Inter-trial variability in sensory-evoked cortical hemodynamic responses: the role of the magnitude of pre-stimulus fluctuations

Brain imaging techniques utilize hemodynamic changes that accompany brain activation. However, stimulus-evoked hemodynamic responses display considerable inter-trial variability and the sources of this variability are poorly understood. One of the sources of this response variation could be ongoing spontaneous hemodynamic fluctuations. We recently investigated this issue by measuring cortical hemodynamics in response to sensory stimuli in anesthetized rodents using 2-dimensional optical imaging spectroscopy. We suggested that sensory-evoked cortical hemodynamics displayed distinctive response characteristics and magnitudes depending on the phase of ongoing fluctuations at stimulus onset due to a linear superposition of evoked and ongoing hemodynamics (Saka et al., 2010). However, the previous analysis neglected to examine the possible influence of variability of the size of ongoing fluctuations. Consequently, data were further analyzed to examine whether the size of pre-stimulus hemodynamic fluctuations also influenced the magnitude of subsequent stimulus-evoked responses. Indeed, in the case of all individual trials, a moderate correlation between the size of the pre-stimulus fluctuations and the magnitudes of the subsequent sensory-evoked responses were observed. However, different correlations between the size of the pre-stimulus fluctuations and magnitudes of the subsequent sensory-evoked cortical hemodynamic responses could be observed depending on their phase at stimulus onset. These analyses suggest that both the size and phase of pre-stimulus fluctuations in cortical hemodynamics contribute to inter-trial variability in sensory-evoked responses

Linear superposition of sensory-evoked and ongoing cortical hemodynamics.

Modern non-invasive brain imaging techniques utilize changes in cerebral blood flow, volume and oxygenation that accompany brain activation. However, stimulus-evoked hemodynamic responses display considerable inter-trial variability even when identical stimuli are presented and the sources of this variability are poorly understood. One of the sources of this response variation could be ongoing spontaneous hemodynamic fluctuations. To investigate this issue, 2-dimensional optical imaging spectroscopy was used to measure cortical hemodynamics in response to sensory stimuli in anesthetized rodents. Pre-stimulus cortical hemodynamics displayed spontaneous periodic fluctuations and as such, data from individual stimulus presentation trials were assigned to one of four groups depending on the phase angle of pre-stimulus hemodynamic fluctuations and averaged. This analysis revealed that sensory evoked cortical hemodynamics displayed distinctive response characteristics and magnitudes depending on the phase angle of ongoing fluctuations at stimulus onset. To investigate the origin of this phenomenon, "null-trials" were collected without stimulus presentation. Subtraction of phase averaged "null trials" from their phase averaged stimulus-evoked counterparts resulted in four similar time series that resembled the mean stimulus-evoked response. These analyses suggest that linear superposition of evoked and ongoing cortical hemodynamic changes may be a property of the structure of inter-trial variability

L'RRK de Triomphe: a solution for LRRK2 GTPase activity?

Leucine-rich repeat kinase 2 (LRRK2) is a central protein in the pathogenesis of Parkinson's disease (PD), yet its normal function has proved stubbornly hard to elucidate. Even though it remains unclear how pathogenic mutations affect LRRK2 to cause PD, recent findings provide increasing cause for optimism. We summarise here the developing consensus over the effect of pathogenic mutations in the Ras of complex proteins and C-terminal of Roc domains on LRRK2 GTPase activity. This body of work has been greatly reinforced by our own study of the protective R1398H variant contained within the LRRK2 GTPase domain. Collectively, data point towards the pathogenicity of GTP-bound LRRK2 and strengthen a working model for LRRK2 GTPase function as a GTPase activated by dimerisation. Together with the identification of the protective R1398H variant as a valuable control for pathogenic mutations, we have no doubt that these triumphs for the LRRK2 field will accelerate research towards resolving LRRK2 function and towards new treatments for PD

Fly-by-light flight control system technology development plan

The results of a four-month, phased effort to develop a Fly-by-Light Technology Development Plan are documented. The technical shortfalls for each phase were identified and a development plan to bridge the technical gap was developed. The production configuration was defined for a 757-type airplane, but it is suggested that the demonstration flight be conducted on the NASA Transport Systems Research Vehicle. The modifications required and verification and validation issues are delineated in this report. A detailed schedule for the phased introduction of fly-by-light system components has been generated. It is concluded that a fiber-optics program would contribute significantly toward developing the required state of readiness that will make a fly-by-light control system not only cost effective but reliable without mitigating the weight and high-energy radio frequency related benefits

Coupling between gamma-band power and cerebral blood volume during recurrent acute neocortical seizures

Characterization of neural and hemodynamic biomarkers of epileptic activity that can be measured using non-invasive techniques is fundamental to the accurate identification of the epileptogenic zone (EZ) in the clinical setting. Recently, oscillations at gamma-band frequencies and above (>30 Hz) have been suggested to provide valuable localizing information of the EZ and track cortical activation associated with epileptogenic processes. Although a tight coupling between gamma-band activity and hemodynamic-based signals has been consistently demonstrated in non-pathological conditions, very little is known about whether such a relationship is maintained in epilepsy and the laminar etiology of these signals. Confirmation of this relationship may elucidate the underpinnings of perfusion-based signals in epilepsy and the potential value of localizing the EZ using hemodynamic correlates of pathological rhythms. Here, we use concurrent multi-depth electrophysiology and 2-dimensional optical imaging spectroscopy to examine the coupling between multi-band neural activity and cerebral blood volume (CBV) during recurrent acute focal neocortical seizures in the urethane-anesthetized rat. We show a powerful correlation between gamma-band power (25-90 Hz) and CBV across cortical laminae, in particular layer 5, and a close association between gamma measures and multi-unit activity (MUA). Our findings provide insights into the laminar electrophysiological basis of perfusion-based imaging signals in the epileptic state and may have implications for further research using non-invasive multi-modal techniques to localize epileptogenic tissue

Vascular Origins of BOLD and CBV fMRI Signals: Statistical Mapping and Histological Sections Compared

Comparison of 3T blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) activation maps to histological sections enables the spatial discrimination of functional magnetic resonance imaging (fMRI) signal changes into different vascular compartments. We use a standard gradient echo–echo planar imaging technique to measure BOLD signal changes in the somatosensory cortex in response to whisker stimulation. Corresponding changes in CBV were estimated following the infusion of a super-paramagnetic contrast agent. We imaged in a tangential imaging plane that covered the cortical surface. Images were associated with post mortem histological sections showing both the surface vasculature and cytochrome oxidase stained whisker barrel cortex. We found a significant BOLD signal change in the large draining veins which occurred in the absence of a corresponding CBV change. Results suggest that in the venous drainage system, ~3mm distant from the area of activity, there is a robust change in blood oxygen saturation with little or no volume change. CBV changes are localised over the somatosensory barrel cortex and overlying arterial supply, supporting the theory that CBV changes are greater in the arterial than in the venous vasculature. This work investigating BOLD signal and underlying hemodynamics provides more information on the vascular origins of these important neuroimaging signals

A Bird’s Eye View of Human Language Evolution

Comparative studies of linguistic faculties in animals pose an evolutionary paradox: language involves certain perceptual and motor abilities, but it is not clear that this serves as more than an input–output channel for the externalization of language proper. Strikingly, the capability for auditory–vocal learning is not shared with our closest relatives, the apes, but is present in such remotely related groups as songbirds and marine mammals. There is increasing evidence for behavioral, neural, and genetic similarities between speech acquisition and birdsong learning. At the same time, researchers have applied formal linguistic analysis to the vocalizations of both primates and songbirds. What have all these studies taught us about the evolution of language? Is the comparative study of an apparently species-specific trait like language feasible? We argue that comparative analysis remains an important method for the evolutionary reconstruction and causal analysis of the mechanisms underlying language. On the one hand, common descent has been important in the evolution of the brain, such that avian and mammalian brains may be largely homologous, particularly in the case of brain regions involved in auditory perception, vocalization, and auditory memory. On the other hand, there has been convergent evolution of the capacity for auditory–vocal learning, and possibly for structuring of external vocalizations, such that apes lack the abilities that are shared between songbirds and humans. However, significant limitations to this comparative analysis remain. While all birdsong may be classified in terms of a particularly simple kind of concatenation system, the regular languages, there is no compelling evidence to date that birdsong matches the characteristic syntactic complexity of human language, arising from the composition of smaller forms like words and phrases into larger ones

How Could Language Have Evolved?

The evolution of the faculty of language largely remains an enigma. In this essay, we ask why. Language's evolutionary analysis is complicated because it has no equivalent in any nonhuman species. There is also no consensus regarding the essential nature of the language “phenotype.” According to the “Strong Minimalist Thesis,” the key distinguishing feature of language (and what evolutionary theory must explain) is hierarchical syntactic structure. The faculty of language is likely to have emerged quite recently in evolutionary terms, some 70,000–100,000 years ago, and does not seem to have undergone modification since then, though individual languages do of course change over time, operating within this basic framework. The recent emergence of language and its stability are both consistent with the Strong Minimalist Thesis, which has at its core a single repeatable operation that takes exactly two syntactic elements a and b and assembles them to form the set {a, b}

Language: UG or Not to Be, That Is the Question

Lieberman’s commentary [1] nicely illustrates our original argument [2] that analysis of language evolution is complicated by a lack of agreement about the concepts of both “language” and “evolution.” Here we address each in turn. First, Lieberman argues against the existence of a language faculty in the sense in which we defined it: a domain- and species-specific computational cognitive system that can generate arbitrarily complex hierarchical syntactic structure. In contrast, Lieberman defines language functionally, as a means of “communication,” with human speech as a “key attribute.” However, as we originally argued [2], while externalized language may be used for communication, the two cannot be equated. Language is a computational operation occurring in the mind of an individual, independent of its possible communicative use, while speech is one possible externalization of language (among others such as sign) and is not an essential aspect of it. Lieberman’s arguments are a prime example of fallaciously confounding the function(s) of a trait with its mechanism [3,4]

Decreased Haemodynamic Response and Decoupling of Cortical Gamma Band Activity and Tissue Oxygen Perfusion after Striatal Interleukin-1 Injection.

Background: Neurovascular coupling describes the mechanism by which the energy and oxygen demand arising from neuronal activity is met by an increase in regional blood flow; known as the haemodynamic response. Interleukin 1 (IL-1) is a pro-inflammatory cytokine and an important mediator of neuronal injury, though mechanisms through which IL-1 exerts its effects in the brain are not fully understood. In this study we set out to investigate if increased cerebral levels of IL-1 have a negative effect on neurovascular coupling in the cortex in response to sensory stimulation. Methods: We used two approaches to measure the neuronal activity and haemodynamic changes in the anaesthetised rat barrel somatosensory cortex in response to mechanical whisker stimulation, before and for 6 h after intrastriatal injection of interleukin-1β or vehicle. First, we used two dimensional optical imaging spectroscopy (2D-OIS) to measure the size of the functional haemodynamic response, indicated by changes of oxyhaemoglobin (HbO2) and total haemoglobin (HbT) concentration. In the same animals immunostaining of immunoglobulin G and SJC-positive extravasated neutrophils was used to confirm the pro-inflammatory effects of IL-1β. Second, to examine the functional coupling between neuronal activity and the haemodynamic response, we used a ‘Clark-style’ electrode combined with a single sharp electrode to simultaneously record local tissue oxygenation (pO2) in layer IV/V of the stimulated barrel cortex and multi-unit activity (MUA) together with local field potentials (LFPs) respectively. Results: 2D-OIS data revealed that the size of the haemodynamic response to mechanical whisker stimulation declined over the 6 h following IL-1β injection whereas the vehicle group remained stable, significant differences being seen after 5 h. Moreover, the size of the transient increases of neuronal LFP activity in response to whisker stimulation decreased after IL-1β injection, significant changes compared to vehicle being seen for gamma-band activity after 1 h and beta-bandactivity after 3 h. The amplitude of the functional pO2 response similarly decreased after 3 h post IL-1β injection, whereas IL-1β had no significant effect on the peak of whisker-stimulation-induced MUA. The stimulation-evoked increases in gamma power and pO2 correlated significantly throughout the 6 h in the vehicle group, but such a correlation was not observed in the IL-1β-injected group. Conclusions: We conclude that intrastriatal IL-1β decouples cortical neuronal activity from its haemodynamic response. This finding may have implications for neurological conditions where IL-1β plays a part, especially those involving reductions in cerebral blood flow (such as stroke)