hMSC-SB623 cell transplantation reversed effects of stroke on peripheral blood factors known to be involved in stroke pathophysiology. Our findings demonstrate that intra-cortical transplants of hMSC-SB623 cells correct stroke-induced circuit disruptions even at the chronic stage, suggesting broad usefulness as a therapeutic for neurological conditions with network hyperexcitability. Additionally, the transplanted cells exert far-reaching immunomodulatory effects whose therapeutic impact remains to be explored.

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

Despite the significant advantages of Shape Memory Polymers (SMPs), material processing and production challenges have limited their applications. Recent advances in fiber manufacturing offer a novel approach to processing polymers, broadening the functions of fibers beyond optical applications. In this study, a thermal drawing technique for SMPs to fabricate Shape Memory Polymer Fibers (SMPFs) tailored for medical applications, featuring programmable stiffness and shape control is developed. Rheological and differential scanning calorimetry analyses are conducted to assess SMP's compatibility with the proposed thermal drawing process and applications, leading to the production of multilumen, multimaterial SMPFs activated at body temperature. Different properties of SMPFs are investigated in three medical devices: stiffness‐adjustable catheters, softening neural interface, and shape‐programmable cochlear implants. Comprehensive characterization of these devices demonstrates the potential of thermally drawn SMPs to be employed in a wide range of applications demanding programmable mechanical properties.

Transitive inference allows people to infer new relations between previously experienced premises. It has been hypothesized that this logical thinking relies on a mental schema that spatially organizes elements, facilitating inferential insights. However, recent evidence challenges the need for these complex cognitive processes. To dig into the neural substrate driving TI cognitive processes, we examine the role of beta and gamma local field potential bands in the prefrontal cortex of 2 monkeys. During the inferential problem-solving period, we discover a tight link between beta and gamma bands modulation and TI complexity. This correlation diminishes its strength before initiating the motor response, indicating the chosen item. Notably, while the beta band maintains a constant relationship with TI performance throughout the trial, the gamma band shows a flexible relationship. This research highlights the role of beta and gamma interplay in cognitive computations when solving TI problems.

Alcohol use disorder (AUD) is a chronic relapsing brain disorder characterized by an impaired ability to stop or control alcohol consumption despite adverse social, occupational, or health consequences. AUD affects nearly one-third of adults at some point during their lives, with an associated cost of approximately $249 billion annually in the U.S. alone. The effects of alcohol consumption are expected to increase significantly during the COVID-19 pandemic, with alcohol sales increasing by approximately 54%, potentially exacerbating health concerns and risk-taking behaviors. Unfortunately, existing pharmacological and behavioral therapies for AUD are associated with poor success rates, with approximately 40% of individuals relapsing within three years of treatment.Pre-clinical studies have shown that chronic alcohol consumption leads to significant changes in synaptic function within the dorsal medial striatum (DMS), one of the brain regions associated with AUD and responsible for mediating goal-directed behavior. Specifically, chronic alcohol consumption has been associated with hyperactivity of dopamine receptor 1 (D1) medium spiny neurons (MSN) and hypoactivity of dopamine receptor 2 (D1) MSNs within the DMS. Optogenetic, chemogenetic, and transgenic approaches have demonstrated that reducing the D1/D2 MSN signaling imbalance decreases alcohol self-administration in rodent models of AUD.Here, we present an electrical stimulation approach that uses ultra-low (≤ 1 Hz) frequency (ULF) spike-timing-dependent plasticity (STDP) in mouse models of AUD to reduce DMS D1/D2 MSN signaling imbalances by stimulating D1-MSN afferents into the GPi and ACC glutamatergic projections to the DMS in a time-locked stimulation sequence. Our data suggest that GPi/ACC ULF-STDP selectively decreases DMS D1-MSN hyperactivity leading to reduced alcohol consumption without evoking undesired affective behaviors using electrical stimulation rather than approaches requiring genetic modification. This work represents a step towards fulfilling the unmet need for a reliable method of treating severe AUD through cell-type-specific control with clinically available neuromodulation tools.

Background Recent studies have identified hearing loss (HL) as a primary risk factor for Alzheimer’s disease (AD) onset. However, the mechanisms linking HL to AD are not fully understood. This study explored the effects of drug-induced hearing loss (DIHL) on the expression of proteins associated with AD progression in mouse models. Methods DIHL was induced in 5xFAD and Tg2576 mice aged 3 to 3.5 weeks using kanamycin (700 mg/kg, subcutaneous) and furosemide (600 mg/kg, intraperitoneal). The accumulation and expression of beta-amyloid (Aβ), ionized calcium-binding adaptor molecule 1 (Iba1), and glial fibrillary acidic protein (GFAP) were measured through immunohistochemistry and immunoblotting. Additionally, the expression of proteins involved in the mammalian target of rapamycin (mTOR) pathway, including downstream effectors p70 ribosomal S6 kinase (p70S6K) and S6, as well as proinflammatory cytokines, was analyzed. Results Compared to control conditions, HL led to a significant increase in the accumulation of Aβ in the hippocampus and cortex. Elevated levels of neuroinflammatory markers, including Iba1 and GFAP, as well as proinflammatory cytokines such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α), were observed. Moreover, DIHL enhanced phosphorylation of mTOR, p70S6K, and S6, indicating activation of the mTOR pathway. Conclusions HL significantly increases Aβ accumulation in the brain. Furthermore, HL activates astrocytes and microglia, leading to increased neuroinflammation and thereby accelerating AD progression. These findings strongly suggest that HL contributes autonomously to neuroinflammation, highlighting the potential for early intervention in HL to reduce AD risk.

Animacy perception, the ability to discern living from non-living entities, is crucial for survival and social interaction, as it includes recognizing abstract concepts such as movement, purpose, and intentions. This process involves interpreting cues that may suggest the intentions or actions of others. It engages the temporal cortex (TC), particularly the superior temporal sulcus (STS) and the adjacent region of the inferior temporal cortex (ITC), as well as the dorsomedial prefrontal cortex (dmPFC). However, it remains unclear how animacy is dynamically encoded over time in these brain areas and whether its processing is distributed or localized. In this study, we addressed these questions by employing a symbolic categorization task involving animate and inanimate objects using natural movie stimuli. Simultaneously, electrocorticography were conducted in both the TC and dmPFC. Time-frequency analysis revealed region-specific frequency representations throughout the observation of the movies. Spatial searchlight decoding analysis demonstrated that animacy processing is represented in a distributed manner. Regions encoding animacy information were found to be dispersed across the fundus and lip of the STS, as well as in the ITC. Next, we examined whether these dispersed regions form functional networks. Independent component analysis revealed that the spatial distribution of the component with the most significant animacy information corresponded with the dispersed regions identified by the spatial decoding analysis. Furthermore, Granger causality analysis indicated that these regions exhibit frequency-specific directional functional connectivity, with a general trend of causal influence from the ITC to STS across multiple frequency bands. Notably, a prominent feedback flow in the alpha band from the ITC to both the ventral bank and fundus of the STS was identified. These findings suggest a distributed and functionally interconnected neural substrate for animacy processing across the STS and ITC.

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

Anxiety elicits various physiological responses, including changes in the respiratory rate and neuronal activity within specific brain regions such as the medial prefrontal cortex (mPFC). Previous research suggests that the olfactory bulb (OB) modulates the mPFC through respiration-coupled oscillations (RCOs), which have been linked to fear-related freezing behavior. Nevertheless, the impact of breathing on frontal brain networks during other negative emotional responses, such as anxiety-related states characterized by higher breathing rates, remains unclear. To address this, we subjected rats to the elevated plus maze (EPM) paradigm while simultaneously recording respiration and local field potentials in the OB and mPFC. Our findings demonstrate distinct respiratory patterns during EPM exploration: slower breathing frequencies prevailed in the closed arms, whereas faster frequencies were observed in the open arms, independent of locomotor activity, indicating that anxiety-like states are associated with increased respiratory rates. Additionally, we identified RCOs at different frequencies, mirroring the bimodal distribution of respiratory frequencies. RCOs exhibited higher power during open-arm exploration, when they showed greater coherence with breathing at faster frequencies. Furthermore, we confirmed that nasal respiration drives RCOs in frontal brain regions and found a stronger effect during faster breathing. Interestingly, we observed that the frequency of prefrontal gamma oscillations modulated by respiration increased with breathing frequency. Overall, our study provides evidence for a significant influence of breathing on prefrontal cortex networks during anxious states, shedding light on the complex interplay between respiratory physiology and emotional processing.

Introduction In primary auditory cortex (A1), nicotinic acetylcholine receptors (nAChRs) containing α2 subunits are expressed in layer 5 Martinotti cells (MCs)—inhibitory interneurons that send a main axon to superficial layers to inhibit distal apical dendrites of pyramidal cells (PCs). MCs also contact interneurons in supragranular layers that, in turn, inhibit PCs. Thus, MCs may regulate PCs via inhibition and disinhibition, respectively, of distal and proximal apical dendrites. Auditory inputs to PCs include thalamocortical inputs to middle layers relaying information about characteristic frequency (CF) and near-CF stimuli, and intracortical long-distance (“horizontal”) projections to multiple layers carrying information about spectrally distant (“nonCF”) stimuli. CF and nonCF inputs integrate to create broad frequency receptive fields (RFs). Systemic administration of nicotine activates nAChRs to “sharpen” RFs—to increase gain within a narrowed RF—resulting in enhanced responses to CF stimuli and reduced responses to nonCF stimuli. While nicotinic mechanisms to increase gain have been identified, the mechanism underlying RF narrowing is unknown. Methods Here, we examine the role of α2 nAChRs in mice with α2 nAChR-expressing neurons labeled fluorescently, and in mice with α2 nAChRs genetically deleted. Results The distribution of fluorescent neurons in auditory cortex was consistent with previous studies demonstrating α2 nAChRs in layer 5 MCs, including nonpyramidal somata in layer 5 and dense processes in layer 1. We also observed label in subcortical auditory regions, including processes, but no somata, in the medial geniculate body, and both fibers and somata in the inferior colliculus. Using electrophysiological (current-source density) recordings in α2 nAChR knock-out mice, we found that systemic nicotine failed to enhance CF-evoked inputs to layer 4, suggesting a role for subcortical α2 nAChRs, and failed to reduce nonCF-evoked responses, suggesting that α2 nAChRs regulate horizontal projections to produce RF narrowing. Discussion The results support the hypothesis that α2 nAChRs function to simultaneously enhance RF gain and narrow RF breadth in A1. Notably, a similar neural circuit may recur throughout cortex and hippocampus, suggesting widespread conserved functions regulated by α2 nAChRs.

Tinnitus has been identified as a potential contributor to anxiety. Thalamo-cortical pathway plays a crucial role in the transmission of auditory and emotional information, but its casual link to tinnitus-associated anxiety remains unclear. In this study, we explore the neural activities in the thalamus and cortex of the sodium salicylate (NaSal)-treated mice, which exhibit both hyperacusis and anxiety-like behaviors. We find an increase in gamma band oscillations (GBO) in both auditory cortex (AC) and prefrontal cortex (PFC), as well as phase-locking between cortical GBO and thalamic neural activity. These changes are attributable to a suppression of GABAergic neuron activity in thalamic reticular nucleus (TRN), and optogenetic activation of TRN reduces NaSal-induced hyperacusis and anxiety-like behaviors. The elevation of endocannabinoid (eCB)/ cannabinoid receptor 1 (CB1R) transmission in TRN contributes to the NaSal-induced abnormalities. Our results highlight the regulative role of TRN in the auditory and limbic thalamic-cortical pathways.

Coordinated reset deep brain stimulation (CR DBS), a promising treatment for Parkinson’s disease (PD), is hypothesized to desynchronize neuronal populations. However, little in vivo data probes this hypothesis. In a parkinsonian nonhuman primate, we found that subthalamic CR DBS suppressed subthalamic and cortical-subthalamic coherences in the beta band, correlating with motor improvements. Our results support the desynchronizing mechanism of CR DBS and propose potential biomarkers for closed-loop CR DBS.

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

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

There is experimental evidence of varying correlation among the elements of the neuromuscular system over the course of the reach-and-grasp task. The aim of this study was to investigate if modifications in correlations and clustering can be detected in the local field potential (LFP) recordings of the motor cortex during the task. To this end, we analyzed the LFP recordings from a previously published study on monkeys that performed a reach-and-grasp task for targets with a vertical or horizontal orientation. LFP signals were recorded from the motor and premotor cortex of macaque monkeys as they performed the task. We found very robust changes in the correlations of the multielectrode LFP recordings that corresponded to task epochs. Mean LFP correlation increased significantly during reach and then decreased during grasp. This pattern was very robust for both left and right arm reaches irrespective of target orientation. A hierarchical cluster analysis also demonstrated similar changes. In focusing on correlations, our study has contributed new insights to the understanding of LFP signals and their relationship to movement. A sliding window computation of the number of clusters was performed to probe the capacities of the LFP clusters for detecting upcoming task events. For a very high percentage of trials (97.89%), there was a downturn in cluster number following the Pellet Drop (GO signal) that reached a minimum preceding the Start of grasp, hence indicating that cluster analyses of LFPs could contribute to signaling an increased probability of the Start of grasp.