**6. TCD for PFO detection**

Right to left shunt from patent foramen ovale (PFO) is a common anatomical variation in which there is an opening between the right and left atria, and it can be a potential risk factor for cryptogenic stroke [15]. Several randomized clinical trials support closure of PFO in patients between age 16 and 60 years who suffer from cryptogenic stroke from paradoxical embolism through PFO. TCD can detect microbubbles that cross from the right to the left atrium during a Valsalva maneuver, indicating the presence of a PFO. A meta-analysis by Mojadidi et al. showed that TCD has a sensitivity of 97% and a specificity of 93% for the detection of PFO compared to transesophageal echocardiography, which is the gold standard imaging modality for PFO detection [16]. However, TCD is less invasive and less expensive than TEE, making it an attractive alternative for PFO detection in certain patient populations. In addition, TCD can be performed at the bedside, allowing for real-time evaluation of PFO during a Valsalva maneuver, which can provide valuable information about the hemodynamic significance of the PFO in stroke pathogenesis. Overall, TCD is a reliable and cost-effective tool for the detection of PFO in patients with cryptogenic stroke.

While TCD is very sensitivity and specific for the detection of PFO, it relies heavily on the operator's technical skills and availability of trained technicians. Recently, a robotic-assistant TCD (ra-TCD) system with artificial intelligence (AI)-enhanced signal detection algorithms has been tested in clinical research to mitigate the variability in TCD acquisition. The BUBL study is a multicenter, prospective trial comparing raTCD to TTE for PFO detection (NCT04604015) [17]. The study found that raTCD

detecting all and large RLS at approximately three times the rate of TTE (primary outcome, any RLS: raTCD 64% vs. TTE 20% [absolute difference 43.4% (95% CI 34.3–52.5%), p < 0.001]) [18]. Ongoing studies are testing whether these results are generalizable in routine practice.
