Kentaroh Takagaki

Crossmodal propagation of sensory-evoked and spontaneous activity in the rat neocortex

In the cortex, neural responses to crossmodal stimulation are seen both in higher association areas and in primary sensory areas, and are thought to play a role in integration of crossmodal sensations. We used voltage-sensitive dye imaging (VSDI) to study the spatiotemporal characteristics of such crossmodal neural activity. We imaged three cortical regions in rat: primary visual cortex (V1), barrel field of primary somatosensory cortex (S1bf) and parietal association area (PA, flanked by V1 and S1bf). We find that sensory-evoked population activity can propagate in the form of a distinct propagating wave, robustly in either crossmodal direction. In single trials, the waveforms changed continuously during propagation, with dynamic variability from trial to trial, which we interpret as evidence for cortical involvement in the spreading process. To further characterize the functional anatomy of PA, we also studied the propagation of spontaneous sleep-like waves in this area. Using a novel flow-detection algorithm, we detected a propagation bias within PA of spontaneous waves--these tend to propagate parallel to the crossmodal axis, rather than orthogonal to it. Taken together, these findings demonstrate that intracortical networks show pre-attentive crossmodal propagation of activity, and suggest a potential mechanism for the establishment of crossmodal integration.

Asymmetric Multisensory Interactions of Visual and Somatosensory Responses in a Region of the Rat Parietal Cortex

Perception greatly benefits from integrating multiple sensory cues into a unified percept. To study the neural mechanisms of sensory integration, model systems are required that allow the simultaneous assessment of activity and the use of techniques to affect individual neural processes in behaving animals. While rodents qualify for these requirements, little is known about multisensory integration and areas involved for this purpose in the rodent. Using optical imaging combined with laminar electrophysiological recordings, the rat parietal cortex was identified as an area where visual and somatosensory inputs converge and interact. Our results reveal similar response patterns to visual and somatosensory stimuli at the level of current source density (CSD) responses and multi-unit responses within a strip in parietal cortex. Surprisingly, a selective asymmetry was observed in multisensory interactions: when the somatosensory response preceded the visual response, supra-linear summation of CSD was observed, but the reverse stimulus order resulted in sub-linear effects in the CSD. This asymmetry was not present in multi-unit activity however, which showed consistently sub-linear interactions. These interactions were restricted to a specific temporal window, and pharmacological tests revealed significant local intra-cortical contributions to this phenomenon. Our results highlight the rodent parietal cortex as a system to model the neural underpinnings of multisensory processing in behaving animals and at the cellular level.

INTERACTIONS BETWEEN TWO PROPAGATING WAVES IN RAT VISUAL CORTEX

Sensory-evoked propagating waves are frequently observed in sensory cortex. However, it is largely unknown how an evoked propagating wave affects the activity evoked by subsequent sensory inputs, or how two propagating waves interact when evoked by simultaneous sensory inputs. Using voltage-sensitive dye imaging, we investigated the interactions between two evoked waves in rat visual cortex, and the spatiotemporal patterns of depolarization in the neuronal population due to wave-to-wave interactions. We have found that visually-evoked propagating waves have a refractory period of about 300 ms, within which the response to a subsequent visual stimulus is suppressed. Simultaneous presentation of two visual stimuli at different locations can evoke two waves propagating toward each other, and these two waves fuse. Fusion significantly shortens the latency and half-width of the response, leading to changes in the spatial profile of evoked population activity. The visually-evoked propagating wave may also be suppressed by a preceding spontaneous wave. The refractory period following a propagating wave and the fusion between two waves may contribute to visual sensory processing by modifying the spatiotemporal profile of population neuronal activity evoked by sensory events.

Flow detection of propagating waves with temporospatial correlation of activity.

Voltage-sensitive dye imaging (VSDI) allows population patterns of cortical activity to be recorded with high temporal resolution, and recent findings ascribe potential significance to these spatial propagation patterns--both for normal cortical processing and in pathologies such as epilepsy. However, analysis of these spatiotemporal patterns has been mostly qualitative to date. In this report, we describe an algorithm to quantify fast local flow patterns of cortical population activation, as measured with VSDI. The algorithm uses correlation of temporal features across space, and therefore differs from conventional optical flow algorithms which use correlation of spatial features over time. This alternative approach allows us to take advantage of the characteristics of fast optical imaging data, which have very high temporal resolution but less spatial resolution. We verify the method both on artificial and biological data, and demonstrate its use.

Normalization of Voltage-Sensitive Dye Signal with Functional Activity Measures

In general, signal amplitude in optical imaging is normalized using the well-established ΔF/F method, where functional activity is divided by the total fluorescent light flux. This measure is used both directly, as a measure of population activity, and indirectly, to quantify spatial and spatiotemporal activity patterns. Despite its ubiquitous use, the stability and accuracy of this measure has not been validated for voltage-sensitive dye imaging of mammalian neocortex in vivo. In this report, we find that this normalization can introduce dynamic biases. In particular, the ΔF/F is influenced by dye staining quality, and the ratio is also unstable over the course of experiments. As methods to record and analyze optical imaging signals become more precise, such biases can have an increasingly pernicious impact on the accuracy of findings, especially in the comparison of cytoarchitechtonic areas, in area-of-activation measurements, and in plasticity or developmental experiments. These dynamic biases of the ΔF/F method may, to an extent, be mitigated by a novel method of normalization, ΔF/ΔFepileptiform. This normalization uses as a reference the measured activity of epileptiform spikes elicited by global disinhibition with bicuculline methiodide. Since this normalization is based on a functional measure, i.e. the signal amplitude of “hypersynchronized” bursts of activity in the cortical network, it is less influenced by staining of non-functional elements. We demonstrate that such a functional measure can better represent the amplitude of population mass action, and discuss alternative functional normalizations based on the amplitude of synchronized spontaneous sleep-like activity. These findings demonstrate that the traditional ΔF/F normalization of voltage-sensitive dye signals can introduce pernicious inaccuracies in the quantification of neural population activity. They further suggest that normalization-independent metrics such as waveform propagation patterns, oscillations in single detectors, and phase relationships between detector pairs may better capture the biological information which is obtained by high-sensitivity imaging.

Wave propagation of cortical population activity under urethane anesthesia is state dependent.

BackgroundPropagating waves of excitation have been observed extensively in the neocortex, during both spontaneous and sensory-evoked activity, and they play a critical role in spatially organizing information processing. However, the state-dependence of these spatiotemporal propagation patterns is largely unexplored. In this report, we use voltage-sensitive dye imaging in the rat visual cortex to study the propagation of spontaneous population activity in two discrete cortical states induced by urethane anesthesia.ResultsWhile laminar current source density patterns of spontaneous population events in these two states indicate a considerable degree of similarity in laminar networks, lateral propagation in the more active desynchronized state is approximately 20% faster than in the slower synchronized state. Furthermore, trajectories of wave propagation exhibit a strong anisotropy, but the preferred direction is different depending on cortical state.ConclusionsOur results show that horizontal wave propagation of spontaneous neural activity is largely dependent on the global activity states of local cortical circuits.

Measurement, modeling, and prediction of temperature rise due to optogenetic brain stimulation

Abstract. Optogenetics is one of the most important techniques in neurophysiology, with potential clinical applications. However, the strong light needed may cause harmful temperature rises. So far, there are no methods to reliably estimate brain heating and safe limits in actual optogenetic experiments. We used thermal imaging to directly measure such temperature rises at the surface of live mouse brains during laser illumination with wavelengths and intensities typical for optogenetics. We then modeled the temperature rise with a simple logarithmic model. Our results indicate that previous finite-element models can underestimate temperature increases by an order of magnitude. We validate our empirical model by predicting the temperature rise caused by pulsed stimulation paradigms. These predictions fit closely to the empirical data and constitute a better estimate of real temperature increases. Additionally, we provide a web-based app for easy calculation that can be used as a tool for safe design of optogenetic experiments.

Periodic Lateralized Epileptiform Discharges (PLEDs) in Patients With Neurosyphilis and HIV Infection.

Periodic lateralized epileptiform discharges (PLEDs) are an electroencephalographic pattern recorded in the setting of a variety of brain abnormalities. It is best recognized for its association with acute viral encephalitis, stroke, tumor, or latestatus epilepticus. However, there are other conditions that have been recognized as the underlying pathology for PLEDs such as alcohol withdrawal, Creutzfeldt–Jacob disease, anoxic brain injury, and hemiplegic migraine. However, there are only rare case reports of PLEDs in patients with neurosyphilis. Here, we report 2 patients presenting with encephalopathy and seizures with PLEDs, ipsilateral or contralateral to their main brain magnetic resonance imaging abnormalities. Further workup revealed neurosyphilis in both patients, one in association with human immunodeficiency virus (HIV) infection. Given the increasing incidence of neurosyphilis with or without HIV infection, these cases suggest neurosyphilis as a consideration in the differential for patients presenting with PLEDs.

Development of the posterior basic rhythm in children with autism

OBJECTIVE Early detection of autism is critical for effective intervention, but currently, no simple screening tests are available. Furthermore, little is known about the development of brain dynamics in young children. We examine the early neurophysiological manifestations of autism by retrospectively analyzing EEG. In particular, we focus on maturation of the posterior basic rhythm (PBR), which is one of the most characteristic features of the normal EEG, and comprises a discrete functional state. METHODS Subjects with a diagnosis of autism (n=74), as well as normal (n=134) and epileptic (n=108) controls, were extracted retrospectively from our digital EEG database. Segments with clear PBR were extracted, and standard signal analysis methods were used to calculate peak PBR frequency, power, and coherence. RESULTS In our cohort, a subset of autistic children show accelerated development of the PBR, with early maturation especially in the 2- to 4-year old range. The overall coherence of PBR-specific activity is also lower in autistic children in our cohort. CONCLUSIONS These findings provide evidence that autism is associated with accelerated development of the PBR. SIGNIFICANCE These findings generate a clinical hypothesis for future prospective studies on the efficacy of these simple measures as a diagnostic or screening tool.

Coarse-Graining to Investigate Cerebral Cortex Dynamics

Advances in multi-channel/multi-detector recordings and data analysis over the last decades have led to an explosion in the exploration of complex neural dynamics in mammalian cortex. Powerful methods have been applied to investigate such dynamics, including connectivity measures (correlation, causality, resting state synchrony, etc.), spatiotemporal pattern analyses, and finite-element modelling based on model neurons. These methods were initially applied to data from simple experimental models such as invertebrate neurons/ganglia/tecta, cell cultures, and organotypic slice preparations. Advances in the field have triggered the expanded use of such measures on more complex data, for example to mammalian ex vivo preparations, anesthetized preparations, and mammalian awake behaving preparations. With the increasing surgical, behavioral, and physiological complexity of the preparations themselves, less invasive measurement methods such as optical recordings, massively implanted arrays, or fMRI and other electromagnetic methods must be used to ensure robustness; however, these measures tend to feature lower signal-to-noise ratios, and are often prone to various biases. Furthermore, the high dimensionality of the data itself leads directly to potential errors in programming of analysis algorithms and overinterpretation of statistically significant but biologically insignificant findings. Given this situation, we advocate for the complementary use of the classical biological approach: the use of simplified preparations which may be limited in scope, but which highlight fundamental principles. We illustrate this approach with three experimental examples which use experimental and observational approaches to coarse-grain dynamic spatiotemporal activity patterns, to make coarse-graining observations of clinically relevant oscillations, and to coarse-grain complex behavior in mammalian discrimination learning.