Mapping Extracranial Doppler Flow Dynamics During Physiological Provocation in Healthy Volunteers

Single group. All participants receive the same sequence of standardised, non-invasive physiological provocations during one recording session, delivered by trained study staff at the study site. There is no control or comparator group and no randomisation. Staged enrolment — run-in group and expansion group: enrolment proceeds in two stages within this single group. The first 5 participants enrolled form the run-in group. Enrolment then continues to a total of up to 20 participants, who form the expansion group. The run-in group is not a separate study arm and does not receive a different exposure: run-in participants undergo exactly the same provocations, in the same order, with the same monitoring, visit schedule and follow-up as expansion participants. The run-in group exists solely as a feasibility and signal-quality checkpoint, to confirm that the multichannel Doppler configuration can reliably acquire analysable signals from the target vessels under study conditions. Progression to the expansion group is governed by a go / no-go review conducted by the sponsor scientific lead and the principal investigator, convened within 5 business days of the fifth run-in participant completing the main recording visit and the 24 hour safety follow-up, and held before any expansion-group enrolment. A go decision requires both of the following. First, signal quality: a first baseline recording of acceptable signal-to-noise, defined as the successful generation of numeric Doppler outputs (resistance index, pulsatility index, peak systolic and end diastolic values) over at least 10 seconds for at least 4 of the 6 target vessel sites, in at least 4 of the 5 run-in participants. Second, safety: no safety concerns and no serious adverse events attributable to ultrasound device use or probe fixation. If either criterion is not met, the review committee documents how to proceed, which may include pausing, modifying the procedure with ethics approval where required, applying other mitigations, or stopping. The decision is by consensus and is documented and signed by both reviewers. Any procedure change decided at that review is classified by its effect on the comparability of run-in and expansion data, and that classification determines whether run-in data are pooled with expansion data in the primary analysis. Only expansion-group participants are eligible for the imaging sub-study. Setting and monitoring: the participant is positioned at a head-of-bed angle of 30 degrees and remains at that angle for the whole recording session; the bed is not moved between provocations. Continuous multichannel Doppler ultrasound recordings are made from the superficial temporal arteries (bilateral), the ophthalmic artery terminal branches including the supratrochlear arteries (bilateral), and the cervical internal carotid arteries. Electrocardiography and pulse oximetry are monitored continuously throughout. Non-invasive blood pressure is measured at baseline, immediately before the first trial of each provocation, and additionally as clinically indicated. Establishing the stable baseline: once the Doppler probes are placed and secured in the fixation frame and the physiological monitoring is running, the participant lies at rest at the head-of-bed angle of 30 degrees for 3 minutes. A continuous 60 second baseline recording is then acquired. The baseline is accepted as stable when the operator confirms, immediately before the first provocation, that the Doppler signal at each target vessel is continuously present and free of movement or fixation artefact, and that heart rate and oxygen saturation are steady. If those conditions are not met, probe placement or fixation is adjusted, the rest period is extended and a further 60 second baseline is recorded; the first provocation does not begin until an acceptable baseline is obtained. The heart rate recorded over this baseline is documented as the session baseline heart rate and is the reference against which the bradycardia stop criterion is judged for the remainder of the session. This session baseline is separate from the pre-trial baseline that opens each individual provocation trial, described below; a pre-trial baseline commences only after the preceding recovery period is complete. Provocations are performed in the following fixed order, with three repetitions each before moving to the next test: Superficial temporal artery compression, performed bilaterally. Gentle compression is applied distal to the Doppler probes for 10 seconds per trial, three trials on the left side followed by three trials on the right side, released immediately on any symptom. Each recording block is 60 seconds: 30 seconds baseline, of which the final 10 seconds is the count-in, 10 seconds of compression, and 20 seconds of recorded recovery. Trials are separated by 60 seconds. If any stop criterion occurs on either side, no further superficial temporal artery compression is performed on either side and the participant is clinically evaluated. Breath-hold. The participant exhales fully and holds at end-expiration (empty-lung breath-hold). Each recording block is 60 seconds: 10 seconds baseline, a 10 second count-in, a 20 second hold, and 20 seconds of recorded recovery. Trials are separated by 60 seconds. The participant may release the hold at any time. Valsalva manoeuvre. Each recording block is 60 seconds: 10 seconds baseline, a 10 second count-in, a 10 second strain held at 40 mmHg against a digital manometer, and 30 seconds of recorded recovery. Trials are separated by 60 seconds. Two practice strains are performed during familiarisation. Hyperventilation. Each recording block is 180 seconds: a 10 second count-in, 120 seconds of paced hyperventilation to a metronome at 30 breaths per minute, and 50 seconds of recorded recovery. Trials are separated by 2 minutes to allow carbon dioxide to normalise. Common or internal carotid artery compression. Performed by an experienced clinician using gentle but firm pressure at the level of the neck, for a maximum of 5 seconds per trial, with immediate release if any symptom occurs. Three trials per side, with at least 2 minutes rest between trials. Each recording block is 60 seconds: 30 seconds baseline, occlusion of 5 seconds or less, and 25 seconds of recorded recovery. Pre-specified stop criteria apply to every provocation: presyncope, chest pain, new neurological symptoms, new arrhythmia, or investigator concern; or any of the following numeric limits: oxygen saturation below 92 per cent; heart rate above 160 beats per minute; systolic blood pressure above 160 mmHg; diastolic blood pressure below 50 mmHg; or bradycardia, defined as whichever occurs first of a fall in heart rate of 30 beats per minute or more below the session baseline, or an absolute heart rate below 40 beats per minute. Where a limit is breached the actual value is recorded, the trial is stopped, the participant is returned to a safe position, and the value is escalated to the attending clinician. If a trial is terminated early, no further repeats of that provocation are attempted unless the clinician judges it safe and the participant wishes to continue. Duration and adherence: individual participation is approximately 2 to 4 hours during one main recording visit. Screening occurs at a preceding visit, either on the same day immediately prior or up to 14 days earlier, and includes carotid duplex ultrasound. A telephone safety follow-up is made at 24 hours. Adherence is monitored by direct observation of every provocation by study staff, and each trial is recorded on the case report form. Imaging sub-study: a subset of up to five participants, drawn only from the expansion group, also undergoes a single non-contrast magnetic resonance angiogram of the head, expected to take 60 to 90 minutes, within 0 to 14 days of the main recording visit. This is performed at a third-party imaging service provider on the investigator's referral. Selection of these participants is by invitation on the basis of MRI eligibility and the practical feasibility of scheduling the scan within that window; it is not determined by order of enrolment or order of opt-in, and run-in group participants are not eligible. MRI safety screening is performed by trained imaging staff. Participation in the sub-study is optional, and declining it does not affect participation in any other part of the study. If an invited participant declines, withdraws or cannot complete the scan, a replacement is invited from the remaining expansion group participants, up to a maximum of five completed scans. The Doppler ultrasound and monitoring systems used are commercially available, off-the-shelf devices, used without modification and within their approved intended purpose, as measurement tools only. No investigational medical device is under study, and the study does not evaluate the safety, effectiveness or performance of any device.