Rationale:
It is known that field potential amplitude is inversely proportional to the distance between the stimulating and recording electrode. Some components of CCEPs also appear to decay in this way as well. We hypothesized that CCEPs generated from a true long-range anatomical connection will have higher amplitude than can be explained by volume conduction of locally generated components of the evoked potential waveform. We specifically compared stimulation involving the cingulum bundle (which we expect to have long-range connections) to control cortex.
Method:
Single pulse electrical stimulation was performed at 1 Hz in trains of 20 seconds at multiple sites in 2 participants with refractory epilepsy undergoing stereo-EEG monitoring. CCEPs were averaged and the amplitude was defined as the root mean squared error (RMSE) from the end of the stimulus artifact to 50 ms after the onset. The CCEP amplitude versus distance relationship was fit as a power law. The CCEP amplitude was converted to a Z-score, reflecting the number of standard deviations above what is expected for distance. We compared the mean values of the CCEP raw amplitude and CCEP Z-score between recording-stimulation electrode pairs which targeted cingulate cortex compared to control pairs which did not include cingulate cortex.
Results:
For participant #1, the mean Z-score for stimulation involving cingulate cortex was significantly larger than for control cortex (0.40 vs. 0.08, p=0.012, t-test), even though the raw amplitude was less for cingulate than control cortex (47 µV vs. 58 µV, p=0.33). For participant #2, the mean Z-score for stimulation involving cingulate cortex was significantly larger than for control cortex (0.65 vs. 0.28, p=0.014, t-test), even though the raw amplitude was significantly less for cingulate than control cortex (44 µV vs. 143 µV, p< 0.001). For both participants, the largest Z-score ( >2.5) was triggered by stimulation to the anterior cingulate and recording from the anterior insula. Both participants also had a large Z-score ( >1.8) from stimulation to the anterior cingulate and recording posteriorly in the precuneus (Pt #1) or the posterior cingulate cortex (Pt #2). The proportion of outliers (Z-scores > 2) in cingulate cortex versus control was significantly different for Pt #1 (5/70 vs. 3/181, p=0.04, Fisher test) though not for Pt (1/45 vs. 2/135, p=1.0).
Conclusion:
In 2 patients, CCEPs triggered from or recorded in the cingulate cortex showed CCEP amplitudes larger than expected for distance, despite average raw CCEP amplitudes. This matches our anatomical understanding, for example, that the anterior and posterior cingulate are linked via the cingulum bundle. The largest outlier in both patients was between the anterior cingulate and the anterior insula, a known pathway based on neuroanatomical tracing in non-human primates. We propose that positive outliers in the CCEPs versus distance relationship will identify true anatomical connectivity more generally, though more work will be required to prove this.
Funding:
:This was work was supported by the T32 NS748019 (ASD), the Woodruff Foundation and K08 NS105929 (NPP), and R01 NS088748 (DLD).
FIGURES
Figure 1