Multisecond Timescales Research Articles

Brief Stimuli Cast a Persistent Long-Term Trace in Visual Cortex.

Visual processing is strongly influenced by recent stimulus history, a phenomenon termed adaptation. Prominent theories cast adaptation as a consequence of optimized encoding of visual information by exploiting the temporal statistics of the world. However, this would require the visual system to track the history of individual briefly experienced events, within a stream of visual input, to build up statistical representations over longer timescales. Here, using an openly available dataset from the Allen Brain Observatory, we show that neurons in the early visual cortex of the mouse indeed maintain long-term traces of individual past stimuli that persist despite the presentation of several intervening stimuli, leading to long-term and stimulus-specific adaptation over dozens of seconds. Long-term adaptation was selectively expressed in cortical, but not in thalamic, neurons, which only showed short-term adaptation. Early visual cortex thus maintains concurrent stimulus-specific memory traces of past input, enabling the visual system to build up a statistical representation of the world to optimize the encoding of new information in a changing environment.SIGNIFICANCE STATEMENT In the natural world, previous sensory input is predictive of current input over multisecond timescales. The visual system could exploit these predictabilities by adapting current visual processing to the long-term history of visual input. However, it is unclear whether the visual system can track the history of individual briefly experienced images, within a stream of input, to build up statistical representations over such long timescales. Here, we show that neurons in early visual cortex of the mouse brain exhibit remarkably long-term adaptation to brief stimuli, persisting over dozens of seconds, and despite the presentation of several intervening stimuli. The visual cortex thus maintains long-term traces of individual briefly experienced past images, enabling the formation of statistical representations over extended timescales.

Kinetics of cytochrome P450 3A4 inhibition by heterocyclic drugs defines a general sequential multistep binding process

Cytochrome P450 (P450) 3A4 is the enzyme most involved in the metabolism of drugs and can also oxidize numerous steroids. This enzyme is also involved in one-half of pharmacokinetic drug–drug interactions, but details of the exact mechanisms of P450 3A4 inhibition are still unclear in many cases. Ketoconazole, clotrimazole, ritonavir, indinavir, and itraconazole are strong inhibitors; analysis of the kinetics of reversal of inhibition with the model substrate 7-benzoyl quinoline showed lag phases in several cases, consistent with multiple structures of P450 3A4 inhibitor complexes. Lags in the onset of inhibition were observed when inhibitors were added to P450 3A4 in 7-benzoyl quinoline O-debenzylation reactions, and similar patterns were observed for inhibition of testosterone 6β-hydroxylation by ritonavir and indinavir. Upon mixing with inhibitors, P450 3A4 showed rapid binding as judged by a spectral shift with at least partial high-spin iron character, followed by a slower conversion to a low-spin iron–nitrogen complex. The changes were best described by two intermediate complexes, one being a partial high-spin form and the second another intermediate, with half-lives of seconds. The kinetics could be modeled in a system involving initial loose binding of inhibitor, followed by a slow step leading to a tighter complex on a multisecond time scale. Although some more complex possibilities cannot be dismissed, these results describe a system in which conformationally distinct forms of P450 3A4 bind inhibitors rapidly and two distinct P450–inhibitor complexes exist en route to the final enzyme–inhibitor complex with full inhibitory activity.

The Modular Organization of Pain Brain Networks: An fMRI Graph Analysis Informed by Intracranial EEG.

Intracranial EEG (iEEG) studies have suggested that the conscious perception of pain builds up from successive contributions of brain networks in less than 1 s. However, the functional organization of cortico-subcortical connections at the multisecond time scale, and its accordance with iEEG models, remains unknown. Here, we used graph theory with modular analysis of fMRI data from 60 healthy participants experiencing noxious heat stimuli, of whom 36 also received audio stimulation. Brain connectivity during pain was organized in four modules matching those identified through iEEG, namely: 1) sensorimotor (SM), 2) medial fronto-cingulo-parietal (default mode-like), 3) posterior parietal-latero-frontal (central executive-like), and 4) amygdalo-hippocampal (limbic). Intrinsic overlaps existed between the pain and audio conditions in high-order areas, but also pain-specific higher small-worldness and connectivity within the sensorimotor module. Neocortical modules were interrelated via “connector hubs” in dorsolateral frontal, posterior parietal, and anterior insular cortices, the antero-insular connector being most predominant during pain. These findings provide a mechanistic picture of the brain networks architecture and support fractal-like similarities between the micro-and macrotemporal dynamics associated with pain. The anterior insula appears to play an essential role in information integration, possibly by determining priorities for the processing of information and subsequent entrance into other points of the brain connectome.

Multisecond ligand dissociation dynamics from atomistic simulations

Coarse-graining of fully atomistic molecular dynamics simulations is a long-standing goal in order to allow the description of processes occurring on biologically relevant timescales. For example, the prediction of pathways, rates and rate-limiting steps in protein-ligand unbinding is crucial for modern drug discovery. To achieve the enhanced sampling, we perform dissipation-corrected targeted molecular dynamics simulations, which yield free energy and friction profiles of molecular processes under consideration. Subsequently, we use these fields to perform temperature-boosted Langevin simulations which account for the desired kinetics occurring on multisecond timescales and beyond. Adopting the dissociation of solvated sodium chloride, trypsin-benzamidine and Hsp90-inhibitor protein-ligand complexes as test problems, we reproduce rates from molecular dynamics simulation and experiments within a factor of 2–20, and dissociation constants within a factor of 1–4. Analysis of friction profiles reveals that binding and unbinding dynamics are mediated by changes of the surrounding hydration shells in all investigated systems.

Relationship between cortical state and spiking activity in the lateral geniculate nucleus of marmosets.

How parallel are the primate visual pathways? In the present study, we demonstrate that parallel visual pathways in the dorsal lateral geniculate nucleus (LGN) show distinct patterns of interaction with rhythmic activity in the primary visual cortex (V1). In the V1 of anaesthetized marmosets, the EEG frequency spectrum undergoes transient changes that are characterized by fluctuations in delta-band EEG power. We show that, on multisecond timescales, spiking activity in an evolutionary primitive (koniocellular) LGN pathway is specifically linked to these slow EEG spectrum changes. By contrast, on subsecond (delta frequency) timescales, cortical oscillations can entrain spiking activity throughout the entire LGN. Our results are consistent with the hypothesis that, in waking animals, the koniocellular pathway selectively participates in brain circuits controlling vigilance and attention. The major afferent cortical pathway in the visual system passes through the dorsal lateral geniculate nucleus (LGN), where nerve signals originating in the eye can first interact with brain circuits regulating visual processing, vigilance and attention. In the present study, we investigated how ongoing and visually driven activity in magnocellular (M), parvocellular (P) and koniocellular (K) layers of the LGN are related to cortical state. We recorded extracellular spiking activity in the LGN simultaneously with local field potentials (LFP) in primary visual cortex, in sufentanil-anaesthetized marmoset monkeys. We found that asynchronous cortical states (marked by low power in delta-band LFPs) are linked to high spike rates in K cells (but not P cells or M cells), on multisecond timescales. Cortical asynchrony precedes the increases in K cell spike rates by 1-3s, implying causality. At subsecond timescales, the spiking activity in many cells of all (M, P and K) classes is phase-locked to delta waves in the cortical LFP, and more cells are phase-locked during synchronous cortical states than during asynchronous cortical states. The switch from low-to-high spike rates in K cells does not degrade their visual signalling capacity. By contrast, during asynchronous cortical states, the fidelity of visual signals transmitted by K cells is improved, probably because K cell responses become less rectified. Overall, the data show that slow fluctuations in cortical state are selectively linked to K pathway spiking activity, whereas delta-frequency cortical oscillations entrain spiking activity throughout the entire LGN, in anaesthetized marmosets.

Chemical composition, microstructure, and hygroscopic properties of aerosol particles at the Zotino Tall Tower Observatory (ZOTTO), Siberia, during a summer campaign

Abstract. In this study we describe the hygroscopic properties of accumulation- and coarse-mode aerosol particles sampled at the Zotino Tall Tower Observatory (ZOTTO) in central Siberia (61° N, 89° E) from 16 to 21 June 2013. The hygroscopic growth measurements were supplemented with chemical analyses of the samples, including inorganic ions and organic/elemental carbon. In addition, the microstructure and chemical compositions of aerosol particles were analyzed by x-ray micro-spectroscopy (STXM-NEXAFS) and transmission electron microscopy (TEM). A mass closure analysis indicates that organic carbon accounted for 61 and 38 % of particulate matter (PM) in the accumulation mode and coarse mode, respectively. The water-soluble fraction of organic matter was estimated to be 52 and 8 % of PM in these modes. Sulfate, predominantly in the form of ammoniated sulfate, was the dominant inorganic component in both size modes: ~ 34 % in the accumulation mode vs. ~ 47 % in the coarse mode. The hygroscopic growth measurements were conducted with a filter-based differential hygroscopicity analyzer (FDHA) over the range of 5–99.4 % RH in the hydration and dehydration operation modes. The FDHA study indicates that both accumulation and coarse modes exhibit pronounced water uptake approximately at the same relative humidity (RH), starting at ~ 70 %, while efflorescence occurred at different humidities, i.e., at ~ 35 % RH for submicron particles vs. ~ 50 % RH for supermicron particles. This ~ 15 % RH difference was attributed to higher content of organic material in the submicron particles, which suppresses water release in the dehydration experiments. The kappa mass interaction model (KIM) was applied to characterize and parameterize non-ideal solution behavior and concentration-dependent water uptake by atmospheric aerosol samples in the 5–99.4 % RH range. Based on KIM, the volume-based hygroscopicity parameter, κv, was calculated. The κv,ws value related to the water-soluble (ws) fraction was estimated to be ~ 0.15 for the accumulation mode and ~ 0.36 for the coarse mode, respectively. The obtained κv,ws for the accumulation mode is in good agreement with earlier data reported for remote sites in the Amazon rain forest (κv ≈ 0.15) and a Colorado mountain forest (κv ≈ 0.16 ). We used the Zdanovskii–Stokes–Robinson (ZSR) mixing rule to predict the chemical composition dependent hygroscopicity, κv,p. The obtained κv,p values overestimate the experimental FDHA-KIM-derived κv,ws by factors of 1.8 and 1.5 for the accumulation and coarse modes, respectively. This divergence can be explained by incomplete dissolution of the hygroscopic inorganic compounds resulting from kinetic limitations due to a sparingly soluble organic coating. The TEM and STXM-NEXAFS results indicate that aged submicron (> 300 nm) and supermicron aerosol particles possess core–shell structures with an inorganic core, and are enriched in organic carbon at the mixed particle surface. The direct FDHA kinetic studies provide a bulk diffusion coefficient of water of ~ 10−12 cm2 s−1 indicating a semi-solid state of the organic-rich phase leading to kinetic limitations of water uptake and release during hydration and dehydration cycles. Overall, the present ZOTTO data set, obtained in the growing season, has revealed a strong influence of organic carbon on the hygroscopic properties of the ambient aerosols. The sparingly soluble organic coating controls hygroscopic growth, phase transitions, and microstructural rearrangement processes. The observed kinetic limitations can strongly influence the outcome of experiments performed on multi-second timescales, such as the commonly applied HTDMA (Hygroscopicity Tandem Differential Mobility Analyzer) and CCNC (Cloud Condensation Nuclei Counter) measurements.

Amplitude and phase-locking adaptation of neural oscillation in the rat auditory cortex in response to tone sequence

Sensory adaptation allows stimulus sensitivity to be dynamically modulated according to stimulus statistics and plays pivotal roles in efficient neural computation. Here, it is hypothesized that in the auditory cortex, phase locking of local field potentials (LFPs) to test tones exhibits an adaptation property, i.e., phase-locking adaptation, which is distinct from the amplitude adaptation of oscillatory components. Series of alternating tone sequences were applied in which the inter-tone interval (ITI) and frequency difference (ΔF) between successive tones were varied. Then, adaptation was characterized by the temporal evolution of the band-specific amplitude and phase locking evoked by the test tones. Differences as well as similarities were revealed between amplitude and phase-locking adaptations. First, both amplitude and phase-locking adaptations were enhanced by short ITIs and small ΔFs. Second, the amplitude adaptation was more effective in a higher frequency band, while the phase-locking adaptation was more effective in a lower frequency band. Third, as with the adaptation of multiunit activities (MUAs), the amplitude adaptation occurred mainly within a second, while the phase-locking showed multi-second adaptation specifically in the gamma band for short ITI and small ΔF conditions. Fourth, the amplitude adaptation and phase-locking adaptation were co-modulated in a within-second time scale, while this co-modulation was not observed in a multi-second time scale. These findings suggest that the amplitude and phase-locking adaptations have different mechanisms and functions. The phase-locking adaptation is likely to play more crucial roles in encoding a temporal structure of stimulus than the amplitude adaptation.

Quantum Light Signatures and Nanosecond Spectral Diffusion from Cavity-Embedded Carbon Nanotubes

Single-walled carbon nanotubes (SWCNTs) are considered for novel optoelectronic and quantum photonic devices, such as single photon sources, but methods must be developed to enhance the light extraction and spectral purity, while simultaneously preventing multiphoton emission as well as spectral diffusion and blinking in dielectric environments of a cavity. Here we demonstrate that utilization of nonpolar polystyrene as a cavity dielectric completely removes spectral diffusion and blinking in individual SWCNTs on the millisecond to multisecond time scale, despite the presence of surfactants. With these cavity-embedded SWCNT samples, providing a 50-fold enhanced exciton emission into the far field, we have been able to carry out photophysical studies for the first time with nanosecond timing resolution. We uncovered that fast spectral diffusion processes (1-3 ns) remain that make significant contributions to the spectral purity, thereby limiting the use of SWCNTs in quantum optical applications requiring indistinguishable photons. Measured quantum light signatures reveal pronounced photon antibunching (g(2)(0) = 0.15) accompanied by side-peak bunching signatures indicative of residual blinking on the submicrosecond time scale. The demonstrated enhanced single photon emission from cavity-embedded SWCNTs is promising for applications in quantum key distribution, while the demonstrated passivation effect of polystyrene with respect to the stability of the optical emission opens a novel pathway toward optoelectronic devices with enhanced performance.

Delay Time and Concentration Effects During Bioconjugation of Nanosecond Laser-Generated Nanoparticles in a Liquid Flow

Fast ex situ functionalization of gold nanoparticles with fluorophore-labeled cell-penetrating peptides is investigated with a novel liquid flow cascade injection system. Successful conjugation is proved by various methods, such as UV−vis spectrometry and electron microscopy, whereas nanoparticle size-quenching is clearly observed. By variation of the peptide concentration introduced promptly after particle generation, gold nanoparticle bioconjugates with different degrees of cluster formation and/or aggregation and different peptide surface coverage values are obtained. The sizes of synthesized inorganic−organic gold nanoparticle bioconjugate show obvious correlation with time-delayed conjugation, giving evidence that laser-generated nanoparticles continue growing outside the cavitation bubble in the multisecond time scale until achieving their final size. Introducing 6.6 μM bioactive ligands, the highest conjugation efficiency of 93% and ζ potential of 27.5 mV is reached at the shortest delay time (200 ...

Rhythms of sleep: orchestrating memory consolidation (Commentary on Clemens et al.)

During sleep, consolidation of declarative memory is thought to be mediated by a ‘dialogue’ between hippocampal and neocortical networks, promoting the reorganization of recent memory traces (Buzsaki, 1996; Clemens et al., 2005). Consistent with this hypothesis, several rodent studies have established a temporal relationship between 12 and 15 Hz cortical sleep spindle oscillations and high-frequency ripple bursts originating in the hippocampus (Clemens et al., 2006, 2007, 2011). Both spindles and ripples are thought to facilitate synaptic plasticity and the consolidation of memory. An accumulating body of evidence indicates that network-level ‘reactivation’ of recent experience occurs during ripple bursts in rodents (Ji & Wilson, 2007; Marshall & Born, 2007), while human studies demonstrate that spindle activity during post-learning sleep predicts enhanced retention of recently learned material (Siapas & Wilson, 1998; Sirota et al., 2003; Schabus et al., 2004; O’Neill et al., 2010). Nevertheless, the dynamics underlying a potential role for spindle–ripple interactions in cortical plasticity remain largely unknown. In their new study, Clemens et al. (2011); (this issue) report the first human data examining millisecond-timescale temporal interactions between hippocampal ripples and cortical sleep spindles. Intracranial EEG data were acquired in epilepsy patients from implanted parahippocampal foramen ovale electrodes, which the authors have previously established as sensitive for detecting 80–140 Hz ripple bursts similar to those described in the hippocampus proper (Sirota & Buzsaki, 2005). Clemens et al. (2011) demonstrate a correlation between spindles and hippocampal ripples on two distinct timescales. First, in line with the findings of prior studies (Sirota & Buzsaki, 2005; Clemens et al., 2006, 2007, 2011), ripple activity was increased during the ± 1 s window surrounding spindles. More significantly, however, Clemens and colleagues also found that ripple bursts were tightly phase-locked to the ‘troughs’ of the individual oscillations comprising a spindle (at which time neuronal excitation presumably reaches a maximum), with ripple activity reaching a peak just a few milliseconds prior to each trough. This phase-locking of ripples to spindle troughs on a millisecond timescale has been reported in only one prior study [in rodents (Clemens et al., 2007)], and is relevant to elucidating mechanisms of sleep-dependent plasticity for several reasons. Firstly, coordinated activity on this timescale cannot be explained via a generic influence of the < 1 Hz cortical slow oscillation, known to group sleep rhythms on the multi-second timescale (Steriade, 2003; Tamminen et al., 2010), suggesting there may be a particular functional significance for these more precisely timed interactions between ripples and spindles. Secondly, this observation supports the longstanding suggestion that hippocampal output during ripple bursts induces plasticity in cortical targets: as ripples are associated with the ‘reactivation’ of specific recent memory traces, timing their expression to maximally excitatory phases of a spindle could optimally facilitate hippocampus-mediated cortical plasticity. Interestingly, Clemens et al. (2011) found that ripple activity consistently peaks just prior to spindle troughs. In contrast, Sirota et al. (2003) reported that both ripples and CA1 unit activity peaked approximately 50 ms after spindle troughs in rodents, speculating that neocortical activity exerted a modulating influence on hippocampal networks, triggering the expression of ripples. The present findings may prompt some renewed discussion about the causal direction of this particular hippocampal–cortical interaction, as some models of sleep-dependent memory consolidation favor the notion that hippocampal memory reactivation during ripple bursts should exert a driving influence on mechanisms of plasticity in the cortex rather than vice versa. Regardless of such remaining questions, these observations by Clemens and colleagues add an important level of nuance to our understanding of oscillatory brain dynamics underlying sleep-dependent memory consolidation in humans, providing further evidence that the functional significance of sleep spindles lies in their facilitation of hippocampus-mediated cortical plasticity during sleep.

Correlated multisecond oscillations in firing rate in the basal ganglia: modulation by dopamine and the subthalamic nucleus

Previous studies from this laboratory have shown that many neurons in the basal ganglia have multisecond (<0.5 Hz) periodicities in firing rate in awake rats. The frequency and regularity of these oscillations are significantly increased by systemically injected dopamine (DA) agonists. Because oscillatory activity should have greater functional impact if shared by many neurons, the level of correlation of multisecond oscillations was assessed by recording pairs of neurons in the globus pallidus and substantia nigra pars reticulata in the same hemisphere, or pairs of globus pallidus neurons in opposite hemispheres in awake, immobilized rats. Cross-correlation (90–180 s lags) and spectral analysis were used to characterize correlated oscillations. Thirty-eight percent of pairs recorded in baseline ( n=50) demonstrated correlated multisecond oscillations. Phase relationships were near 0 or 180°. DA agonist injection significantly increased the incidence of correlation (intra- and interhemispheric) to 94% ( n=17). After DA agonist injection, phase relationships of globus pallidus/substantia nigra neuron pairs were exclusively concentrated near 180°, and phases of interhemispheric pairs of globus pallidus neurons were concentrated near 0°. After subthalamic nucleus lesion ( n=8), the incidence of correlated multisecond oscillations (or of multisecond oscillations per se) was not changed, although the consistent phase relationship between the globus pallidus and substantia nigra pars reticulata was disrupted. Subthalamic lesion also blocked apomorphine-induced decreases in oscillatory period and increases in oscillation amplitude, and significantly attenuated apomorphine-induced changes in mean firing rate. The data demonstrate that multisecond oscillations in the basal ganglia can be correlated between nuclei, and that DA receptor activation increases the level of correlation and organizes internuclear phase relationships at these multisecond time scales. While the subthalamic nucleus is not necessary for generating or transmitting these slow oscillations, it is involved in DA agonist-induced modulation of mean firing rate, oscillatory period, and internuclear phase relationship. These data further support a role for DA in modulating coherent oscillatory activity in the basal ganglia, and for the subthalamic nucleus in shaping the effects of DA receptor stimulation on basal ganglia output.

Parametric instability of a pendulum

The pendulum, which can rotate in a vertical plane about a horizontal axis, consists of a tube with a pneumatically propelled internal slider which is driven periodically from one end of the tube to the other without changing the pendulum’s angular momentum. The resultant parametric oscillations can be observed in great detail, in both linear and nonlinear regimes, because of the multisecond time scales which characterize the system. It is shown that, in addition to the expected conditions for instability to occur, there is also an amplitude threshold caused by sliding friction in the pendulum’s bearings.