Garth John Thompson

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.

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.

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

Phase-amplitude coupling and infraslow (<1 Hz) frequencies in the rat brain: relationship to resting state fMRI

Resting state functional magnetic resonance imaging (fMRI) can identify network alterations that occur in complex psychiatric diseases and behaviors, but its interpretation is difficult because the neural basis of the infraslow BOLD fluctuations is poorly understood. Previous results link dynamic activity during the resting state to both infraslow frequencies in local field potentials (LFP) (<1 Hz) and band-limited power in higher frequency LFP (>1 Hz). To investigate the relationship between these frequencies, LFPs were recorded from rats under two anesthetics: isoflurane and dexmedetomidine. Signal phases were calculated from low-frequency LFP and compared to signal amplitudes from high-frequency LFP to determine if modulation existed between the two frequency bands (phase-amplitude coupling). Isoflurane showed significant, consistent phase-amplitude coupling at nearly all pairs of frequencies, likely due to the burst-suppression pattern of activity that it induces. However, no consistent phase-amplitude coupling was observed in rats that were anesthetized with dexmedetomidine. fMRI-LFP correlations under isoflurane using high frequency LFP were reduced when the low frequency LFPs influence was accounted for, but not vice-versa, or in any condition under dexmedetomidine. The lack of consistent phase-amplitude coupling under dexmedetomidine and lack of shared variance between high frequency and low frequency LFP as it relates to fMRI suggests that high and low frequency neural electrical signals may contribute differently, possibly even independently, to resting state fMRI. This finding suggests that researchers take care in interpreting the neural basis of resting state fMRI, as multiple dynamic factors in the underlying electrophysiology could be driving any particular observation.

Simultaneous fMRI and Electrophysiology in the Rodent Brain

To examine the neural basis of the blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) signal, we have developed a rodent model in which functional MRI data and in vivo intracortical recording can be performed simultaneously. The combination of MRI and electrical recording is technically challenging because the electrodes used for recording distort the MRI images and the MRI acquisition induces noise in the electrical recording. To minimize the mutual interference of the two modalities, glass microelectrodes were used rather than metal and a noise removal algorithm was implemented for the electrophysiology data. In our studies, two microelectrodes were separately implanted in bilateral primary somatosensory cortices (SI) of the rat and fixed in place. One coronal slice covering the electrode tips was selected for functional MRI. Electrode shafts and fixation positions were not included in the image slice to avoid imaging artifacts. The removed scalp was replaced with toothpaste to reduce susceptibility mismatch and prevent Gibbs ringing artifacts in the images. The artifact structure induced in the electrical recordings by the rapidly-switching magnetic fields during image acquisition was characterized by averaging all cycles of scans for each run. The noise structure during imaging was then subtracted from original recordings. The denoised time courses were then used for further analysis in combination with the fMRI data. As an example, the simultaneous acquisition was used to determine the relationship between spontaneous fMRI BOLD signals and band-limited intracortical electrical activity. Simultaneous fMRI and electrophysiological recording in the rodent will provide a platform for many exciting applications in neuroscience in addition to elucidating the relationship between the fMRI BOLD signal and neuronal activity.

Different dynamic resting state fMRI patterns are linked to different frequencies of neural activity.

Resting state functional magnetic resonance imaging (rsfMRI) results have indicated that network mapping can contribute to understanding behavior and disease, but it has been difficult to translate the maps created with rsfMRI to neuroelectrical states in the brain. Recently, dynamic analyses have revealed multiple patterns in the rsfMRI signal that are strongly associated with particular bands of neural activity. To further investigate these findings, simultaneously recorded invasive electrophysiology and rsfMRI from rats were used to examine two types of electrical activity (directly measured low-frequency/infraslow activity and band-limited power of higher frequencies) and two types of dynamic rsfMRI (quasi-periodic patterns or QPP, and sliding window correlation or SWC). The relationship between neural activity and dynamic rsfMRI was tested under three anesthetic states in rats: dexmedetomidine and high and low doses of isoflurane. Under dexmedetomidine, the lightest anesthetic, infraslow electrophysiology correlated with QPP but not SWC, whereas band-limited power in higher frequencies correlated with SWC but not QPP. Results were similar under isoflurane; however, the QPP was also correlated to band-limited power, possibly due to the burst-suppression state induced by the anesthetic agent. The results provide additional support for the hypothesis that the two types of dynamic rsfMRI are linked to different frequencies of neural activity, but isoflurane anesthesia may make this relationship more complicated. Understanding which neural frequency bands appear as particular dynamic patterns in rsfMRI may ultimately help isolate components of the rsfMRI signal that are of interest to disorders such as schizophrenia and attention deficit disorder.

Effects of Severing the Corpus Callosum on Electrical and BOLD Functional Connectivity and Spontaneous Dynamic Activity in the Rat Brain

Functional networks, defined by synchronous spontaneous blood oxygenation level-dependent (BOLD) oscillations between spatially distinct brain regions, appear to be essential to brain function and have been implicated in disease states, cognitive capacity, and sensing and motor processes. While the topographical extent and behavioral function of these networks has been extensively investigated, the neural functions that create and maintain these synchronizations remain mysterious. In this work callosotomized rodents are examined, providing a unique platform for evaluating the influence of structural connectivity via the corpus callosum on bilateral resting state functional connectivity. Two experimental groups were assessed, a full callosotomy group, in which the corpus callosum was completely sectioned, and a sham callosotomy group, in which the gray matter was sectioned but the corpus callosum remained intact. Results indicated a significant reduction in interhemispheric connectivity in the full callosotomy group as compared with the sham group in primary somatosensory cortex and caudate-putamen regions. Similarly, electrophysiology revealed significantly reduced bilateral correlation in band limited power. Bilateral gamma Band-limited power connectivity was most strongly affected by the full callosotomy procedure. This work represents a robust finding indicating the corpus callosums influence on maintaining integrity in bilateral functional networks; further, functional magnetic resonance imaging (fMRI) and electrophysiological connectivity share a similar decrease in connectivity as a result of the callosotomy, suggesting that fMRI-measured functional connectivity reflects underlying changes in large-scale coordinated electrical activity. Finally, spatiotemporal dynamic patterns were evaluated in both groups; the full callosotomy rodents displayed a striking loss of bilaterally synchronous propagating waves of cortical activity.