Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial (cMPsE02).

BACKGROUND: Various brain stimulation techniques are in use to treat epilepsy. These methods usually require surgical implantation procedures. Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive technique to stimulate the left auricular branch of the vagus nerve at the ear conch. OBJECTIVE: We performed a randomized, double-blind controlled trial (cMPsE02) to assess efficacy and safety of tVNS vs. control stimulation in patients with drug-resistant epilepsy. METHODS: Primary objective was to demonstrate superiority of add-on therapy with tVNS (stimulation frequency 25 Hz, n = 39) versus active control (1 Hz, n = 37) in reducing seizure frequency over 20 weeks. Secondary objectives comprised reduction in seizure frequency from baseline to end of treatment, subgroup analyses and safety evaluation. RESULTS: Treatment adherence was 84% in the 1 Hz group and 88% in the 25 Hz group, respectively. Stimulation intensity significantly differed between the 1 Hz group (1.02 ± 0.83 mA) and the 25 Hz group (0.50 ± 0.47 mA; p = 0.006). Mean seizure reduction per 28 days at end of treatment was -2.9% in the 1 Hz group and 23.4% in the 25 Hz group (p = 0.146). In contrast to controls, we found a significant reduction in seizure frequency in patients of the 25 Hz group who completed the full treatment period (20 weeks; n = 26, 34.2%, p = 0.034). Responder rates (25%, 50%) were similar in both groups. Subgroup analyses for seizure type and baseline seizure frequency revealed no significant differences. Adverse events were usually mild or moderate and comprised headache, ear pain, application site erythema, vertigo, fatigue, and nausea. Four serious adverse events were reported including one sudden unexplained death in epilepsy patients (SUDEP) in the 1 Hz group which was assessed as not treatment-related. CONCLUSIONS: tVNS had a high treatment adherence and was well tolerated. Superiority of 25 Hz tVNS over 1 Hz tVNS could not be proven in this relatively small study, which might be attributed to the higher stimulation intensity in the control group. Efficacy data revealed results that justify further trials with larger patient numbers and longer observation periods.

The relationship between the BOLD-induced T(2) and T(2)(*): a theoretical approach for the vasculature of myocardium.

Recently the blood oxygenation level-dependent (BOLD)-related T(2)* of myocardium was derived as an analytical function of intracapillary blood volume, blood oxygenation, and nuclear spin diffusion. The basis of this approach was to approximate the diffusion-induced field fluctuations a nuclear spin is subjected to by strong collision dynamics, i.e., the field fluctuations are uncorrelated. The same analysis is now performed for spin echo experiments that gives myocardial T(2) as a function of the parameters above and the echotime. An analytical relationship between T(2) and T(2)* relaxation is derived. The dependence of T(2) on diffusion, echo time, and blood oxygenation is congruent with simulation and experimental data. Magn Reson Med 42:1004-1010, 1999.

BOLD-MRI in ten patients with coronary artery disease: evidence for imaging of capillary recruitment in myocardium supplied by the stenotic artery.

Changes of myocardial oxygenation can be studied by measurements of the apparent transverse relaxation time T2*, which is correlated with the oxygenation state of hemoglobin. In this study, ten patients with coronary artery disease (CAD) underwent blood oxygenation level dependent (BOLD) T2* measurements using a segmented gradient echo pulse sequence with ten echoes. T2* measurements were performed in a single short-axis slice of the heart at rest and under pharmacological stress with dipyridamole (DIP), which increases myocardial blood flow. For comparison, all patients underwent X-ray angiography and stress-echocardiography within 4 days after the MR exam. In one patient, MR examination was repeated 10 weeks after percutaneous transluminal coronary angioplasty (PTA). In the differential T2* maps, expected ischemic areas of myocardium were identified in six patients. In these regions, T2+ values (30 +/- 8 ms) were significantly reduced when compared to the remaining myocardium (48 +/- 9 ms, P < 0.01). In four patients, the myocardial region of interest could not be assessed owing to severe susceptibility artifacts in the ischemic region. The success of the PTA treatment could be visualized from a more homogeneous DIP induced increase in T2* within the ischemic myocardium (from 26 +/- 1 to 29 +/- 1 ms before PTA versus 26 +/- 1 to 31 +/- 4 ms after PTA, P < 0.001).

Changes in myocardial oxygenation and perfusion under pharmacological stress with dipyridamole: assessment using T*2 and T1 measurements.

The aim of this pilot-study was to evaluate changes in myocardial oxygenation and perfusion under pharmacological stress with dipyridamole (DIP) by means of MRI. Twenty healthy volunteers were examined using a multi-echo gradient-echo sequence. The differential myocardial signal response due to the blood oxygen level dependent (BOLD) effect was studied under variable conditions of myocardial oxygen supply caused by the vasodilator DIP. Unlike contrast agents (CA) methods, which require at least two injections of CA and DIP, the presented methods require only a single infusion of DIP. To assess changes in myocardial perfusion, a saturation recovery TurboFLASH (SRTFL) sequence with centric reordering for T1 measurements was used with global and slice-selective spin-preparation (five volunteers). The signal response was measured at baseline conditions and when myocardial blood flow was increased during pharmacological stress with DIP. Administration of DIP induced a 17 +/- 9% increase in T2*. Enhanced perfusion resulted in a 15 +/- 5% decrease of T1 after slice-selective spin preparation and a calculated increase in absolute perfusion of about 5.1 ml/(g x min), which reflects coronary reserve. The study shows that DIP-induced alterations in the relationship between myocardial oxygen supply and demand are detectable in healthy volunteers using T2* and T1 measurements. A combination of T2* and T1 examinations could become a useful diagnostic tool for the non-invasive assessment of myocardial oxygenation and perfusion in patients with coronary artery disease (CAD).

Theory of the BOLD effect in the capillary region: an analytical approach for the determination of T2 in the capillary network of myocardium.

This article presents an analytical approach for the quantification of the blood oxygen level dependent (BOLD) effect in the capillary region. The capillary geometry of myocardium is considered. The relaxation rate R*2 is determined as a function of the capillary radius Rc, the intracapillary volume fraction RBV, and the diffusion coefficient D. When the intracapillary volume fraction is small, the approximation R*2 = RBV x tau(-1) x (square root of (1+(taudeltaomega)2)-1) is valid, with the correlation time tau = (Rc2/4D) x (absolute value (ln RBV)/(1 - RBV)). The predictions of this model agree well with numerical simulations and experimental data of others and with data recently measured by our group.