VINCI-AD: An Investigation of Transcutaneous Vagus Nerve Stimulation in Mild Cognitive Impairment.

Orthostatic stress is measured via the active stand test whereby participants lie supine for 5 minutes with beat to beat blood pressure (BP) monitoring. They then stand and BP response to orthostatic challenge is measured. To standardise assessments, they are all taken at 14:00 each day, without nicotine or caffeine consumed that day, and all routine meds are taken as usual each morning. Orthostatic hypotension is defined by consensus as a sustained reduction of systolic blood pressure (SBP) of at least 20 mmHg or diastolic blood pressure (DBP) of 10 mmHg within 3 minutes of standing

Likert based questionnaires have been developed to assess for the routine side effects noted in the literature for acute t-VNS treatment including pain, skin discomfort, tingling, headache, tinnitus. These Likert scales are rated 1 to 5 with 1 = worse symptoms and 5 = no symptoms, and will be undertaken after active and sham stimulation. Participants will be given contact details of the principal investigator and study coordinator at the hospital who they can contact if they have concerns or any new symptoms arise.

Tolerability of the device will be assessed via in-person questionnaires involving Likert-based scales rated 1 to 5 with 1 = poorly tolerable / painful and 5 = no discomfort noted / comfortable

The Face Name Association Test is a cross-modal associative memory test involving Face-Name pairs, of which the participant is shown 30 pairs and then asked to recall if they have been shown before, and if so what their name was. t-VNS has been shown to boost associative memory as assessed by this task in cognitively unimpaired older adults, but has not been assessed in those with MCI. Near-infrared spectroscopy (NIRS) assessment will be ongoing during cognitive assessments, and the assessments will be undertaken 3 times, once at baseline, once during sham once during active t-VNS with 7-10 days between assessments

The Sustained Attention to Response Task (SART) is a computer-based go/no-go task that requires participants to withhold behavioral response to a single, infrequent target (often the digit 3) presented amongst a background of frequent non-targets (0-2, 4-9). There is evidence supporting the role of the SART as a measure of working memory, sustained attention, and impulse/inhibitory control. We will measure participants' response times and accuracy, at baseline, during active and sham t-VNS with near infrared spectroscopy (NIRS) measurements ongoing during task.

Sea Hero Quest is a multi-platform mobile game designed to help advance the understanding of spatial navigation and 3D navigation, which is one of the first skills lost in dementia. We will measure participants' ability to navigate through 5 pre-specified levels of Sea Hero Quest, specifically speed and accuracy of navigation. Near-infrared specroscopy (NIRS) measurement will be ongoing during assessment and the assessments will be undertaken at baseline, during active and sham t-VNS.

Heart rate variability (HRV) is an index of the beat- to beat variability between heart beats. Increased vagal tone (and thus vagal action) is generally associated with a lower heart rate and increased HRV. Indices of HRV including SDNN, RMSSD, HF/LF ratio will be obtained during 5 minutes of rest pre -orthostatic stress. Baseline HRV, and HRV during both active t-VNS and sham t-VNS will be obtained for each participant

Non-invasive VNS has been shown to downregulate inflammatory cytokine release in healthy young participants, but has not been assessed in participants with MCI. We aim to measure a wide array of blood based cytokines and chemokines using the Luminex assay. Serum and plasma samples will be taken at baseline assessment, after acute active t-VNS and sham t-VNS.

Participants' objective ability to utilise and troubleshot the t-VNS device will be assessed via modified Kettle test; a brief Occupational Therapy performance-based measure designed to assess cognitive skills in a functional context.