Neurovascular coupling enables adaptation of Cerebral Blood Flow (CBF) to support neuronal activity. Modern techniques enable the simultaneous recording of neuronal activities and hemodynamic parameters. However, the neurovascular coupling mechanism remains understudied. In this study, we applied a Phase-Amplitude Cross-Frequency Coupling (PAC) algorithm to investigate multimodal neuro signals including surface electroencephalogram (EEG) and CBF from transcranial Doppler ultrasonography (TCD). We also investigated the causal relationship between EEG and CBF with using Granger Causality (GC) analysis.
Methods Twenty simultaneous recordings of EEG and TCD Cerebral Blood Flow Velocity (CBFV) from 17 acute ischemic stroke patients admitted to the Neurointensive Care Unit, Tiantan Hospital, Capital Medical University (Beijing, China) were studied. Each patient had simultaneous, continuous monitoring of EEG and bilateral CBFV in either the Middle Cerebral Arteries (MCA) or Posterior Cerebral Arteries (PCA). PAC was calculated between the phase of CBFV in frequency bands (0–0.05 and 0.05–0.15 Hz) and the EEG amplitude in five bands (δ, θ, α, β, γ). The global PAC was calculated as the sum of all PACs across the six EEG channels and five EEG bands for each patient. The hemispherical asymmetry of Cross-Frequency Coupling (CFC) was calculated as the difference between left and right PAC. GC analysis was carried out to investigate causal interactions between slow waves of FV (Frequency Band: 0.006 - 0.4 Hz) and the amplitude of EEG in five frequency bands. Mean GC index across EEG frequency bands was calculated to estimate the causal relationship between EEG and CBFFV and then correlated with NIH Stroke Scale (NIHSS) at admission/discharge and the modified Rankin Scale (mRS, favorable outcome when mRS ≤ 2) at discharge.
The PAC between CBFV and EEG was significantly higher in β and γ bands than in the other three bands. Occipital region (P3-O1 and P4-O2 channels) showed stronger PAC than\ the other regions. The deceased group tended to have smaller global PAC than the survival group (the area under the receiver operating characteristic curve [AUROC] was 0.81, p = 0.57). The unfavorable outcome group showed smaller global PAC than the favorable group (AUROC = 0.65, p = 0.23). The PAC asymmetry between the two brain hemispheres correlates with the degree of stenosis in stroke patients (p = 0.01). Granger analysis identified a causal relationship from EEG –> FV, indicating past EEG contained information that predicted CBFV. The NIHSS negatively correlates with mean GC index value, which means a stronger causality between EEG and FV exists in patients who are less severely affected. No significant difference in GC index exists between patients with favorable and unfavorable outcomes (p>0.05).
We showed that CBFV interacts with EEG in β and γ bands through a phase-amplitude CFC relationship, with the strongest PAC found in the occipital region and that the degree of hemispherical asymmetry of CFC correlates with the degree of stenosis. A G-causality causal relationship from EEG → CBFV may exist in patients with ischemic stroke. The strength of G-causality may be related to stroke severity at discharge.
Figure 1. |(A) Mean phase-amplitude cross-frequency coupling (PAC) between CBFV (0–0.05 Hz) and EEG of six channels in five frequency bands (δ, θ, α, β, γ) of the 16 patients. (B) Statistical comparison of mean PAC between CBFV (0–0.05 Hz) and EEG in the 5 frequency bands (δ, θ, α, β, γ). (C) Mean PAC between CBFV (0.05–0.15 Hz) and EEG of six channels in five frequency bands of the 16 patients. (D) Statistical comparison of mean PAC between CBFV (0.05–0.15 Hz) and EEG in the 5 frequency bands.
Figure 2. Proportions of 5-minute windows showing statistically significant GCI for each recording (n=20).