Ongoing Spontaneous Activity Research Articles

Phase-Compensated Averaging for Analyzing Electroencephalography and Magnetoencephalography Epochs

Stimulus-locked averaging for electroencephalography and/or megnetoencephalography (EEG/MEG) epochs cancels out ongoing spontaneous activities by treating them as noise. However, such spontaneous activities are the object of interest for EEG/MEG researchers who study phase-related phenomena, e.g., long-distance synchronization, phase-reset, and event-related synchronization/desynchronization (ERD/ERS). We propose a complex-weighted averaging method, called phase-compensated averaging, to investigate phase-related phenomena. In this method, any EEG/MEG channel is used as a trigger for averaging by setting the instantaneous phases at the trigger timings to 0 so that cross-channel averages are obtained. First, we evaluated the fundamental characteristics of this method by performing simulations. The results showed that this method could selectively average ongoing spontaneous activity phase-locked in each channel; that is, it evaluates the directional phase-synchronizing relationship between channels. We then analyzed flash evoked potentials. This method clarified the directional phase-synchronizing relationship from the frontal to occipital channels and recovered another piece of information, perhaps regarding the sequence of experiments, which is lost when using only conventional averaging. This method can also be used to reconstruct EEG/MEG time series to visualize long-distance synchronization and phase-reset directly, and on the basis of the potentials, ERS/ERD can be explained as a side effect of phase-reset.

Sparsification of neuronal activity in the visual cortex at eye-opening

Eye-opening represents a turning point in the function of the visual cortex. Before eye-opening, the visual cortex is largely devoid of sensory inputs and neuronal activities are generated intrinsically. After eye-opening, the cortex starts to integrate visual information. Here we used in vivo two-photon calcium imaging to explore the developmental changes of the mouse visual cortex by analyzing the ongoing spontaneous activity. We found that before eye-opening, the activity of layer 2/3 neurons consists predominantly of slow wave oscillations. These waves were first detected at postnatal day 8 (P8). Their initial very low frequency (0.01 Hz) gradually increased during development to approximately 0.5 Hz in adults. Before eye-opening, a large fraction of neurons (>75%) was active during each wave. One day after eye-opening, this dense mode of recruitment changed to a sparse mode with only 36% of active neurons per wave. This was followed by a progressive decrease during the following weeks, reaching 12% of active neurons per wave in adults. The possible role of visual experience for this process of sparsification was investigated by analyzing dark-reared mice. We found that sparsification also occurred in these mice, but that the switch from a dense to a sparse activity pattern was delayed by 3-4 days as compared with normally-reared mice. These results reveal a modulatory contribution of visual experience during the first days after eye-opening, but an overall dominating role of intrinsic factors. We propose that the transformation in network activity from dense to sparse is a prerequisite for the changed cortical function at eye-opening.

A Simple Model of Cortical Dynamics Explains Variability and State Dependence of Sensory Responses in Urethane-Anesthetized Auditory Cortex

The responses of neocortical cells to sensory stimuli are variable and state dependent. It has been hypothesized that intrinsic cortical dynamics play an important role in trial-to-trial variability; the precise nature of this dependence, however, is poorly understood. We show here that in auditory cortex of urethane-anesthetized rats, population responses to click stimuli can be quantitatively predicted on a trial-by-trial basis by a simple dynamical system model estimated from spontaneous activity immediately preceding stimulus presentation. Changes in cortical state correspond consistently to changes in model dynamics, reflecting a nonlinear, self-exciting system in synchronized states and an approximately linear system in desynchronized states. We propose that the complex and state-dependent pattern of trial-to-trial variability can be explained by a simple principle: sensory responses are shaped by the same intrinsic dynamics that govern ongoing spontaneous activity.

C-nociceptors sensitized to cold in a patient with small-fiber neuropathy and cold allodynia

Cold allodynia is a common sign of neuropathic pain patients but its underlying mechanisms are still largely unknown, partly because the populations of neurons responding to cold stimuli and their transduction mechanisms have not been fully determined. We report a patient with a small-fiber neuropathy of unknown origin, whose main complaint is cold allodynia. Microneurographic recordings showed ongoing spontaneous activity and abnormal responses to cold and menthol in identified subtypes of C-nociceptors. These findings provide the first direct evidence in human of abnormal peripheral nociceptor behavior potentially responsible for cold allodynia. The responsiveness of C-nociceptors to menthol suggests an abnormal expression or function of TRPM8 channels in this patient with a small-fiber polyneuropathy.

GABA Transporter Preserving Ongoing Spontaneous Neuronal Activity at Firing Subthreshold

There has been compelling evidence that the GABA transporter is crucial not only for removing gamma-aminobutyric acid (GABA) from but also releasing it into extracellular space, thereby clamping ambient GABA (GABA in extracellular space) at a certain level. The ambient GABA is known to activate extrasynaptic GABA receptors and provide tonic inhibitory current into neurons. We investigated how the transporter regulates the level of ambient GABA, mediates tonic neuronal inhibition, and influences ongoing spontaneous neuronal activity. A cortical neural network model is proposed in which GABA transporters on lateral (L) and feedback (F) inhibitory (GABAergic) interneurons are functionally made. Principal (P) cell assemblies participate in expressing information about elemental sensory features. At membrane potentials below the reversal potential, there is net influx of GABA, whereas at membrane potentials above the reversal potential, there is net efflux of GABA. Through this transport mechanism, ambient GABA concentration is kept within a submicromolar range during an ongoing spontaneous neuronal activity time period. Here we show that the GABA transporter on L cells regulates the overall level of ambient GABA across cell assemblies, and that on F cells it does so within individual cell assemblies. This combinatorial regulation of ambient GABA allows P cells to oscillate near firing threshold during the ongoing time period, thereby reducing their reaction time to externally applied stimuli. We suggest that the GABA transporter, with its forward and reverse transport mechanism, could regulate the ambient GABA. This transporter-mediated ambient GABA regulation may contribute to establishing an ongoing subthreshold neuronal state by which the network can respond rapidly to subsequent sensory input.

Learning and Memory: While You Rest, Your Brain Keeps Working

A recent study shows that brain activity recorded while the human subject is at 'rest' is significantly affected by a prior learning episode. These results suggest that understanding resting brain activity may be critical to understanding how humans learn from experience.

Role of RVM neurons in capsaicin-evoked visceral nociception and referred hyperalgesia

Most forms of visceral pain generate intense referred hyperalgesia but the mechanisms of this enhanced visceral hypersensitivity are not known. The on-cells of the rostral ventromedial medulla (RVM) play an important role in descending nociceptive facilitation and can be sensitized to somatic mechanical stimulation following peripheral nerve injury or hindpaw inflammation. Here we have tested the hypothesis that visceral noxious stimulation sensitizes RVM ON-like cells, thus promoting an enhanced descending facilitation that can lead to referred visceral hyperalgesia. Intracolonic capsaicin instillation (ICI) was applied to rats in order to create a hyperalgesic state dependent on noxious visceral stimulation. This instillation produced acute pain-related behaviors and prolonged referred hyperalgesia that were prevented by the RVM microinjection of AP5, an NMDA selective antagonist. In electrophysiological experiments, ON-like RVM neurons showed ongoing spontaneous activity following ICI that lasted for ∼ 20 min and an enhanced responsiveness to von Frey and heat stimulation of the hindpaw and to colorectal distention (CRD) that lasted for at least 50 min post capsaicin administration. Moreover, ON-like cells acquired a novel response to CRD and responded to heat stimulation in the innocuous range. OFF-like neurons responded to capsaicin administration with a brief (<5 min) inhibition of activity followed by an enhanced inhibition to noxious stimulation and a novel inhibition to innocuous stimulation (CRD and heat) at early time points (10 min post capsaicin). These results support the hypothesis that noxious visceral stimulation may cause referred hypersensitivity by promoting long-lasting sensitization of RVM ON-like cells.

Probabilistic algorithms for MEG/EEG source reconstruction using temporal basis functions learned from data

We present two related probabilistic methods for neural source reconstruction from MEG/EEG data that reduce effects of interference, noise, and correlated sources. Both methods localize source activity using a linear mixture of temporal basis functions (TBFs) learned from the data. In contrast to existing methods that use predetermined TBFs, we compute TBFs from data using a graphical factor analysis based model [Nagarajan, S.S., Attias, H.T., Hild, K.E., Sekihara, K., 2007a. A probabilistic algorithm for robust interference suppression in bioelectromagnetic sensor data. Stat Med 26, 3886–3910], which separates evoked or event-related source activity from ongoing spontaneous background brain activity. Both algorithms compute an optimal weighting of these TBFs at each voxel to provide a spatiotemporal map of activity across the brain and a source image map from the likelihood of a dipole source at each voxel. We explicitly model, with two different robust parameterizations, the contribution from signals outside a voxel of interest. The two models differ in a trade-off of computational speed versus accuracy of learning the unknown interference contributions. Performance in simulations and real data, both with large noise and interference and/or correlated sources, demonstrates significant improvement over existing source localization methods.

Sensitization of central trigeminovascular neurons: Blockade by intravenous naproxen infusion

We have previously observed that migraine attacks impervious to triptan therapy were readily terminated by subsequent i.v. administration of the non-steroidal anti-inflammatory drug (NSAID) ketorolac. Since such attacks were associated with periorbital allodynia—a symptom of central sensitization—we examined whether infusion of the NSAID naproxen can block sensitization of central trigeminovascular neurons in the medullary dorsal horn, using in vivo single-unit recording in the rat. Topical exposure of the cerebral dura to inflammatory soup (IS) for 5 min resulted in a short-term burst of activity (<8 min) and a long-lasting (>120 min) neuronal hyper-responsiveness to stimulation of the dura and periorbital skin (group 1). Infusion of naproxen (1 mg/kg) 2 h after IS (group 1) brought all measures of neuronal responsiveness back to the baseline values recorded prior to IS, and depressed ongoing spontaneous activity well below baseline. When given preemptively 1 h before IS (group 2), naproxen blocked the short-term burst of activity and every long-term measure of neuronal hyper-responsiveness that was studied in the central neurons. The same preemptive treatment, however, failed to block IS-induced short-term bursts of activity in C-unit meningeal nociceptors (group 3). The results suggest that parenteral administration of naproxen, unlike triptan therapy, can exert direct inhibition over central trigeminovascular neurons in the dorsal horn. Though impractical as a routine migraine therapy, parenteral NSAID administration should be useful as a non-narcotic rescue therapy for migraine in the setting of the emergency department.

Spontaneous pattern generation by a network with dynamic synapses

Experimental evidence demonstrates that the ongoing spontaneous activity in the visual cortex in the absence of visual stimulation can exhibit complex spatiotemporal patterns. Voltage-sensitive dye imaging studies reveal that activity patterns similar to orientation maps can emerge and dynamically switch in V1 of anesthetized cats [1]. It has been shown that these patterns can be generated by an intracortical network which has intrinsic preferred states correlated with functional maps [2]. The suggested connectivity in such a network depends on the preferred orientation and on the degree of orientation selectivity of the interconnected neurons. In this network, single condition orientation maps are steady states of the neural dynamics and form a ring attractor. To account for dynamical switching between these intrinsic states, we introduced short-term depression into the synaptic connections in the network. We study the effects of synaptic dynamics on the stability of attractor states. We found that synaptic depression, first, stabilizes the overall network activity excluding the possibility of amplitude instability. On the other hand, synaptic depression provides a mechanism of smooth transition between states corresponding to neighboring orientations, observed experimentally. Together with a fluctuating afferent input synaptic dynamics induce dynamic switches between the ring attractor and linear phases. As a result, a complex behaviour emerges with statistical properties similar to the experimentally observed phenomena.

Coherent ongoing subthreshold state of a cortical neural network regulated by slow- and fast-spiking interneurons

Although details of cortical interneurons in anatomy and physiology have been well understood, little is known about how they contribute to ongoing spontaneous neuronal activity that could have a great impact on subsequent neuronal information processing. Simulating a cortical neural network model of an early sensory area, we investigated whether and how two distinct types of inhibitory interneurons, or fast-spiking interneurons with narrow axonal arbors and slow-spiking interneurons with wide axonal arbors, have a spatiotemporal influence on the ongoing activity of principal cells and subsequent cognitive information processing. In the model, dynamic cell assemblies, or population activation of principal cells, expressed information about specific sensory features. Within cell assemblies, fast-spiking interneurons give a feedback inhibitory effect on principal cells. Between cell assemblies, slow-spiking interneurons give a lateral inhibitory effect on principal cells. Here, we show that these interneurons keep the network at a subthreshold level for action potential generation under the ongoing state, by which the reaction time of principal cells to sensory stimulation could be accelerated. We suggest that the best timing of inhibition mediated by fast-spiking interneurons and slow-spiking interneurons allows the network to remain near threshold for rapid responses to input.

Nav 1.8-Null Mice Show Stimulus-Dependent Deficits in Spinal Neuronal Activity

BackgroundThe voltage gated sodium channel Nav 1.8 has a highly restricted expression pattern to predominantly nociceptive peripheral sensory neurones. Behaviourally Nav 1.8-null mice show an increased acute pain threshold to noxious mechanical pressure and also deficits in inflammatory and visceral, but not neuropathic pain. Here we have made in vivo electrophysiology recordings of dorsal horn neurones in intact anaesthetised Nav 1.8-null mice, in response to a wide range of stimuli to further the understanding of the functional roles of Nav 1.8 in pain transmission from the periphery to the spinal cord.ResultsNav 1.8-null mice showed marked deficits in the coding by dorsal horn neurones to mechanical, but not thermal, -evoked responses over the non-noxious and noxious range compared to littermate controls. Additionally, responses evoked to other stimulus modalities were also significantly reduced in Nav 1.8-null mice where the reduction observed to pinch > brush. The occurrence of ongoing spontaneous neuronal activity was significantly less in mice lacking Nav 1.8 compared to control. No difference was observed between groups in the evoked activity to electrical activity of the peripheral receptive field.ConclusionThis study demonstrates that deletion of the sodium channel Nav 1.8 results in stimulus-dependent deficits in the dorsal horn neuronal coding to mechanical, but not thermal stimuli applied to the neuronal peripheral receptive field. This implies that Nav 1.8 is either responsible for, or associated with proteins involved in mechanosensation.

Ongoing Spontaneous Activity Controls Access to Consciousness: A Neuronal Model for Inattentional Blindness

Even in the absence of sensory inputs, cortical and thalamic neurons can show structured patterns of ongoing spontaneous activity, whose origins and functional significance are not well understood. We use computer simulations to explore the conditions under which spontaneous activity emerges from a simplified model of multiple interconnected thalamocortical columns linked by long-range, top-down excitatory axons, and to examine its interactions with stimulus-induced activation. Simulations help characterize two main states of activity. First, spontaneous gamma-band oscillations emerge at a precise threshold controlled by ascending neuromodulator systems. Second, within a spontaneously active network, we observe the sudden “ignition” of one out of many possible coherent states of high-level activity amidst cortical neurons with long-distance projections. During such an ignited state, spontaneous activity can block external sensory processing. We relate those properties to experimental observations on the neural bases of endogenous states of consciousness, and particularly the blocking of access to consciousness that occurs in the psychophysical phenomenon of “inattentional blindness,” in which normal subjects intensely engaged in mental activity fail to notice salient but irrelevant sensory stimuli. Although highly simplified, the generic properties of a minimal network may help clarify some of the basic cerebral phenomena underlying the autonomy of consciousness.

Architectural and synaptic mechanisms underlying coherent spontaneous activity in V1.

To investigate the existence and the characteristics of possible cortical operating points of the primary visual cortex, as manifested by the coherent spontaneous ongoing activity revealed by real-time optical imaging based on voltage-sensitive dyes, we studied numerically a very large-scale ( approximately 5 x 10(5)) conductance-based, integrate-and-fire neuronal network model of an approximately 16-mm(2) patch of 64 orientation hypercolumns, which incorporates both isotropic local couplings and lateral orientation-specific long-range connections with a slow NMDA component. A dynamic scenario of an intermittent desuppressed state (IDS) is identified in the computational model, which is a dynamic state of (i) high conductance, (ii) strong inhibition, and (iii) large fluctuations that arise from intermittent spiking events that are strongly correlated in time as well as in orientation domains, with the correlation time of the fluctuations controlled by the NMDA decay time scale. Our simulation results demonstrate that the IDS state captures numerically many aspects of experimental observation related to spontaneous ongoing activity, and the specific network mechanism of the IDS may suggest cortical mechanisms and the cortical operating point underlying observed spontaneous activity.

Patterns of Ongoing Activity and the Functional Architecture of the Primary Visual Cortex

Ongoing spontaneous activity in the cerebral cortex exhibits complex spatiotemporal patterns in the absence of sensory stimuli. To elucidate the nature of this ongoing activity, we present a theoretical treatment of two contrasting scenarios of cortical dynamics: (1) fluctuations about a single background state and (2) wandering among multiple “attractor” states, which encode a single or several stimulus features. Studying simplified network rate models of the primary visual cortex (V1), we show that the single state scenario is characterized by fast and high-dimensional Gaussian-like fluctuations, whereas in the multiple state scenario the fluctuations are slow, low dimensional, and highly non-Gaussian. Studying a more realistic model that incorporates correlations in the feed-forward input, spatially restricted cortical interactions, and an experimentally derived layout of pinwheels, we show that recent optical-imaging data of ongoing activity in V1 are consistent with the presence of either a single background state or multiple attractor states encoding many features.

Interaction of sensory responses with spontaneous depolarization in layer 2/3 barrel cortex.

The rodent primary somatosensory cortex is spontaneously active in the form of locally synchronous membrane depolarizations (UP states) separated by quiescent hyperpolarized periods (DOWN states) both under anesthesia and during quiet wakefulness. In vivo whole-cell recordings and tetrode unit recordings were combined with voltage-sensitive dye imaging to analyze the relationship of the activity of individual pyramidal neurons in layer 2/3 to the ensemble spatiotemporal dynamics of the spontaneous depolarizations. These were either brief and localized to an area of a barrel column or occurred as propagating waves dependent on local glutamatergic synaptic transmission in layer 2/3. Spontaneous activity inhibited the sensory responses evoked by whisker deflection, accounting almost entirely for the large trial-to-trial variability of sensory-evoked postsynaptic potentials and action potentials. Subthreshold sensory synaptic responses evoked while a cortical area was spontaneously depolarized were smaller, briefer and spatially more confined. Surprisingly, whisker deflections evoked fewer action potentials during the spontaneous depolarizations despite neurons being closer to threshold. The ongoing spontaneous activity thus regulates the amplitude and the time-dependent spread of the sensory response in layer 2/3 barrel cortex.

Somata of nerve-injured sensory neurons exhibit enhanced responses to inflammatory mediators

The effects of inflammatory mediators in modulating the activity of nerve-injured dorsal root ganglion (DRG) neurons were studied in rats in an in vitro nerve-DRG preparation 2–4 weeks after a loose ligation of the sciatic nerve (chronic constriction injury, CCI). An inflammatory soup (IS) of bradykinin, serotonin, prostaglandin E 2 and histamine (each 10 −5 M, pH=7.4) was applied topically to the DRG. Evoked responses were recorded extracellularly from teased dorsal root fibers or intracellularly with sharp electrodes from somata of DRG neurons with myelinated (Aβ and Aδ) or unmyelinated (C) axons. IS increased the rate of ongoing spontaneous activity recorded from dorsal root fibers of CCI neurons and evoked activity in a subpopulation of previously ‘silent’ fibers in CCI rats but not those of unoperated controls. In comparison with DRG somata of control rats, those of CCI become more excitable as evidenced by a lower threshold to depolarizing current and a greater depolarization in response to IS. Inflammatory mediators, by increasing the excitability of DRG neurons, may contribute to paresthesiae, pain and hyperalgesia after peripheral nerve injury.

C-fiber modulation of the rat type I slowly adapting mechanoreceptor

Effects of C-fiber activation on type I slowly adapting mechanoreceptor responses were investigated in a rat in vitro nerve–skin preparation using controlled mechanical stimuli. Two changes in behavior were evoked by antidromic C-fiber stimulation: (1) The type I response to mechanical stimuli was modulated in a graded fashion by antidromic C-fiber activation. The average decrease in mechanoresponse from baseline discharge was 53% at 20-Hz, 51% at 5-Hz, and 30% at 1-Hz stimulation rate. The type I response recovered to baseline levels following termination of antidromic electrical stimulation. (2) Antidromic C-fiber activation generated a spontaneous ongoing activity in many skin units; this was independent of mechanical stimulation and outlasted electrical stimulation. The fact that neither antidromic electrical stimulation of the crushed nerve trunk nor selective A-fiber activation elicited these reactions suggests that they were mediated via action potentials of slowly conducting (C-fiber) axons. Immunohistochemical staining revealed both substance P- and calcitonin gene-related peptide-like immunoreactivity in small unmyelinated nerve fibers entering the touch dome. These results support the concepts that (1) the type I slowly adapting mechanoreceptor in rat receives input from nociceptive terminals within the touch dome. (2) The function of type I slowly adapting mechanoreceptors is modulated by axon reflex activation of nociceptor terminals, which may play a role in altering the type I response during states of mechanical allodynia and have paracrine and autocrine influences on maintenance of touch dome structure.

Somatosensory cortical neuronal population activity across states of anaesthesia.

Experiments were carried out to learn about changes in sensory cortical processing associated with different levels of anaesthesia. Traditionally this question has been addressed by studying single neurons. Because state changes are likely to influence the relationships between neurons, the present experiments were undertaken to investigate the spatial and temporal firing patterns distributed across cortex. Using 5 x 5 or 10 x 10 microelectrode arrays, spontaneous and stimulus-evoked activity of multineuron clusters was recorded from rat somatosensory 'barrel' cortex (the whisker representation) during a light surgical stage of urethane anaesthesia, and after two supplemental doses of urethane which led to intermediate and deep levels of anaesthesia. At all depths of anaesthesia, spontaneously occurring action potentials at a single electrode tended to be clustered into 'bursts.' With increasing anaesthetic depth, bursts became more prominent and rhythmic, and increasingly synchronized between cortical barrel-columns. Burst frequency decreased and fewer spikes occurred outside bursts, leading to a decrease in the overall spontaneous firing rate. The cortical territory engaged by individual whiskers contracted with increasing depth of anaesthesia, leading to the spatial segregation of whisker representations. At all stages of anaesthesia, whisker stimulation produced the maximal cortical response when delivered close to burst onset. These observations show that ongoing spontaneous activity modulates sensory response properties and makes peripheral tactile information accessible to a cortical territory whose size is determined by the phase of burst cycle. The possible significance of the cyclic cortical responsiveness encountered during urethane anaesthesia to cortical processing in awake rats is considered.

Biochemical, Electrophysiological and Neurohormonal Studies with B-20991, a Selective 5-HT1A Receptor Agonist

Different receptor subtypes mediate the effects produced by serotonin (5-HT) in mammals. Besides their proved anxiolytic action, agonists of the 5-HT_1A receptor subtype show prospects as antidepressants or neuroprotective agents in case of ischemia. In order to better define the pharmacological profile and determine the selectivity for the 5-HT receptor type, the properties of the new 5-HT_1A receptor agonist 2[[4-(o-methoxyphenyl)piperazin-1-yl]-methyl]-1.3-dioxoperhydroimidazo[1.5-a]pyridine (B-20991), an arylpiperazine derivative, have now been further studied. B-20991 was found to antagonize the forskolin-induced increase of cAMP synthesis in a HeLa cell line transfected with the human 5-HT_1A in a process sensitive to the selective blocker N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY 100635). Additionally, B-20991 showed a dose-dependent inhibition of the spontaneous on-going activity of serotonin (5-HT) neurons in the dorsal raphe nucleus in rats, an effect that was reversed by treatment with WAY 100635. This, together with the fact that the hypothermia induced by B-20991 in mice was also antagonized by WAY 100635, suggests that the new compound acts upon somatodendritic 5-HT_1A receptors. Additional activation of 5-HT_1A postsynaptic receptors was indicated by the increase of corticosterone plasma levels induced by B-20991 in the rat. These results demonstrate that B-20991 is a selective 5-HT_1A receptor agonist acting both pre- and postsynaptically, which represents an useful pharmacological tool to study 5-HT_1A-receptor-mediated effects.