Stimulated electrode Recording electrode Conclusions Depts of 1Neurosurgery and 2Neurology , Hofstra University School of Medicine, North Shore LIJ Health System, New Hyde Park, NY 3Feinstein Institute for Medical Research, Manhassat, NY 4Albert Einstein College of Medicine, Bronx, NY, 5National Institute of Neuroscience, Budapest, Hungary A.D. Mehta1,3, L. Entz1,3,5, S. Bickel1,3,4, C.J. Keller1,4, D. Groppe1,3, S. Jain2, I. Ulbert5 e Relationship of Resting State fMRI Correlation and Anticorrelation to Electrically-Evoked Potentials in the Human Brain Introduction Functional MRI studies carried out during rest (R-fMRI) suggest a functional architecture of spatially distributed networks that is represented in low-frequency (<0.1Hz) spontaneous fluctuations of the blood oxygen level-dependent (BOLD) signal. Functional connectivity analysis of this signal reveals both correlated and anti-correlated areas. In order to examine the neurophysiological underpinnings related to the direction of correlation, we investigated the relationship of these correlations to electrophysiological measures. Studies were carried out using direct electrical stimulation of the cerebral cortex with intracranial electrodes in patients undergoing invasive electrode implantation for seizure monitoring. Methods We performed systematic bipolar stimulation of all electrodes by administering a single pulse electrical current (10mA, 0.5Hz, 0.2 msec pulse width, 20 trials per electrode pair) on six patients undergoing intracranial monitoring for intractable epilepsy. Electrodes were localized using post-operative CT and MRI and aligned upon the reconstructed cortical surface of a pre-operative MRI scan. Resting state fMRI scans (3T) were performed prior to electrode implantation. Probing Sensorimotor Areas We would like to acknowledge Michael Milham, Clare Kelly, G. Klein, A. Dykstra, and F. Lado for their assistance with this work. is work was supported by the Page and Otto Marx Jr Foundation and the Epilepsy Foundation of America. Spectral analysis of CCEP and RSFC Results Correlated fluctuations of the BOLD signal at rest reliably predict electrically-evoked potentials Positively correlated regions exhibit higher CCEP power in all frequencies during the N1 and low frequencies (<11Hz) during N2 Anticorrelated regions exhibit higher CCEP power in high frequencies (>25Hz) during N1 / N2 Further investigation is warranted with regard to the spatial and temporal relationship between CCEPs, RSFC, and spontaneous ECoG CCEPs were thresholded (Z>6 above baseline during N2) to determine significance Resting state correlation values (RSFC) within voxels underlying electrodes were extracted and averaged Matrices from each method were analyzed -1 -.3 +.3 +1 -1 -.3 +.3 +1 -1 -.3 +.3 +1 No significant difference between CCEP waveforms whose region had negative RSFC or non-significant RSFC Negative RSFC Positive RSFC Non−significant RSFC Negative RSFC Nonsignificant RSFC Positive RSFC 0 10 20 30 40 50 CCEP z-score ANOVA 0 5 10 15 Negative RSFC Positive RSFC Mean CCEP All >10 >25 >50 >75 >90 >95th percentile Mean CCEP Z-value S1 S2 S3 S6 S4 S5 0 All Electrodes Group 5 10 15 0 5 10 15 Significant Negative RSFC Non-significant RSFC Significant Positive RSFC 250ms +20uv S1 S2 S3 S4 S5 S6 Regions with more positive RSFC showed stronger CCEPs but regions with more negative RSFCs did not Co-localization of CCEPs and RSFC across brain In 5/6 subjects, significant CCEPs exhibited higher RSFC than non-significant CCEPs A similar finding was observed when local electrodes (within 3cm of stimulation site) were removed from analysis Regressing out distance from stimulation site yielded similar results 0 5 10 15 −0.5 0 0.5 1 CCEP RSFC R=0.63 0 0.05 0.1 0.15 −1 −0.5 0 0.5 1 Distance (mm ) RSFC R=0.73 -1 1 ROI, 128 sites 0 5 10 15 0 CCEP Residuals R=0.62 −1 −0.5 0 0.5 1 20 0 10 20 30 0 0.04 0.08 0.12 −0.5 0 0.5 1.0 1.5 2.0 CCEP Distance (mm ) -1 RSFC 20 r = 0.31 CCEP S5 r = 0.32 S6 10 20 0 10 20 0 n = 25 n = 20 r = 0.24 S3 0 10 20 r = 0.21 S4 0 10 20 n = 39 n = 35 r = 0.28 r = 0.29 S1 S2 0 10 20 0 20 −0.2 0 0.2 0.4 10 RSFC n = 44 n =15 0 0.05 0.10 0.15 0.20 Mean RSFC Z-value S1 S2 S3 S6 + - + - + - S4 + - S5 + - + - + - + - 0 0.05 0.10 0.15 0.20 0 0.05 0.10 0.15 0.20 All Electrodes 0 0.05 0.10 0.15 0.20 Mean RSFC Z-value + - + - + - CCEP Response + - + - + - Non-Local Electrodes Group + Significant CCEP - Non-significant CCEP + - 0 0.05 0.10 0.15 0.20 Mean RSFC Z-value N1 + - 0 0.05 0.10 0.15 0.20 N2 + - 0 0.05 0.10 0.15 0.20 Mean RSFC Z-value + - 0 0.05 0.10 0.15 0.20 All Electrodes Non-local Electrodes Group analysis for N1 (10-70ms) and N2 (70-500ms) Spectral analysis of CCEP and RSFC We observed no difference between the amplitude of evoked response between regions with negative and non-significant RSFC2. However, changes may exist in the evoked spectral properties between groups. Power in delta and gamma frequencies of spontaneous ECoG have been shown to correlate with RSFC1. Anticorrelations are thought to represent segregated networks and may communicate with each other via neuronal oscillations at certain frequency bands. erefore, we applied time-frequency decomposition to CCEPs to further investigate this relationship. EEGLAB was used to calculate event related spectral pertubation (ERSP) and inter-trial coherence (ITC) from 0.5-200Hz. CCEPs converted to frequency domain and power during N1 (10-70ms) and N2 (70-500ms) was compared to RSFC correlation N1: Significantly higher CCEP power in all frequencies for positive RSFC when compared to non-significant and negative RSFC 1-4Hz RSFC < -0.3 -0.3 < RSFC < +0.3 (non-significant) RSFC > 0.3 N1 4-8Hz 8-11Hz 11-25Hz 25-70Hz 1-200Hz Normalized Power 665 2981 1007 70-200Hz 1-4Hz RSFC < -0.3 -0.3 < RSFC < +0.3 (non-significant) RSFC > 0.3 N2 4-8Hz 8-11Hz 11-25Hz 25-70Hz 1-200Hz 665 2981 1007 70-200Hz 0 1 p < 0.05 N1: Low gamma (25-70Hz) shows higher CCEP power for negative RSFC than non-significant RSFC N2: Higher CCEP power in lower frequencies (<11Hz) for positive RSFC compared to non-signficnant and negative RSFC N2: Negative RSFC shows significantly higher CCEP power in higher frequencies (>11Hz) compared to non-significant RSFC One subject, all stimulation sites, all electrode responses Avg of ERSP Freq Hz -200 0 200 400 0 3 5 9 17 29 52 98 200 -5 0 5 -200 0 200 uV ERP Inter-trial coherence -200 0 200 400 0 3 5 9 17 29 52 98 200 0 0.5 1 1-200Hz 0 100 200 300 400 500 80-200Hz Trial 1-200Hz 5 10 15 20 -200 -100 0 100 200 80-200Hz -200 0 200 400 0 100 200 300 Time (ms) -200 0 200 400 -200 0 200 400 0 100 200 300 400 500 Trial 5 10 15 20 5 10 15 20 dB 1 He BJ, Snyder AZ, Zempel JM, Smyth MD, Raichle ME. Electrophysiological correlates of the brain’s intrinsic large scale functional architecture. PNAS, 2008; 39-44. 2 Keller CJ, Bickel S, Entz L, Ulbert I, Milham MP, Kelly C, Mehta AD. Intrinsic functional architecture predicts electrically evoked responses in the human brain. PNAS, 2011; 308-13. Comparison of positive and negative RSFC and CCEP Examples of relationship between RSFC and CCEP Seed Time Series Cortico-cortical evoked potentials (CCEP) Resting state functional connectivity (RSFC) -1 -.3 +.3 +1 Z-value Z-score of CCEP at each electrode RSFC (Fisher z- transformed r-value) at each electrode 0 .5 1s .2 .1 .3 .4 N1 N2 Stimulation 0 1s Correlate Significant response Non-significant response Stimulated electrodes 30s 0 % BOLD change Correlated Time Series -200uV Freq Hz 0 3 5 9 17 29 52 98 200 -200 0 200 uV Trial 5 10 15 20 0 3 5 9 17 29 52 98 200 Avg of ERSP -200 0 200 400 ERP Inter-trial coherence -200 0 200 400 1-200Hz 0 100 200 300 400 500 80-200Hz 1-200Hz 80-200Hz -200 0 200 400 Time (ms) -200 0 200 400 -200 0 200 400 0 100 200 300 400 500 Trial 5 10 15 20 -5 0 5 0 0.5 1 -200 -100 0 100 200 0 100 200 300 dB Stimulated electrode Recording electrode N1 N2 Each trendline represents 1 stimulation site (80-128 response sites) Consistent high frequency (80-200Hz) oscillations following stimulation Stereotyped ERP with high inter-trial coherence No clear distinction between regions of positive / negative RSFC and ERP or spectral properties of CCEP Sample sizes for each group are noted in white text Probing Language Areas Stimulation -1 -.3 +.3 +1 Probing Broca’s Area 0 10 20 30 40 50 -0.5 0 0.5 1.0 r = 0.55 0 10 20 30 40 50 -0.5 0 0.5 1.0 r = 0.56 All Electrodes Significant Electrodes CCEP RSFC RSFC CCEP 0 0.1 0.2 0.3 0.4 0.5 0.6 + - Mean RSFC Z-value + Significant CCEP - Non-significant CCEP Stimulation - 200 uV 500 ms -1 -.3 +.3 +1 Probing Wernicke’s Area r = 0.47 0 5 10 15 20 25 30 -0.5 0 0.5 1.0 0 5 10 15 20 25 30 -0.5 0 0.5 1.0 r = 0.63 CCEP RSFC RSFC CCEP All Electrodes Significant Electrodes 0 0.1 0.2 0.3 0.4 0.5 0.6 + - Mean RSFC Z-value + Significant CCEP - Non-significant CCEP Stimulated electrode Significant CCEP Non-significant CCEP Stimulated electrode Significant CCEP Non-significant CCEP 0 .5 1s .2 .1 .3 .4 N1 N2 Stimulation -200uV 0 .5 1s .2 .1 .3 .4 N1 N2 Stimulation -200uV Stim