Effects of Anesthesia on White Matter BOLD Signals in Monkeys
Tung-Lin Wu1,2, Feng Wang1,3, Li Min Chen1,3, Adam W. Anderson1,2,3, Zhaohua Ding1,3, and John C. Gore1,2,3

1Vanderbilt University Institute of Imaging Science, Nashville, TN, United States, 2Biomedical Engineering, Vanderbilt University, Nashville, TN, United States, 3Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, United States


We previously reported the first evidence of anisotropic rsfMRI-BOLD signals in white matter which appear to reflect a functional structure not previously detected. To prove these signals have a functional basis, we performed imaging of live squirrel monkeys under different baselines of neural activity by altering anesthesia levels. Specifically, we compared how different anesthesia levels modulate fractional power and spatio-temporal correlation tensors in white matter. Our results demonstrate that low frequency BOLD signal fluctuations behave similarly in grey and white matter. This indicates that anisotropic rsfMRI-BOLD signals in white matter encode neural activity.

Target Audience

Investigators who are interested in brain function, white matter and fMRI


Resting state functional magnetic resonance imaging (rsfMRI) has been widely used to measure functional connectivity between cortical regions of the brain. However, neither BOLD (blood oxygenation level dependent) activation nor resting state signals in white matter have been well-established. Recently, there has been growing evidence of reliable detections of hemodynamic changes in white matter, and we have reported the measurement of anisotropic resting state correlations within white matter that reveal an underlying functional structure. We recently introduced the concept of a spatio-temporal correlation tensor as a description of the functional architecture of white matter, purely on the basis of rsfMRI data [1]. However, the neural and biophysical bases for these correlated fluctuations remain unclear. We therefore carried out imaging studies on live squirrel monkeys under different levels of anesthesia in order to assess changes within MRI signal variations for different baseline levels of neural activity. Anesthesia reduces spontaneous neural electrical activity in the brain, and it has been shown that with increased anesthesia levels, functional connectivity decreases between macaque cortices [2]. We specifically aimed to compare how different anesthesia levels modulate fractional power and spatio-temporal correlation tensors in white matter in a resting state.


Four adult male squirrel monkeys have been included in this study to date. All MR images were acquired on a 9.4T 21cm horizontal bore magnet with a customized quadrature birdcage coil (inner diameter = 85mm) and Varian/Agilent MR spectrometer. Each monkey was anesthetized and mechanically ventilated (respiration rate maintained at 40 cycles/min), with head and body stabilized in an MR compatible frame. Vital signs including heart rate, core body temperature, end tidal CO2, and SpO2 were monitored and maintained throughout the entire imaging session. Functional scans at decreasing isoflurane levels (1.25%, 0.8% and 0.5%) were acquired. At least 10 minutes were allocated for anesthesia stabilization between runs while physiological signs were continuously monitored. Resting state BOLD-sensitive images were acquired using a T2*-weighted GE-EPI sequence (TR/TE=750/16ms, 2 shots, resolution of 1x1x1 mm3, 1.5s/volume, 300 volumes). T1-weighted images were collected using a fast multi-gradient echo sequence (TR/TE=3000/2.78 ms, ETL=4, Ti=600 ms, flip angle=80). Resting data were corrected for slice-timing, motion, and smoothed using standard Spm8 in Matlab. RETROICOR was then performed to correct for cardiac and respiratory interferences as well as linear detrending. Fractional power maps were computed by transforming each voxel time series into its power spectral density via a Fourier Transform, and calculating the ratio of the summed power in the low frequency range (0.01-0.08Hz) to that of the entire frequency range. Lastly, spatio-temporal correlation tensors were constructed from the set of anisotropic nearest-neighbor correlation coefficients for every voxel with the method reported in [3].

Results and Discussion

Group analyses of fractional power in white and gray matter are presented in Figure 1. The boxplots demonstrate that low frequency oscillations in white matter behave similarly to gray matter as neural activity baseline is varied. Specifically, a linear decreasing trend in fractional power was observed in both regions as we increased the isoflurane level. Figure 2 shows how the fractional power changed as the isoflurane levels were altered. Although fractional power in gray matter is more susceptible to changes in anesthesia level, white matter presents a similar trend. Figure 3 presents a group analysis of the major eigenvalues of the spatio-temporal correlation tensors. It is evident that larger eigenvalues (i.e. greater nearest neighbor connectivity) are associated with lower anesthesia level. We examined the possibility that confounds such as cardiac beating, respiration and motion may have contributed to the low frequency oscillation changes as the anesthesia levels were varied. However, our analyses provide evidence that this is not the case. With physiological patterns regressed, the power spectra of motion parameters remained rather constant at different anesthesia levels. Fractional power maps were also computed for white noise scans which were immune to anesthesia level changes, indicating our observation was not simply a global scanner drift artifact. Overall, these findings confirm that BOLD signal fluctuations in white matter can be detected in a resting state, are anisotropic in nature, and consistent with underlying neural activity.


Our study demonstrates that low frequency BOLD signal fluctuations behave similarly in both gray and white regions as neural baseline activity varies. This is indicative that neural activity is encoded in white matter resting state signals.


We thank Mrs. Chaohui Tang and Mr. Fuxue Xin of the Vanderbilt University Institute of Imaging Science for their assistance in animal preparation and care during MRI data collection. This study is supported by NIH grants NS069909-01 to LMC and NS078680-01 to JCG.


[1] Ding Z et al. (2015) Visualizing Functional Pathways in the Human Brain Using Correlation Tensors and Magnetic Resonance Imaging. Magnetic Resonance Imaging (In Press) [2] Hutchison RM et al. (2014) Isoflurane induces dose-dependent alterations in the cortical connectivity profiles and dynamic properties of the brain’s functional architecture. Hum Brain Mapp 35:5754 –5775. CrossRef Medline [3] Ding Z et al. (2013) Spatio-temporal correlation tensors reveal functional structure in human brain. PLoS One 8(12): e82107.


Figure 1. Effects of anesthesia on fractional power in gray matter and white matter. N=9,14,11 runs for 0.5%, 0.875% and 1.25% isoflurane levels respectively. **p<0.0005 and *p<0.005 (Mann-Whitney Test)

Figure 2. Fractional power maps for one selected slice from one of the monkeys across different isoflurane levels. The fractional power ratio of white over gray matter ranges from 60%-75%.

Figure 3. Effects of anesthesia on major eigenvalues of the functional tensors (a measure of the correlation coefficient). N=7,12,10 runs for 0.5%, 0.875% and 1.25% isoflurane levels respectively. Larger tensors are more visible under an isoflurane level of 0.5% and 0.875% when compared to isoflurane level of 1.25%.*p<0.005 (Mann-Whitney Test)

Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)