Matthew Magnuson

Infraslow LFP correlates to resting-state fMRI BOLD signals

The slow fluctuations of the blood-oxygenation-level dependent (BOLD) signal in resting-state fMRI are widely utilized as a surrogate marker of ongoing neural activity. Spontaneous neural activity includes a broad range of frequencies, from infraslow (<0.5 Hz) fluctuations to fast action potentials. Recent studies have demonstrated a correlative relationship between the BOLD fluctuations and power modulations of the local field potential (LFP), particularly in the gamma band. However, the relationship between the BOLD signal and the infraslow components of the LFP, which are directly comparable in frequency to the BOLD fluctuations, has not been directly investigated. Here we report a first examination of the temporal relation between the resting-state BOLD signal and infraslow LFPs using simultaneous fMRI and full-band LFP recording in rat. The spontaneous BOLD signal at the recording sites exhibited significant localized correlation with the infraslow LFP signals as well as with the slow power modulations of higher-frequency LFPs (1-100 Hz) at a delay comparable to the hemodynamic response time under anesthesia. Infraslow electrical activity has been postulated to play a role in attentional processes, and the findings reported here suggest that infraslow LFP coordination may share a mechanism with the large-scale BOLD-based networks previously implicated in task performance, providing new insight into the mechanisms contributing to the resting state fMRI signal.

Comparison of α-chloralose, medetomidine and isoflurane anesthesia for functional connectivity mapping in the rat

Functional connectivity measures based upon low-frequency blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) signal fluctuations have become a widely used tool for investigating spontaneous brain activity in humans. Still unknown, however, is the precise relationship between neural activity, the hemodynamic response and fluctuations in the MRI signal. Recent work from several groups had shown that correlated low-frequency fluctuations in the BOLD signal can be detected in the anesthetized rat - a first step toward elucidating this relationship. Building on this preliminary work, through this study, we demonstrate that functional connectivity observed in the rat depends strongly on the type of anesthesia used. Power spectra of spontaneous fluctuations and the cross-correlation-based connectivity maps from rats anesthetized with alpha-chloralose, medetomidine or isoflurane are presented using a high-temporal-resolution imaging sequence that ensures minimal contamination from physiological noise. The results show less localized correlation in rats anesthetized with isoflurane as compared with rats anesthetized with alpha-chloralose or medetomidine. These experiments highlight the utility of using different types of anesthesia to explore the fundamental physiological relationships of the BOLD signal and suggest that the mechanisms contributing to functional connectivity involve a complicated relationship between changes in neural activity, neurovascular coupling and vascular reactivity.

Spatiotemporal dynamics of low frequency fluctuations in BOLD fMRI of the rat

To examine spatiotemporal dynamics of low frequency fluctuations in rat cortex.

Dynamic Properties of Functional Connectivity in the Rodent

Functional connectivity mapping with resting-state magnetic resonance imaging (MRI) has become an immensely powerful technique that provides insight into both normal cognitive function and disruptions linked to neurological disorders. Traditionally, connectivity is mapped using data from an entire scan (minutes), but it is well known that cognitive processes occur on much shorter time scales (seconds). Recent studies have demonstrated that the correlation between the blood oxygenation level-dependent (BOLD) MRI signal from different areas varies over time, motivating a further exploration of these fluctuations in apparent connectivity. However, it has also been shown that similar changes in correlation can arise when the timing relationships between voxels are randomized (Handwerker et al., 2012 ). In this work, we show that functional connectivity in the anesthetized rat exhibits dynamic properties that are similar to those previously observed in awake humans (Chang and Glover, 2010 ) and anesthetized monkeys (Hutchison et al., 2012 ). Sliding window correlation between BOLD time courses obtained from bilateral cortical and subcortical regions of interest results in periods of variable positive and negative correlation for most pairs of areas except homologous areas in opposite hemispheres, which exhibit a primarily positive correlation. A comparison with sliding window correlation of randomly matched time courses suggests that with the exception of homologous areas and sensorimotor connections, the dynamics cannot be distinguished from random fluctuations in correlation over time, supporting the idea that some of these dynamic patterns may be due to inherent properties of the signal rather than variations in neural coherence. Within the pairs of areas where the dynamics are most different from those of randomly matched time courses, ten common patterns of connectivity are identified, and their occurrence as a function of time is plotted for all animals. The observation of time-varying correlation in the rodent model will facilitate the future multimodal experiments needed to determine whether the changes in apparent connectivity are linked to underlying neural variability.

Neural correlates of time-varying functional connectivity in the rat

Functional connectivity between brain regions, measured with resting state functional magnetic resonance imaging, holds great potential for understanding the basis of behavior and neuropsychiatric diseases. Recently it has become clear that correlations between the blood oxygenation level dependent (BOLD) signals from different areas vary over the course of a typical scan (6-10 min in length), though the changes are obscured by standard methods of analysis that assume the relationships are stationary. Unfortunately, because similar variability is observed in signals that share no temporal information, it is unclear which dynamic changes are related to underlying neural events. To examine this question, BOLD data were recorded simultaneously with local field potentials (LFP) from interhemispheric primary somatosensory cortex (SI) in anesthetized rats. LFP signals were converted into band-limited power (BLP) signals including delta, theta, alpha, beta and gamma. Correlation between signals from interhemispheric SI was performed in sliding windows to produce signals of correlation over time for BOLD and each BLP band. Both BOLD and BLP signals showed large changes in correlation over time and the changes in BOLD were significantly correlated to the changes in BLP. The strongest relationship was seen when using the theta, beta and gamma bands. Interestingly, while steady-state BOLD and BLP correlate with the global fMRI signal, dynamic BOLD becomes more like dynamic BLP after the global signal is regressed. As BOLD sliding window connectivity is partially reflecting underlying LFP changes, the present study suggests it may be a valuable method of studying dynamic changes in brain states.

Broadband Local Field Potentials Correlate with Spontaneous Fluctuations in Functional Magnetic Resonance Imaging Signals in the Rat Somatosensory Cortex Under Isoflurane Anesthesia

Resting-state functional magnetic resonance imaging (fMRI) is widely used for exploring spontaneous brain activity and large-scale networks; however, the neural processes underlying the observed resting-state fMRI signals are not fully understood. To investigate the neural correlates of spontaneous low-frequency fMRI fluctuations and functional connectivity, we developed a rat model of simultaneous fMRI and multiple-site intracortical neural recordings. This allowed a direct comparison to be made between the spontaneous signals and interhemispheric connectivity measured with the two modalities. Results show that low-frequency blood oxygen level-dependent (BOLD) fluctuations (<0.1 Hz) correlate significantly with slow power modulations (<0.1 Hz) of local field potentials (LFPs) in a broad frequency range (1-100 Hz) under isoflurane anesthesia (1%-1.8%). Peak correlation occurred between neural and hemodynamic activity when the BOLD signal was delayed by ~4 sec relative to the LFP signal. The spatial location and extent of correlation was highly reproducible across studies, with the maximum correlation localized to a small area surrounding the site of microelectrode recording and to the homologous area in the contralateral hemisphere for most rats. Interhemispheric connectivity was calculated using BOLD correlation and band-limited LFP (1-4, 4-8, 8-14, 14-25, 25-40, and 40-100 Hz) coherence. Significant coherence was observed for the slow power changes of all LFP frequency bands as well as in the low-frequency BOLD data. A preliminary investigation of the effect of anesthesia on interhemispheric connectivity indicates that coherence in the high-frequency LFP bands declines with increasing doses of isoflurane, whereas coherence in the low-frequency LFP bands and the BOLD signal increases. These findings suggest that resting-state fMRI signals might be a reflection of broadband LFP power modulation, at least in isoflurane-anesthetized rats.

Quasi-periodic patterns (QPP): Large-scale dynamics in resting state fMRI that correlate with local infraslow electrical activity

Functional connectivity measurements from resting state blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) are proving a powerful tool to probe both normal brain function and neuropsychiatric disorders. However, the neural mechanisms that coordinate these large networks are poorly understood, particularly in the context of the growing interest in network dynamics. Recent work in anesthetized rats has shown that the spontaneous BOLD fluctuations are tightly linked to infraslow local field potentials (LFPs) that are seldom recorded but comparable in frequency to the slow BOLD fluctuations. These findings support the hypothesis that long-range coordination involves low frequency neural oscillations and establishes infraslow LFPs as an excellent candidate for probing the neural underpinnings of the BOLD spatiotemporal patterns observed in both rats and humans. To further examine the link between large-scale network dynamics and infraslow LFPs, simultaneous fMRI and microelectrode recording were performed in anesthetized rats. Using an optimized filter to isolate shared components of the signals, we found that time-lagged correlation between infraslow LFPs and BOLD is comparable in spatial extent and timing to a quasi-periodic pattern (QPP) found from BOLD alone, suggesting that fMRI-measured QPPs and the infraslow LFPs share a common mechanism. As fMRI allows spatial resolution and whole brain coverage not available with electroencephalography, QPPs can be used to better understand the role of infraslow oscillations in normal brain function and neurological or psychiatric disorders.

Functional connectivity in blood oxygenation level-dependent and cerebral blood volume-weighted resting state functional magnetic resonance imaging in the rat brain

To directly compare functional connectivity and spatiotemporal dynamics acquired with blood oxygenation level‐dependent (BOLD) and cerebral blood volume (CBV)‐weighted functional magnetic resonance imaging (fMRI) in anesthetized rats.

Time-dependent effects of isoflurane and dexmedetomidine on functional connectivity, spectral characteristics, and spatial distribution of spontaneous BOLD fluctuations.

Anesthesia is often necessary to perform fMRI experiments in the rodent model; however, commonly used anesthetic protocols may manifest changing brain conditions over the duration of the study. This possibility was explored in the current work. Eleven rats were anesthetized with 2% isoflurane anesthesia; four rats were anesthetized for a short period (30 min, simulating induction and fMRI setup) and seven rats were anesthetized for a long period (3 h, simulating surgical preparation). Following the initial anesthetic period, isoflurane was discontinued, and a dexmedetomidine bolus (0.025 mg/kg) and continuous subcutaneous infusion (0.05 mg/kg/h) were administered. Blood‐oxygen‐level dependent resting state imaging was performed every 30 min from 0.75 h post dexmedetomidine bolus until 5.75 h post‐bolus. Evaluation of power spectra obtained from time courses in the primary somatosensory cortex revealed, in general, a monotonic increase in low‐frequency power (0.05–0.3 Hz) in both groups over the duration of resting state imaging. Greater low‐band spectral power (0.05–0.15 Hz) is present in the short isoflurane group for the first 2.75 h, but the spectra become highly uniform at 3.25 h. The emergence of a ~0.18 Hz peak, beginning at the 3.75 h time point, exists in both groups and evolves similarly, increasing in strength as the duration of dexmedetomidine sedation (and time since isoflurane cessation) extends. In the long isoflurane group only, bilateral functional connectivity strengthens with anesthetic duration, and correlation is linearly linked to low‐band spectral power. Convergence of connectivity and spectral metrics between the short and long isoflurane groups occurs at ~3.25 h, suggesting the effects of isoflurane have subsided. Researchers using dexmedetomidine following isoflurane for functional studies should be aware of the duration specific effects of the pre‐scan isoflurane durations as well as the continuing influences of long‐term imaging under dexmedetomidine. Copyright

A DTI Tractography analysis of Infralimbic and Prelimbic Connectivity in the Mouse using High-throughput MRI

BACKGROUND High throughput, brain-wide analysis of neural circuit connectivity is needed to understand brain function across species. Combining such tractography techniques with small animal models will allow more rapid integration of systems neuroscience with molecular genetic, behavioral, and cellular approaches. METHODS We collected DTI and T2 scans on 3 series of 6 fixed mouse brains ex vivo in a 9.4 Tesla magnet. The DTI analysis of ten mouse brains focused on comparing prelimbic (PL) and Infralimbic (IL) probabilistic tractography. To validate the DTI results a preliminary set of 24 additional mice were injected with BDA into the IL and PL. The DTI results and preliminary BDA results were also compared to previously published rat connectivity. RESULTS We focused our analyses on the connectivity of the mouse prelimbic (PL) vs. infralimbic (IL) cortices. We demonstrated that this DTI analysis is consistent across scanned mice, with prior analyses of rat IL/PL connectivity, and with mouse PL and IL projections using the BDA tracer. CONCLUSIONS High-throughput ex vivo DTI imaging in the mouse delineated both common and differential connectivity of the IL and PL cortex. The scanning methodology provided a balance of tissue contrast, signal-to-noise ratio, resolution and throughput. Our results are largely consistent with previously published anterograde staining techniques in rats, and the preliminary tracer study of the mouse IL and PL provided here.