Study rationale and clinical trial design.

A. Immunomodulation neural pathways associated with vagus nerve stimulation include cholinergic anti-inflammatory pathway, sympathetic nervous system, and hypothalamic-pituitary-adrenal (HPA) axis. Immunogenic stimuli activate vagal afferents terminating primarily in the dorsal vagal complex. Ascending projections from the dorsal vagal complex reach the paraventricular nucleus (PVN) and rostral ventromedial medulla (RVM), activating the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic system, respectively, to regulate the immune response. taVNS can affect cardiovascular function through the sympathetic system or efferent vagus nerve. B-C. Clinical trial structure and treatment protocol. Patients in the taVNS group received electrical stimulation (0.4 mA, 250 µs pulse width, 20 Hz) for 20 minutes twice daily. Sham group patients wore the ear clip on the earlobe for the same duration. D. Ear clip application for taVNS treatment.

Patient demography

. HH: Hunt & Hess classification. mRS: modified Rankin Scale. Y: yes. N: no.

The effects of taVNS on cardiac function.

A. Signals encoding treatment period and ECG signals in a representative patient. B. 3-lead ECG configuration in the intensive care unit. C. P wave, T wave, and QRS complex are delineated from clean ECG II signals. D and E. Heart rate and corrected QT interval changes from the first hospitalized day in the two treatment groups.

The effects of taVNS on overall heart rate variability and parasympathetic activity.

A-B. Changes in standard deviation of NN interval (SDNN) changes and Root mean squares of successive differences over time for the two treatment groups. The color represents the treatment group. Green triangles represent the mean. C. Correlation between standard ECG features underlying autonomic activities. D. Factor analysis showed that there are two factors underlying the standard ECG features. The first factor is referred to as overall heart rate variability. The second factor is referred to as parasympathetic activity. E-F. The effect of taVNS on the two factors. pNNI_50: Percentage of Number of successive NN Intervals that differ by more than 50 ms. CVI: cardiac vagal index. Total power: total power below 0.4Hz of normal RR interval. nhf_power: relative power of the high-frequency band (0.15–0.4 Hz). CSI: cardiac sympathetic index.

Effects of repetitive taVNS on vascular function.

A. Representative vital signs and their physiology. Arterial line blood pressure (see supplementary Figure 5), intracranial pressure, and mean blood pressure measured regularly by nurses (BP) were recorded. Blood pressure is an index of vasodilation. PPI is the ratio between the pulsatile and the non-pulsatile blood flow, reflecting the cardiac output. B-C. Mean BP and ICP changes from the first hospitalization day did not differ significantly between the treatment groups. D-E. PPI change from the first hospitalized day was lower in the VNS treatment group, while RR change was higher.

The acute effects of taVNS on cardiac function.

A. Daily fluctuation of heart rate of a subject receiving VNS treatment. The treatment period, a 20-minute period before and after treatment, is highlighted. Note that a small proportion of ECG signals to derive heart rate was missing due to the expected cyclical restarting of the monitoring system. B (D). Normalized heart rate (QTc) aligned at the treatment onset over time for the two treatment groups. The heart rate (QTc) is normalized based on the mean and standard error of heart rate for each day. C. The difference in HR between the treatment period, post-treatment period, and pre-treatment period for the two groups. Wilcoxon signed ranked test was used to test if the HR difference is statistically different from 0 in the VNS treatment group. Bonferroni-corrected p-value for HR difference between post-treatment and treatment period is 0.03 (N=188, Cohen’s d = 0.1). Mann–Whitney U tests were used to compare cardiac function metric differences between the two treatment groups. E-F. The difference in QTc and RMSSD between the treatment period, post-treatment period, and pre-treatment period for the two groups G. The relationship between heart rate changes following acute taVNS and functional outcome.

Relationship between HR changes following acute taVNS and clinical outcomes.

Summary of effects of acute and repetitive taVNS on cardiovascular function in SAH patients

. Metrics for cardiovascular function include heart rate variability, heart rate, QT interval, blood pressure, intracranial pressure, peripheral perfusion index, and respiration rate.