Spontaneous Cortical Activity Research Articles

Repetitive nociceptive stimulation increases spontaneous neural activation similar to nociception-induced activity in mouse insular cortex

Recent noninvasive neuroimaging technology has revealed that spatiotemporal patterns of cortical spontaneous activity observed in chronic pain patients are different from those in healthy subjects, suggesting that the spontaneous cortical activity plays a key role in the induction and/or maintenance of chronic pain. However, the mechanisms of the spontaneously emerging activities supposed to be induced by nociceptive inputs remain to be established. In the present study, we investigated spontaneous cortical activities in sessions before and after electrical stimulation of the periodontal ligament (PDL) by applying wide-field and two-photon calcium imaging to anesthetized GCaMP6s transgenic mice. First, we identified the sequential cortical activation patterns from the primary somatosensory and secondary somatosensory cortices to the insular cortex (IC) by PDL stimulation. We, then found that spontaneous IC activities that exhibited a similar spatiotemporal cortical pattern to evoked activities by PDL stimulation increased in the session after repetitive PDL stimulation. At the single-cell level, repetitive PDL stimulation augmented the synchronous neuronal activity. These results suggest that cortical plasticity induced by the repetitive stimulation leads to the frequent PDL stimulation-evoked-like spontaneous IC activation. This nociception-induced spontaneous activity in IC may be a part of mechanisms that induces chronic pain.

Signatures of somatosensory cortical dysfunction in Alzheimer's disease and HIV-associated neurocognitive disorder.

Alzheimer’s disease is the most common type of dementia in the general population, while HIV-associated neurocognitive disorder is the most common neurological comorbidity in those infected with HIV and affects between 40 and 70% of this population. Both conditions are associated with cognitive impairment and have been associated with aberrant functioning in sensory cortices, but far less is known about their disparate effects on neural activity. Identifying such disparate effects is important because it may provide critical data on the similarities and differences in the neuropathology underlying cognitive decline in each condition. In the current study, we utilized magnetoencephalography, extensive neuropsychological testing and a paired-pulse somatosensory gating paradigm to probe differences in somatosensory processing in participants from two ongoing magnetoencephalography studies. The resulting participant groups included 27 cognitively normal controls, 26 participants with HIV-associated neurocognitive disorder and 21 amyloid biomarker-confirmed patients with Alzheimer’s disease. The data were imaged using a beamformer and voxel time series were extracted to identify the oscillatory dynamics serving somatosensory processing, as well as the amplitude of spontaneous cortical activity preceding stimulation onset. Our findings indicated that people with Alzheimer’s disease and HIV-associated neurocognitive disorder exhibit normal somatosensory gating but have distinct aberrations in other elements of somatosensory cortical function. Essentially, those with Alzheimer’s disease exhibited accentuated neural responses to somatosensory stimulation, along with spontaneous gamma activity preceding stimulus onset. In contrast, those with HIV-associated neurocognitive disorder exhibited normal responses to somatosensory stimulation but had sharply elevated spontaneous gamma activity prior to stimulus onset. These distinct aberrations may reflect the impact of different neuropathological mechanisms underlying each condition. Further, given the differential pattern of deficits in somatosensory cortical function, these measures may function as unique biomarkers in each condition and be useful in identifying persons with HIV who may go on to develop Alzheimer’s disease.

Normal aging in mice is associated with a global reduction in cortical spectral power and network-specific declines in functional connectivity

Normal aging is associated with a variety of neurologic changes including declines in cognition, memory, and motor activity. These declines correlate with neuronal changes in synaptic structure and function. Degradation of brain network activity and connectivity represents a likely mediator of age-related functional deterioration resulting from these neuronal changes. Human studies have demonstrated both general decreases in spontaneous cortical activity and disruption of cortical networks with aging. Current techniques used to study cerebral network activity are hampered either by limited spatial resolution (e.g. electroencephalography, EEG) or limited temporal resolution (e.g., functional magnetic resonance imaging, fMRI). Here we utilize mesoscale imaging of neuronal activity in Thy1-GCaMP6f mice to characterize neuronal network changes in aging with high spatial resolution across a wide frequency range. We show that while evoked activity is unchanged with aging, spontaneous neuronal activity decreases across a wide frequency range (0.01–4 Hz) involving all regions of the cortex. In contrast to this global reduction in cortical power, we found that aging is associated with functional connectivity (FC) deterioration of select networks including somatomotor, cingulate, and retrosplenial nodes. These changes are corroborated by reductions in homotopic FC and node degree within somatomotor and visual cortices. Finally, we found that whole-cortex delta power and delta band node degree correlate with exploratory activity in young but not aged animals. Together these data suggest that aging is associated with global declines in spontaneous cortical activity and focal deterioration of network connectivity, and that these reductions may be associated with age-related behavioral declines.

An increase in spontaneous activity mediates visual habituation.

SUMMARYThe cerebral cortex is spontaneously active, but the function of this ongoing activity remains unclear. To test whether spontaneous activity encodes learned experiences, we measured the response of neuronal populations in mouse primary visual cortex with chronic two-photon calcium imaging during visual habituation to a specific oriented stimulus. We find that, during habituation, spontaneous activity increases in neurons across the full range of orientation selectivity, eventually matching that of evoked levels. This increase in spontaneous activity robustly correlates with the degree of habituation. Moreover, boosting spontaneous activity with two-photon optogenetic stimulation to the levels of visually evoked activity accelerates habituation. Our study shows that cortical spontaneous activity is linked to habituation, and we propose that habituation unfolds by minimizing the difference between spontaneous and stimulus-evoked activity levels. We conclude that baseline spontaneous activity could gate incoming sensory information to the cortex based on the learned experience of the animal.

Altered spontaneous cortical activity predicts pain perception in individuals with cerebral palsy.

Cerebral palsy is the most common paediatric neurological disorder and results in extensive impairment to the sensorimotor system. However, these individuals also experience increased pain perception, resulting in decreased quality of life. In the present study, we utilized magnetoencephalographic brain imaging to examine whether alterations in spontaneous neural activity predict the level of pain experienced in a cohort of 38 individuals with spastic diplegic cerebral palsy and 67 neurotypical controls. Participants completed 5 min of an eyes closed resting-state paradigm while undergoing a magnetoencephalography recording. The magnetoencephalographic data were then source imaged, and the power within the delta (2–4 Hz), theta (5–7 Hz), alpha (8–12 Hz), beta (15–29 Hz), low gamma (30–59 Hz) and high gamma (60–90 Hz) frequency bands were computed. The resulting power spectral density maps were analysed vertex-wise to identify differences in spontaneous activity between groups. Our findings indicated that spontaneous cortical activity was altered in the participants with cerebral palsy in the delta, alpha, beta, low gamma and high gamma bands across the occipital, frontal and secondary somatosensory cortical areas (all pFWE < 0.05). Furthermore, we also found that the altered beta band spontaneous activity in the secondary somatosensory cortices predicted heightened pain perception in the individuals with cerebral palsy (P = 0.039). Overall, these results demonstrate that spontaneous cortical activity within individuals with cerebral palsy is altered in comparison to their neurotypical peers and may predict increased pain perception in this patient population. Potentially, changes in spontaneous resting-state activity may be utilized to measure the effectiveness of current treatment approaches that are directed at reducing the pain experienced by individuals with cerebral palsy.

Neurophysiology of the Developing Cerebral Cortex: What We Have Learned and What We Need to Know.

This review article aims to give a brief summary on the novel technologies, the challenges, our current understanding, and the open questions in the field of the neurophysiology of the developing cerebral cortex in rodents. In the past, in vitro electrophysiological and calcium imaging studies on single neurons provided important insights into the function of cellular and subcellular mechanism during early postnatal development. In the past decade, neuronal activity in large cortical networks was recorded in pre- and neonatal rodents in vivo by the use of novel high-density multi-electrode arrays and genetically encoded calcium indicators. These studies demonstrated a surprisingly rich repertoire of spontaneous cortical and subcortical activity patterns, which are currently not completely understood in their functional roles in early development and their impact on cortical maturation. Technological progress in targeted genetic manipulations, optogenetics, and chemogenetics now allow the experimental manipulation of specific neuronal cell types to elucidate the function of early (transient) cortical circuits and their role in the generation of spontaneous and sensory evoked cortical activity patterns. Large-scale interactions between different cortical areas and subcortical regions, characterization of developmental shifts from synchronized to desynchronized activity patterns, identification of transient circuits and hub neurons, role of electrical activity in the control of glial cell differentiation and function are future key tasks to gain further insights into the neurophysiology of the developing cerebral cortex.

Globally Aging Cortical Spontaneous Activity Revealed by Multiple Metrics and Frequency Bands Using Resting-State Functional MRI.

Most existing aging studies using functional MRI (fMRI) are based on cross-sectional data but misinterpreted their findings (i.e., age-related differences) as longitudinal outcomes (i.e., aging-related changes). To delineate aging-related changes the of human cerebral cortex, we employed the resting-state fMRI (rsfMRI) data from 24 healthy elders in the PREVENT-AD cohort, obtaining five longitudinal scans per subject. Cortical spontaneous activity is measured globally with three rsfMRI metrics including its amplitude, homogeneity, and homotopy at three different frequency bands (slow-5: 0.02–0.03 Hz, slow-4: 0.03–0.08 Hz, and slow-3 band: 0.08–0.22 Hz). General additive mixed models revealed a universal pattern of the aging-related changes for the global cortical spontaneous activity, indicating increases of these rsfMRI metrics during aging. This aging pattern follows specific frequency and spatial profiles where higher slow bands show more non-linear curves and the amplitude exhibits more extensive and significant aging-related changes than the connectivity. These findings provide strong evidence that cortical spontaneous activity is aging globally, inspiring its clinical utility as neuroimaging markers for neruodegeneration disorders.

Analysis of cellular and synaptic mechanisms behind spontaneous cortical activity in vitro: Insights from optimization of spiking neuronal network models

Spontaneous network bursts, the intervals of intense network-wide activity interleaved with longer periods of sparse activity, are a hallmark phenomenon observed in cortical networks at postnatal developmental stages. Generation, propagation and termination of network bursts depend on a combination of synaptic, cellular and network mechanisms; however, the interplay between these mechanisms is not fully understood. We study this interplay in silico, using a new data-driven framework for generating spiking neuronal networks fitted to the microelectrode array recordings. We recorded the network bursting activity from rat postnatal cortical networks under several pharmacological conditions. In each condition, the function of specific excitatory and inhibitory synaptic receptors was reduced in order to examine their impact on global network dynamics. The obtained data was used to develop two complementary model fitting protocols for automatic model generation. These protocols allowed us to disentangle systematically the modeled cellular and synaptic mechanisms that affect the observed network bursts. We confirmed that the change in excitatory and inhibitory synaptic transmission in silico, consistent with pharmacological conditions, can account for the changes in network bursts relative to the control data. Reproducing the exact recorded network bursts statistics required adapting both the synaptic transmission and the cellular excitability separately for each pharmacological condition. Our results bring new understanding of the complex interplay between cellular, synaptic and network mechanisms supporting the burst dynamics. While here we focused on analysis of in vitro data, our approach can be applied ex vivo and in vivo given that the appropriate experimental data is available.

Analysis of cellular and synaptic mechanisms behind spontaneous cortical activity in vitro: Insights from optimization of spiking neuronal network models

Analysis of cellular and synaptic mechanisms behind spontaneous cortical activity in vitro: Insights from optimization of spiking neuronal network models

Analysis of cellular and synaptic mechanisms behind spontaneous cortical activity in vitro: Insights from optimization of spiking neuronal network models

Analysis of cellular and synaptic mechanisms behind spontaneous cortical activity in vitro: Insights from optimization of spiking neuronal network models

Analysis of cellular and synaptic mechanisms behind spontaneous cortical activity in vitro: Insights from optimization of spiking neuronal network models

Analysis of cellular and synaptic mechanisms behind spontaneous cortical activity in vitro: Insights from optimization of spiking neuronal network models

3D microelectrode cluster and stimulation paradigm yield powerful analgesia without noticeable adverse effects.

The lack of satisfactory treatment for persistent pain profoundly impairs the quality of life for many patients. Stimulation of brainstem pain control systems can trigger powerful analgesia, but their complex network organization frequently prevents separation of analgesia from side effects. To overcome this long-standing challenge, we developed a biocompatible gelatin-embedded cluster of ultrathin microelectrodes that enables fine-tuned, high-definition three-dimensional stimulation in periaqueductal gray/dorsal raphe nucleus in awake rats. Analgesia was assessed from both motor reactions and intracortical signals, corresponding to pain-related signals in humans. We could select an individual-specific subset of microelectrodes in each animal that reliably provided strong pain inhibition during normal and hyperalgesia conditions, without noticeable behavioral side effects. Gait, spontaneous cortical activity at rest, and cortical tactile responses were minimally affected, indicating a highly selective action. In conclusion, our developed biocompatible microelectrode cluster and stimulation paradigm reliably enabled powerful, fine-tuned, and selective analgesia without noticeable side effects.

Spontaneous cortical MEG activity undergoes unique age- and sex-related changes during the transition to adolescence

BackgroundWhile numerous studies have examined the developmental trajectory of task-based neural oscillations during childhood and adolescence, far less is known about the evolution of spontaneous cortical activity during this time period. Likewise, many studies have shown robust sex differences in task-based oscillations during this developmental period, but whether such sex differences extend to spontaneous activity is not understood. MethodsHerein, we examined spontaneous cortical activity in 111 typically-developing youth (ages 9–15 years; 55 male). Participants completed a resting state magnetoencephalographic (MEG) recording and a structural MRI. MEG data were source imaged and the power within five canonical frequency bands (delta, theta, alpha, beta, gamma) was computed. The resulting power spectral density maps were analyzed via vertex-wise ANCOVAs to identify spatially-specific effects of age, sex, and their interaction. ResultsWe found robust increases in power with age in all frequencies except delta, which decreased over time, with findings largely confined to frontal cortices. Sex effects were distributed across frontal and temporal regions; females tended to have greater delta and beta power, whereas males had greater alpha. Importantly, there was a significant age-by-sex interaction in theta power, such that males exhibited decreasing power with age while females showed increasing power with age in the bilateral superior temporal cortices. DiscussionThese data suggest that the strength of spontaneous activity undergoes robust change during the transition from childhood to adolescence (i.e., puberty onset), with intriguing sex differences in some cortical areas. Future developmental studies should probe task-related oscillations and spontaneous activity in parallel.

Go with the FLOW: visualizing spatiotemporal dynamics in optical widefield calcium imaging.

Widefield calcium imaging has recently emerged as a powerful experimental technique to record coordinated large-scale brain activity. These measurements present a unique opportunity to characterize spatiotemporally coherent structures that underlie neural activity across many regions of the brain. In this work, we leverage analytic techniques from fluid dynamics to develop a visualization framework that highlights features of flow across the cortex, mapping wavefronts that may be correlated with behavioural events. First, we transform the time series of widefield calcium images into time-varying vector fields using optic flow. Next, we extract concise diagrams summarizing the dynamics, which we refer to as FLOW (flow lines in optical widefield imaging) portraits. These FLOW portraits provide an intuitive map of dynamic calcium activity, including regions of initiation and termination, as well as the direction and extent of activity spread. To extract these structures, we use the finite-time Lyapunov exponent technique developed to analyse time-varying manifolds in unsteady fluids. Importantly, our approach captures coherent structures that are poorly represented by traditional modal decomposition techniques. We demonstrate the application of FLOW portraits on three simple synthetic datasets and two widefield calcium imaging datasets, including cortical waves in the developing mouse and spontaneous cortical activity in an adult mouse.

Building an Open Source Classifier for the Neonatal EEG Background: A Systematic Feature-Based Approach From Expert Scoring to Clinical Visualization.

Neonatal brain monitoring in the neonatal intensive care units (NICU) requires a continuous review of the spontaneous cortical activity, i.e., the electroencephalograph (EEG) background activity. This needs development of bedside methods for an automated assessment of the EEG background activity. In this paper, we present development of the key components of a neonatal EEG background classifier, starting from the visual background scoring to classifier design, and finally to possible bedside visualization of the classifier results. A dataset with 13,200 5-minute EEG epochs (8–16 channels) from 27 infants with birth asphyxia was used for classifier training after scoring by two independent experts. We tested three classifier designs based on 98 computational features, and their performance was assessed with respect to scoring system, pre- and post-processing of labels and outputs, choice of channels, and visualization in monitor displays. The optimal solution achieved an overall classification accuracy of 97% with a range across subjects of 81–100%. We identified a set of 23 features that make the classifier highly robust to the choice of channels and missing data due to artefact rejection. Our results showed that an automated bedside classifier of EEG background is achievable, and we publish the full classifier algorithm to allow further clinical replication and validation studies.

Impact of HIV-infection on human somatosensory processing, spontaneous cortical activity, and cortical thickness: A multimodal neuroimaging approach.

HIV‐infection has been associated with widespread alterations in brain structure and function, although few studies have examined whether such aberrations are co‐localized and the degree to which clinical and cognitive metrics are related. We examine this question in the somatosensory system using high‐resolution structural MRI (sMRI) and magnetoencephalographic (MEG) imaging of neural oscillatory activity. Forty‐four participants with HIV (PWH) and 55 demographically‐matched uninfected controls completed a paired‐pulse somatosensory stimulation paradigm during MEG and underwent 3T sMRI. MEG data were transformed into the time‐frequency domain; significant sensor level responses were imaged using a beamformer. Virtual sensor time series were derived from the peak responses. These data were used to compute response amplitude, sensory gating metrics, and spontaneous cortical activity power. The T1‐weighted sMRI data were processed using morphological methods to derive cortical thickness values across the brain. From these, the cortical thickness of the tissue coinciding with the peak response was estimated. Our findings indicated both PWH and control exhibit somatosensory gating, and that spontaneous cortical activity was significantly stronger in PWH within the left postcentral gyrus. Interestingly, within the same tissue, PWH also had significantly reduced cortical thickness relative to controls. Follow‐up analyses indicated that the reduction in cortical thickness was significantly correlated with CD4 nadir and mediated the relationship between HIV and spontaneous cortical activity within the left postcentral gyrus. These data indicate that PWH have abnormally strong spontaneous cortical activity in the left postcentral gyrus and such elevated activity is driven by locally reduced cortical gray matter thickness.

Adaptation of spontaneous activity in the developing visual cortex

Spontaneous activity drives the establishment of appropriate connectivity in different circuits during brain development. In the mouse primary visual cortex, two distinct patterns of spontaneous activity occur before vision onset: local low-synchronicity events originating in the retina and global high-synchronicity events originating in the cortex. We sought to determine the contribution of these activity patterns to jointly organize network connectivity through different activity-dependent plasticity rules. We postulated that local events shape cortical input selectivity and topography, while global events homeostatically regulate connection strength. However, to generate robust selectivity, we found that global events should adapt their amplitude to the history of preceding cortical activation. We confirmed this prediction by analyzing in vivo spontaneous cortical activity. The predicted adaptation leads to the sparsification of spontaneous activity on a slower timescale during development, demonstrating the remarkable capacity of the developing sensory cortex to acquire sensitivity to visual inputs after eye-opening.

An Integrate-and-Fire Spiking Neural Network Model Simulating Artificially Induced Cortical Plasticity

We describe an integrate-and-fire (IF) spiking neural network that incorporates spike-timing-dependent plasticity (STDP) and simulates the experimental outcomes of four different conditioning protocols that produce cortical plasticity. The original conditioning experiments were performed in freely moving non-human primates (NHPs) with an autonomous head-fixed bidirectional brain-computer interface (BCI). Three protocols involved closed-loop stimulation triggered from (1) spike activity of single cortical neurons, (2) electromyographic (EMG) activity from forearm muscles, and (3) cycles of spontaneous cortical beta activity. A fourth protocol involved open-loop delivery of pairs of stimuli at neighboring cortical sites. The IF network that replicates the experimental results consists of 360 units with simulated membrane potentials produced by synaptic inputs and triggering a spike when reaching threshold. The 240 cortical units produce either excitatory or inhibitory postsynaptic potentials (PSPs) in their target units. In addition to the experimentally observed conditioning effects, the model also allows computation of underlying network behavior not originally documented. Furthermore, the model makes predictions about outcomes from protocols not yet investigated, including spike-triggered inhibition, γ-triggered stimulation and disynaptic conditioning. The success of the simulations suggests that a simple voltage-based IF model incorporating STDP can capture the essential mechanisms mediating targeted plasticity with closed-loop stimulation.

Focal unilateral mechanical lesion in barrel cortex impairs rat’s abilities to discriminate textures

Purpose/aim of the study Whiskers are important sensory organs that play a key role in rodents' discriminative and exploration behaviours and unilateral injuries of the somatosensory cortex related to whisker barrel cortex can change the activity of neurons in the intact contralateral barrel cortex. We evaluated the effects of unilateral mechanical lesion of right barrel cortex on novel texture discrimination in behavioural test and neuronal responses of left barrel cortex. Materials and methods Ten days after a unilateral mechanical lesion in the right barrel cortex, adult male rats were experimented regarding three paired different textures in novel texture discrimination test dependent on whiskers. In addition, responses of left barrel cortical neurons to controlled deflections of right whiskers were recorded using extracellular single-unit recordings technique. Results Data analysis showed that the discrimination ratio and preference indexes as criteria to find a novel texture significantly decreased in the lesion group compared to the intact rats (p < .05). In electrophysiological level, the barrel neural cortical spontaneous activity and the ON and OFF response magnitude of intact barrel cortex neurons in the lesion group decreased compared to the intact group (p < .05). Conclusions The present study showed that unilateral mechanical lesion in the rats' barrel cortex cause a decrease in their abilities for discriminating textures, as well as, the anaesthetized rats whose response properties of intact barrel cortical area changed to whisker deflection, too. These changes can influence on the ability of rats to differentiate textures.

Spontaneous Activity of Neuronal Ensembles in Mouse Motor Cortex: Changes after GABAergic Blockade

The mouse motor cortex exhibits spontaneous activity in the form of temporal sequences of neuronal ensembles in vitro without the need of tissue stimulation. These neuronal ensembles are defined as groups of neurons with a strong correlation between its firing patterns, generating what appears to be a predetermined neural conduction mode that needs study. Each ensemble is commonly accompanied by one or more parvalbumin expressing neurons (PV+) or fast spiking interneurons. Many of these interneurons have functional connections between them, helping to form a circuit configuration similar to a small-world network. However, rich club metrics show that most connected neurons are neurons not expressing parvalbumin, mainly pyramidal neurons (PV−) suggesting feed-forward propagation through pyramidal cells. Ensembles with PV+ neurons are connected to these hubs. When ligand-gated fast GABAergic transmission is blocked, temporal sequences of ensembles collapse into a unique synchronous and recurrent ensemble, showing the need of inhibition for coding cortical spontaneous activity. This new ensemble has a duration and electrophysiological characteristics of brief recurrent interictal epileptiform discharges (IEDs) composed by the coactivity of both PV− and PV+ neurons, demonstrating that GABA transmission impedes its occurrence. Synchronous ensembles are clearly divided into two clusters one of them lasting longer and mainly composed by PV+ neurons. Because an ictal-like event was not recorded after several minutes of IEDs recording, it is inferred that an external stimulus and/or fast GABA transmission are necessary for its appearance, making this preparation ideal to study both the neuronal machinery to encode cortical spontaneous activity and its transformation into brief non-ictal epileptiform discharges.