Stefanie Meyer

Temporal interference stimulation (TIS) aims at targeting deep brain areas during transcranial electrical alternating current stimulation (tACS) by generating interference fields at depth. Although its modulatory effects have been demonstrated in animal and human models and stimulation studies, direct experimental evidence is lacking for its utility in humans (in vivo). Herein, we directly test and compare three different structures: firstly, we perform peripheral nerve and muscle stimulation quantifying muscle twitches as readout, secondly, we stimulate peri-orbitally with phosphene perception as a surrogate marker, and thirdly, we attempt to modulate the mean power of alpha oscillations in the occipital area as measured with electroencephalography (EEG). We found strong evidence for stimulation efficacy on the modulated frequency in the PNS, but we found no evidence for its utility in the CNS. Possible reasons for failing to activate CNS targets could be comparatively higher activation thresholds here or inhibitory stimulation components to the carrier frequency interfering with the effects of the modulated signal.

Background and aims: Neurovascular ultrasound (nvUS) of the epiaortic arteries is an integral part of the etiologic workup in patients with ischemic stroke. Aortic valve disease shares similar vascular risk profiles and therefore not only presents a common comorbidity, but also an etiologic entity. The aim of this study is to investigate the predictive value of specific Doppler curve flow characteristics in epiaortic arteries and the presence of aortic valve disease. Methods: Retrospective, single-center analysis of ischemic stroke patients, both receiving full nvUS of the extracranial common- (CCA), internal- (ICA) and external carotid artery (ECA) and echocardiography (TTE/TEE) during their inpatient stay. A rater blinded for the TTE/TEE results investigated Doppler flow curves for the following characteristics: ‘pulsus tardus et parvus’ for aortic valve stenosis (AS) and ‘bisferious pulse’, ‘diastolic reversal’, ‘zero diastole’ and ‘no dicrotic notch’ for aortic valve regurgitation (AR). Predictive value of these Doppler flow characteristics was investigated using multivariate logistic regression models. Results: Of 1320 patients with complete examination of Doppler flow curves and TTE/TEE, 75 (5.7%) showed an AS and 482 (36.5%) showed an AR. Sixty-one (4.6%) patients at least showed a moderate-to-severe AS and 100 (7.6%) at least showed a moderate-to-severe AR. After adjustment for age, coronary artery disease, arterial hypertension, diabetes mellitus, smoking, peripheral arterial disease, renal failure and atrial fibrillation, the following flow pattern predicted aortic valve disease: ‘pulsus tardus et parvus’ in the CCA and ICA was highly predictive for a moderate-to-severe AS (OR 1158.5, 95% CI 364.2–3684.8, p < 0.001). ‘No dicrotic notch’ (OR 102.1, 95% CI 12.4–839.4, p < 0.001), a ‘bisferious pulse’ (OR 10.8, 95% CI 3.2–33.9, p < 0.001) and a ‘diastolic reversal’ (OR 15.4, 95% CI 3.2–74.6, p < 0.001) in the CCA and ICA predicted a moderate-to-severe AR. The inclusion of Doppler flow characteristics of the ECA did not increase predictive value. Conclusions: Well defined, qualitative Doppler flow characteristics detectable in the CCA and ICA are highly predictive for aortic valve disease. The consideration of these flow characteristics can be useful to streamline diagnostic and therapeutic measures, especially in the outpatient setting.

Duchenne Muscular Dystrophy (DMD) is a debilitating muscle disorder that condemns patients to year-long dependency on glucocorticoids. Chronic glucocorticoid use elicits many unfavourable side-effects without offering satisfying clinical improvement, thus, the search for alternative treatments to alleviate muscle inflammation persists. Taurine, an osmolyte with anti-inflammatory effects, mitigated pathological features in the mdx mouse model for DMD but interfered with murine development. In this study, ectoine is evaluated as an alternative for taurine in vitro in CCL-136 cells and in vivo in the mdx mouse. Pre-treating CCL-136 cells with 0.1 mM taurine and 0.1 mM ectoine prior to exposure with 300 U/mL IFN-γ and 20 ng/mL IL-1β partially attenuated cell death, whilst 100 mM taurine reduced MHC-I protein levels. In vivo, histopathological features of the tibialis anterior in mdx mice were mitigated by ectoine, but not by taurine. Osmolyte treatment significantly reduced mRNA levels of inflammatory disease biomarkers, respectively, CCL2 and SPP1 in ectoine-treated mdx mice, and CCL2, HSPA1A, TNF-α and IL-1β in taurine-treated mdx mice. Functional performance was not improved by osmolyte treatment. Furthermore, ectoine-treated mdx mice exhibited reduced body weight. Our results confirmed beneficial effects of taurine in mdx mice and, for the first time, demonstrated similar and differential effects of ectoine.

Many neuromuscular disease entities possess a significant disease burden and therapeutic options remain limited. Innovative human preclinical models may help to uncover relevant disease mechanisms and enhance the translation of therapeutic findings to strengthen neuromuscular disease precision medicine. By concentrating on idiopathic inflammatory muscle disorders, we summarize the recent evolution of the novel in vitro models to study disease mechanisms and therapeutic strategies. A particular focus is laid on the integration and simulation of multicellular interactions of muscle tissue in disease phenotypes in vitro. Finally, the requirements of a neuromuscular disease drug development workflow are discussed with a particular emphasis on cell sources, co-culture systems (including organoids), functionality, and throughput.