Cortical Networks Relating to Arousal Are Differentially Coupled to Neural Activity and Hemodynamics.

Even in the absence of specific sensory input or a behavioral task, the brain produces structured patterns of activity. This organized activity is modulated by changes in arousal. Here, we use wide-field voltage imaging to establish how arousal relates to cortical network voltage and hemodynamic activity in spontaneously behaving head-fixed male and female mice expressing the voltage-sensitive fluorescent FRET sensor Butterfly 1.2. We find that global voltage and hemodynamic signals are both positively correlated with changes in arousal with a maximum correlation of 0.5 and 0.25, respectively, at a time lag of 0 s. We next show that arousal influences distinct cortical regions for both voltage and hemodynamic signals. These include a broad positive correlation across most sensory-motor cortices extending posteriorly to the primary visual cortex observed in both signals. In contrast, activity in the prefrontal cortex is positively correlated to changes in arousal for the voltage signal while it is a slight net negative correlation observed in the hemodynamic signal. Additionally, we show that coherence between voltage and hemodynamic signals relative to arousal is strongest for slow frequencies below 0.15 Hz and is near zero for frequencies >1 Hz. We finally show that coupling patterns are dependent on the behavioral state of the animal with correlations being driven by periods of increased orofacial movement. Our results indicate that while hemodynamic signals show strong relations to behavior and arousal, these relations are distinct from those observed by voltage activity.

Resting-state MRI reveals spontaneous physiological fluctuations in the kidney and tracks diabetic nephropathy in rats.

The kidneys maintain fluid-electrolyte balance and excrete waste in the presence of constant fluctuations in plasma volume and systemic blood pressure. The kidneys perform these functions to control capillary perfusion and glomerular filtration by modulating the mechanisms of autoregulation. An effect of these modulations are spontaneous, natural fluctuations in glomerular perfusion. Numerous other mechanisms can lead to fluctuations in perfusion and flow. The ability to monitor these spontaneous physiological fluctuations in vivo could facilitate the early detection of kidney disease. The goal of this work was to investigate the use of resting-state magnetic resonance imaging (rsMRI) to detect spontaneous physiological fluctuations in the kidney. We performed rsMRI of rat kidneys in vivo over 10 min, applying motion correction to resolve time series in each voxel. We observed spatially variable, spontaneous fluctuations in rsMRI signal between 0 and 0.3 Hz, in frequency bands associated with autoregulatory mechanisms. We further applied rsMRI to investigate changes in these fluctuations in a rat model of diabetic nephropathy. Spectral analysis was performed on time series of rsMRI signals in the kidney cortex and medulla. The power from spectra in specific frequency bands from the cortex correlated with severity of glomerular pathology caused by diabetic nephropathy. Finally, we investigated the feasibility of using rsMRI of the human kidney in two participants, observing the presence of similar, spatially variable fluctuations. This approach may enable a range of preclinical and clinical investigations of kidney function and facilitate the development of new therapies to improve outcomes in patients with kidney disease.NEW & NOTEWORTHY This work demonstrates the development and use of resting-state MRI to detect low-frequency, spontaneous physiological fluctuations in the kidney consistent with previously observed fluctuations in perfusion and potentially due to autoregulatory function. These fluctuations are detectable in rat and human kidneys, and the power of these fluctuations is affected by diabetic nephropathy in rats.

Time-varying functional connectivity predicts fluctuations in sustained attention in a serial tapping task.

The mechanisms for how large-scale brain networks contribute to sustained attention are unknown. Attention fluctuates from moment to moment, and this continuous change is consistent with dynamic changes in functional connectivity between brain networks involved in the internal and external allocation of attention. In this study, we investigated how brain network activity varied across different levels of attentional focus (i.e., "zones"). Participants performed a finger-tapping task, and guided by previous research, in-the-zone performance or state was identified by low reaction time variability and out-of-the-zone as the inverse. In-the-zone sessions tended to occur earlier in the session than out-of-the-zone blocks. This is unsurprising given the way attention fluctuates over time. Employing a novel method of time-varying functional connectivity, called the quasi-periodic pattern analysis (i.e., reliable, network-level low-frequency fluctuations), we found that the activity between the default mode network (DMN) and task positive network (TPN) is significantly more anti-correlated during in-the-zone states versus out-of-the-zone states. Furthermore, it is the frontoparietal control network (FPCN) switch that differentiates the two zone states. Activity in the dorsal attention network (DAN) and DMN were desynchronized across both zone states. During out-of-the-zone periods, FPCN synchronized with DMN, while during in-the-zone periods, FPCN switched to synchronized with DAN. In contrast, the ventral attention network (VAN) synchronized more closely with DMN during in-the-zone periods compared with out-of-the-zone periods. These findings demonstrate that time-varying functional connectivity of low frequency fluctuations across different brain networks varies with fluctuations in sustained attention or other processes that change over time.

WITHDRAWN: The interaction between random and systematic visual stimulation and infraslow quasiperiodic spatiotemporal patterns of whole brain activity.

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Spatial and Spectral Components of the BOLD Global Signal in Rat Resting-State Functional MRI.

PURPOSE: In resting-state fMRI (rs-fMRI), the global signal average captures widespread fluctuations related to unwanted sources of variance such as motion and respiration, as well as widespread neural activity; however, relative contributions of neural and non-neural sources to the global signal remain poorly understood. This study sought to tackle this problem through the comparison of the BOLD global signal to an adjacent non-brain tissue signal, where neural activity was absent, from the same rs-fMRI scan obtained from anesthetized rats. In this dataset, motion was minimal and ventilation was phase-locked to image acquisition to minimize respiratory fluctuations. Data were acquired using three different anesthetics: isoflurane, dexmedetomidine, and a combination of dexmedetomidine and light isoflurane. METHODS: A power spectral density estimate, a voxel-wise spatial correlation via Pearson's correlation, and a co-activation pattern analysis were performed using the global signal and the non-brain tissue signal. Functional connectivity was calculated using Pearson's linear correlation on default mode network (DMN) regions. RESULTS: We report differences in the spectral composition of the two signals and show spatial selectivity within DMN structures that show an increased correlation to the global signal and decreased intra-network connectivity after global signal regression. All of the observed differences between the global signal and the non-brain tissue signal were maintained across anesthetics. CONCLUSION: These results show that the global signal is distinct from the noise contained in the tissue signal, as support for a neural contribution. This study provides a unique perspective to the contents of the global signal and their origins.

Resting Brain Fluctuations Are Intrinsically Coupled to Visual Response Dynamics.

How do intrinsic brain dynamics interact with processing of external sensory stimuli? We sought new insights using functional magnetic resonance imaging to track spatiotemporal activity patterns at the whole brain level in lightly anesthetized mice, during both resting conditions and visual stimulation trials. Our results provide evidence that quasiperiodic patterns (QPPs) are the most prominent component of mouse resting brain dynamics. These QPPs captured the temporal alignment of anticorrelation between the default mode (DMN)- and task-positive (TPN)-like networks, with global brain fluctuations, and activity in neuromodulatory nuclei of the reticular formation. Specifically, the phase of QPPs prior to stimulation could significantly stratify subsequent visual response magnitude, suggesting QPPs relate to brain state fluctuations. This is the first observation in mice that dynamics of the DMN- and TPN-like networks, and particularly their anticorrelation, capture a brain state dynamic that affects sensory processing. Interestingly, QPPs also displayed transient onset response properties during visual stimulation, which covaried with deactivations in the reticular formation. We conclude that QPPs appear to capture a brain state fluctuation that may be orchestrated through neuromodulation. Our findings provide new frontiers to understand the neural processes that shape functional brain states and modulate sensory input processing.

Propagating patterns of intrinsic activity along macroscale gradients coordinate functional connections across the whole brain.

The intrinsic activity of the human brain, observed with resting-state fMRI (rsfMRI) and functional connectivity, exhibits macroscale spatial organization such as functional networks and gradients. Dynamic analysis techniques have shown that functional connectivity is a mere summary of time-varying patterns with distinct spatial and temporal characteristics. A better understanding of these patterns might provide insight into aspects of the brain's intrinsic activity that cannot be inferred by functional connectivity or the spatial maps derived from it, such as functional networks and gradients. Here, we describe three spatiotemporal patterns of coordinated activity across the whole brain obtained by averaging similar ~20-second-long segments of rsfMRI timeseries. In each of these patterns, activity propagates along a particular macroscale functional gradient, simultaneously across the cerebral cortex and in most other brain regions. In some regions, like the thalamus, the propagation suggests previously-undescribed gradients. The coordinated activity across areas is consistent with known tract-based connections, and nuanced differences in the timing of peak activity between regions point to plausible driving mechanisms. The magnitude of correlation within and particularly between functional networks is remarkably diminished when these patterns are regressed from the rsfMRI timeseries, a quantitative demonstration of their significant role in functional connectivity. Taken together, our results suggest that a few recurring patterns of propagating intrinsic activity along macroscale gradients give rise to and coordinate functional connections across the whole brain.

Spatiotemporal trajectories in resting-state FMRI revealed by convolutional variational autoencoder.

Recent resting-state fMRI studies have shown that brain activity exhibits temporal variations in functional connectivity by using various approaches including sliding window correlation, co-activation patterns, independent component analysis, quasi-periodic patterns, and hidden Markov models. These methods often model the brain activity as a discretized hopping among several brain states that are defined by the spatial configurations of network activity. However, the discretized states are merely a simplification of what is likely to be a continuous process, where each network evolves over time following its unique path. To model these characteristic spatiotemporal trajectories, we trained a variational autoencoder using rs-fMRI data and evaluated the spatiotemporal features of the latent variables obtained from the trained networks. Our results suggest that there are a relatively small number of approximately orthogonal whole-brain spatiotemporal patterns that capture the most prominent features of rs-fMRI data, which can serve as the building blocks to construct all possible spatiotemporal dynamics in resting state fMRI. These spatiotemporal patterns provide insight into how activity flows across the brain in concordance with known network structures and functional connectivity gradients.

Spatiotemporal functional interactivity among large-scale brain networks.

The macro-scale intrinsic functional network architecture of the human brain has been well characterized. Early studies revealed robust and enduring patterns of static connectivity, while more recent work has begun to explore the temporal dynamics of these large-scale brain networks. Little work to date has investigated directed connectivity within and between these networks, or the temporal patterns of afferent (input) and efferent (output) connections between network nodes. Leveraging a novel analytic approach, prediction correlation, we investigated the causal interactions within and between large-scale networks of the brain using resting state fMRI. This technique allows us to characterize information transfer between brain regions in both the spatial (direction) and temporal (duration) scales. Using data from the Human Connectome Project (N = 200) we applied prediction correlation techniques to four resting-state fMRI scans (each scan has TRs = 1200). Three central observations emerged. First, the strongest and longest duration connections were observed within the somatomotor, visual, and dorsal attention networks. Second, the short duration connections were observed for high-degree nodes in the visual and default networks, as well as in the hippocampus. Specifically, the connectivity profile of the highest-degree nodes was dominated by efferent connections to multiple cortical areas. Moderate high-degree nodes, particularly in hippocampal regions, showed an afferent connectivity profile. Finally, multimodal association nodes in lateral prefrontal brain regions demonstrated a short duration, bidirectional connectivity profile, consistent with this region's role in integrative and modulatory processing. These results provide novel insights into the spatiotemporal dynamics of human brain function.

Contribution of animal models toward understanding resting state functional connectivity.

Functional connectivity, which reflects the spatial and temporal organization of intrinsic activity throughout the brain, is one of the most studied measures in human neuroimaging research. The noninvasive acquisition of resting state functional magnetic resonance imaging (rs-fMRI) allows the characterization of features designated as functional networks, functional connectivity gradients, and time-varying activity patterns that provide insight into the intrinsic functional organization of the brain and potential alterations related to brain dysfunction. Functional connectivity, hence, captures dimensions of the brain's activity that have enormous potential for both clinical and preclinical research. However, the mechanisms underlying functional connectivity have yet to be fully characterized, hindering interpretation of rs-fMRI studies. As in other branches of neuroscience, the identification of the neurophysiological processes that contribute to functional connectivity largely depends on research conducted on laboratory animals, which provide a platform where specific, multi-dimensional investigations that involve invasive measurements can be carried out. These highly controlled experiments facilitate the interpretation of the temporal correlations observed across the brain. Indeed, information obtained from animal experimentation to date is the basis for our current understanding of the underlying basis for functional brain connectivity. This review presents a compendium of some of the most critical advances in the field based on the efforts made by the animal neuroimaging community.

The relationship between BOLD and neural activity arises from temporally sparse events.

Resting state functional magnetic resonance (rs-fMRI) imaging offers insights into how different brain regions are connected into functional networks. It was recently shown that networks that are almost identical to the ones created from conventional correlation analysis can be obtained from a subset of high-amplitude data, suggesting that the functional networks may be driven by instantaneous co-activations of multiple brain regions rather than ongoing oscillatory processes. The rs-fMRI studies, however, rely on the blood oxygen level dependent (BOLD) signal, which is only indirectly sensitive to neural activity through neurovascular coupling. To provide more direct evidence that the neuronal co-activation events produce the time-varying network patterns seen in rs-fMRI studies, we examined the simultaneous rs-fMRI and local field potential (LFP) recordings in rats performed in our lab over the past several years. We developed complementary analysis methods that focus on either the temporal or spatial domain, and found evidence that the interaction between LFP and BOLD may be driven by instantaneous co-activation events as well. BOLD maps triggered on high-amplitude LFP events resemble co-activation patterns created from rs-fMRI data alone, though the co-activation time points are defined differently in the two cases. Moreover, only LFP events that fall into the highest or lowest thirds of the amplitude distribution result in a BOLD signal that can be distinguished from noise. These findings provide evidence of an electrophysiological basis for the time-varying co-activation patterns observed in previous studies.

Quasi-periodic patterns contribute to functional connectivity in the brain.

Functional connectivity is widely used to study the coordination of activity between brain regions over time. Functional connectivity in the default mode and task positive networks is particularly important for normal brain function. However, the processes that give rise to functional connectivity in the brain are not fully understood. It has been postulated that low-frequency neural activity plays a key role in establishing the functional architecture of the brain. Quasi-periodic patterns (QPPs) are a reliably observable form of low-frequency neural activity that involve the default mode and task positive networks. Here, QPPs from resting-state and working memory task-performing individuals were acquired. The spatiotemporal pattern, strength, and frequency of the QPPs between the two groups were compared and the contribution of QPPs to functional connectivity in the brain was measured. In task-performing individuals, the spatiotemporal pattern of the QPP changes, particularly in task-relevant regions, and the QPP tends to occur with greater strength and frequency. Differences in the QPPs between the two groups could partially account for the variance in functional connectivity between resting-state and task-performing individuals. The QPPs contribute strongly to connectivity in the default mode and task positive networks and to the strength of anti-correlation seen between the two networks. Many of the connections affected by QPPs are also disrupted during several neurological disorders. These findings contribute to understanding the dynamic neural processes that give rise to functional connectivity in the brain and how they may be disrupted during disease.

Quasi-periodic patterns of intrinsic brain activity in individuals and their relationship to global signal.

Quasiperiodic patterns (QPPs) as reported by Majeed et al., 2011 are prominent features of the brain's intrinsic activity that involve important large-scale networks (default mode, DMN; task positive, TPN) and are likely to be major contributors to widely used measures of functional connectivity. We examined the variability of these patterns in 470 individuals from the Human Connectome Project resting state functional MRI dataset. The QPPs from individuals can be coarsely categorized into two types: one where strong anti-correlation between the DMN and TPN is present, and another where most areas are strongly correlated. QPP type could be predicted by an individual's global signal, with lower global signal corresponding to QPPs with strong anti-correlation. After regression of global signal, all QPPs showed strong anti-correlation between DMN and TPN. QPP occurrence and type was similar between a subgroup of individuals with extremely low motion and the rest of the sample, which shows that motion is not a major contributor to the QPPs. After regression of estimates of slow respiratory and cardiac induced signal fluctuations, more QPPs showed strong anti-correlation between DMN and TPN, an indication that while physiological noise influences the QPP type, it is not the primary source of the QPP itself. QPPs were more similar for the same subjects scanned on different days than for different subjects. These results provide the first assessment of the variability in individual QPPs and their relationship to physiological parameters.

Detection of neural light-scattering activity in vivo: optical transmittance studies in the rat brain.

Optical studies of ex vivo brain slices where blood is absent show that neural activity is accompanied by significant intrinsic optical signals (IOS) related to activity-dependent scattering changes in neural tissue. However, the neural scattering signals have been largely ignored in vivo in widely-used IOS methods where absorption contrast from hemoglobin was employed. Changes in scattering were observed on a time scale of seconds in previous brain slice IOS studies, similar to the time scale for the hemodynamic response. Therefore, potential crosstalk between the scattering and absorption changes may not be ignored if they have comparable contributions to IOS. In vivo, the IOS changes linked to neural scattering have been elusive. To isolate neural scattering signals in vivo, we employed 2 implantable optodes for small-separation (2 mm) transmission measurements of local brain tissue in anesthetized rats. This unique geometry enables us to separate neuronal activity-related changes in neural tissue scattering from changes in blood absorption based upon the direction of the signal change. The changes in IOS scattering and absorption in response to up-states of spontaneous neuronal activity in cortical or subcortical structures have strong correlation to local field potentials, but significantly different response latencies. We conclude that activity-dependent neural tissue scattering in vivo may be an additional source of contrast for functional brain studies that provides complementary information to other optical or MR-based systems that are sensitive to hemodynamic contrast.

Dynamic resting state fMRI analysis in mice reveals a set of Quasi-Periodic Patterns and illustrates their relationship with the global signal.

Time-resolved 'dynamic' over whole-period 'static' analysis of low frequency (LF) blood-oxygen level dependent (BOLD) fluctuations provides many additional insights into the macroscale organization and dynamics of neural activity. Although there has been considerable advancement in the development of mouse resting state fMRI (rsfMRI), very little remains known about its dynamic repertoire. Here, we report for the first time the detection of a set of recurring spatiotemporal Quasi-Periodic Patterns (QPPs) in mice, which show spatial similarity with known resting state networks. Furthermore, we establish a close relationship between several of these patterns and the global signal. We acquired high temporal rsfMRI scans under conditions of low (LA) and high (HA) medetomidine-isoflurane anesthesia. We then employed the algorithm developed by Majeed et al. (2011), previously applied in rats and humans, which detects and averages recurring spatiotemporal patterns in the LF BOLD signal. One type of observed patterns in mice was highly similar to those originally observed in rats, displaying propagation from lateral to medial cortical regions, which suggestively pertain to a mouse Task-Positive like network (TPN) and Default Mode like network (DMN). Other QPPs showed more widespread or striatal involvement and were no longer detected after global signal regression (GSR). This was further supported by diminished detection of subcortical dynamics after GSR, with cortical dynamics predominating. Observed QPPs were both qualitatively and quantitatively determined to be consistent across both anesthesia conditions, with GSR producing the same outcome. Under LA, QPPs were consistently detected at both group and single subject level. Under HA, consistency and pattern occurrence rate decreased, whilst cortical contribution to the patterns diminished. These findings confirm the robustness of QPPs across species and demonstrate a new approach to study mouse LF BOLD spatiotemporal dynamics and mechanisms underlying functional connectivity. The observed impact of GSR on QPPs might help better comprehend its controversial role in conventional resting state studies. Finally, consistent detection of QPPs at single subject level under LA promises a step forward towards more reliable mouse rsfMRI and further confirms the importance of selecting an optimal anesthesia regime.

Noise and non-neuronal contributions to the BOLD signal: applications to and insights from animal studies.

The BOLD signal reflects hemodynamic events within the brain, which in turn are driven by metabolic changes and neural activity. However, the link between BOLD changes and neural activity is indirect and can be influenced by a number of non-neuronal processes. Motion and physiological cycles have long been known to affect the BOLD signal and are present in both humans and animal models. Differences in physiological baseline can also contribute to intra- and inter-subject variability. The use of anesthesia, common in animal studies, alters neural activity, vascular tone, and neurovascular coupling. Most intriguing, perhaps, are the contributions from other processes that do not appear to be neural in origin but which may provide information about other aspects of neurophysiology. This review discusses different types of noise and non-neuronal contributors to the BOLD signal, sources of variability for animal studies, and insights to be gained from animal models.

Instantaneous brain dynamics mapped to a continuous state space.

Measures of whole-brain activity, from techniques such as functional Magnetic Resonance Imaging, provide a means to observe the brain's dynamical operations. However, interpretation of whole-brain dynamics has been stymied by the inherently high-dimensional structure of brain activity. The present research addresses this challenge through a series of scale transformations in the spectral, spatial, and relational domains. Instantaneous multispectral dynamics are first developed from input data via a wavelet filter bank. Voxel-level signals are then projected onto a representative set of spatially independent components. The correlation distance over the instantaneous wavelet-ICA state vectors is a graph that may be embedded onto a lower-dimensional space to assist the interpretation of state-space dynamics. Applying this procedure to a large sample of resting-state and task-active data (acquired through the Human Connectome Project), we segment the empirical state space into a continuum of stimulus-dependent brain states. Upon observing the local neighborhood of brain-states adopted subsequent to each stimulus, we may conclude that resting brain activity includes brain states that are, at times, similar to those adopted during tasks, but that are at other times distinct from task-active brain states. As task-active brain states often populate a local neighborhood, back-projection of segments of the dynamical state space onto the brain's surface reveals the patterns of brain activity that support many experimentally-defined states.

Evaluation of sliding window correlation performance for characterizing dynamic functional connectivity and brain states.

A promising recent development in the study of brain function is the dynamic analysis of resting-state functional MRI scans, which can enhance understanding of normal cognition and alterations that result from brain disorders. One widely used method of capturing the dynamics of functional connectivity is sliding window correlation (SWC). However, in the absence of a "gold standard" for comparison, evaluating the performance of the SWC in typical resting-state data is challenging. This study uses simulated networks (SNs) with known transitions to examine the effects of parameters such as window length, window offset, window type, noise, filtering, and sampling rate on the SWC performance. The SWC time course was calculated for all node pairs of each SN and then clustered using the k-means algorithm to determine how resulting brain states match known configurations and transitions in the SNs. The outcomes show that the detection of state transitions and durations in the SWC is most strongly influenced by the window length and offset, followed by noise and filtering parameters. The effect of the image sampling rate was relatively insignificant. Tapered windows provide less sensitivity to state transitions than rectangular windows, which could be the result of the sharp transitions in the SNs. Overall, the SWC gave poor estimates of correlation for each brain state. Clustering based on the SWC time course did not reliably reflect the underlying state transitions unless the window length was comparable to the state duration, highlighting the need for new adaptive window analysis techniques.

A comparative analysis of mouse and human medial geniculate nucleus connectivity: a DTI and anterograde tracing study.

Understanding the function and connectivity of thalamic nuclei is critical for understanding normal and pathological brain function. The medial geniculate nucleus (MGN) has been studied mostly in the context of auditory processing and its connection to the auditory cortex. However, there is a growing body of evidence that the MGN and surrounding associated areas ('MGN/S') have a diversity of projections including those to the globus pallidus, caudate/putamen, amygdala, hypothalamus, and thalamus. Concomitantly, pathways projecting to the medial geniculate include not only the inferior colliculus but also the auditory cortex, insula, cerebellum, and globus pallidus. Here we expand our understanding of the connectivity of the MGN/S by using comparative diffusion weighted imaging with probabilistic tractography in both human and mouse brains (most previous work was in rats). In doing so, we provide the first report that attempts to match probabilistic tractography results between human and mice. Additionally, we provide anterograde tracing results for the mouse brain, which corroborate the probabilistic tractography findings. Overall, the study provides evidence for the homology of MGN/S patterns of connectivity across species for understanding translational approaches to thalamic connectivity and function. Further, it points to the utility of DTI in both human studies and small animal modeling, and it suggests potential roles of these connections in human cognition, behavior, and disease.