Many POTS patients report cognitive dysfunction, otherwise referred to as brain fog,
mental fog, mental clouding, or mental fatigue. Importantly, this cognitive dysfunction
can occur even while lying down or seated, limiting the ability to engage in work and
educational activities. Despite the prevalence and clinical impact of cognitive
dysfunction in POTS, there are limited studies examining this phenomenon. Many patients
with post-acute sequelae of SARS-COV-2 (PASC, or "Long COVID") experience symptoms such
as subjective cognitive impairment ("brain fog"), fatigue, memory loss, headache, and
fluctuation of blood pressure, amongst other signs and symptoms. Compared to healthy
controls, this study will measure cognitive function in patients with POTS and Long
COVID. This study will also evaluate IV normal saline (999 mL infusion) as a potential
treatment for reduced cognitive function in POTS and Long COVID. This cross-over study
will use a 50 mL saline infusion as a placebo control.

The findings from this study will be an initial first step towards understanding any
neurocognitive impairment in participants with long COVID and POTS patients. This is a
critical first step to future studies to assess underlying pathophysiology and potential
treatments.

Primary hypothesis: Some objective measures of neurocognitive functions will improve in
Long COVID and POTS patients after the infusion of 999 mL of normal saline compared to
50mL placebo control.

The primary analysis will compare the standing 5RTI task on the CANTAB testing scores
between 999 mL saline infusion and 50 mL saline infusion (placebo).

Study Day and Instrumentation:

- A trained research staff member will insert an intravenous line in the vein of the
participant's arm to administer either 999 mL or 50 mL of normal saline, which can
take up to 30 minutes.

- After instrumentation, the participant will lie supine for at least 10 minutes while
their ECG and BP are continuously recorded.

- The participant will stand up quickly (within several seconds) and then stand
quietly for about 11 minutes while the recording continues. The lying-to-stand
procedure will allow us to assess the hemodynamics of IST, POTS, and OH. A chair
will be provided to the participant at any time they want to sit down during the
test.

- After the stand test, the participant will be asked to do the Trail-Making Test
(TMT) in the standing position. They will be asked to join numbers and letters in a
circle. This test should not take more than approximately 10 minutes. A chair will
be provided if they want to sit down at any time during the test.

- The participant will then be seated comfortably in a chair with their feet on the
floor. They will be asked to do the Heart Counting Task (HCT) test. The participant
will be asked to count their heartbeats without using their hands or other means to
feel their pulse, which might affect their performance. This test will take
approximately 10 minutes.

- The research team will then de-instrument the participant except for the Blood
Pressure cuff on the arm. The team will continue to monitor the blood pressure
throughout the study.

- Neuropsychological testing of the cognitive domains of memory, attention and
executive function will be assessed using the Cambridge Neuropsychological Test
Automated Battery (CANTAB) both seated and standing.

- The seated cognitive testing period will last approximately 60 minutes.

- The participant will be asked to stand unaided for up to 30 minutes and repeat
portions of the CANTAB tests. Blood Pressure will be monitored throughout the stand
test. A chair will be provided to the participant in case they would want to sit
down.

- At the end of each stand test, the investigators will assess the patient's symptoms
using the Vanderbilt Orthostatic Symptoms Score (VOSS). VOSS is a 9-item symptom
rating, with each item scoring from 0 (absent) to 10 (worst) for a total score
ranging from 0 to 90.

- The study will then be finished. The investigators will remove the recording patches
and electrodes.

- The participant will then be booked for the second visit according to their
convenience, where all the tests will be repeated, including IV insertion and
infusion of normal saline, supine, and stand, and the cognitive tests (CANTAB, TMT,
and HCT). Repeating these tests will help the research team assess whether the
cognitive functions will improve for the Long COVID and POTS patients with blood
volume expansion with the infusion of normal saline.

CANTAB Testing Protocol: CANTAB tests have demonstrated sensitivity to detecting changes
in neuropsychological performance and include tests of working memory, learning and
executive function; visual, verbal and episodic memory; attention, information processing
and reaction time; social and emotion recognition, decision making and response control.
The subtests that will be used in this study for seated cognitive function are: Reaction
Time Test (psychomotor Speed), Rapid Visual Information processing (Attention), Paired
Associates Learning (Visual Episodic Memory), Spatial Span (Working memory), Verbal
Recognition Memory (Verbal memory), Multitasking Test (Executive Function - Inhibition),
Stocking of Cambridge (Executive Function - Planning) and the Emotional Bias Task
(Emotion Processing). All tests are administered using a touchscreen tablet, and
participants will respond to each test on-screen. Standardized written and audio
instructions are given to participants through the software, and practice trials are
completed before each test, reducing practice effects. Seated testing will be completed
in approximately 60 minutes. The Reaction Time Test, Rapid Visual Processing and Multi
Tasking tests will be repeated upon standing and will take approximately 30 minutes to
complete.

After the in-lab portion of the study, participants will complete a series of validated
questionnaires through a paper or RedCap secure web application for assessment of
psychiatric symptoms. A unique URL link will be sent to the participants via Redcap
Survey. These online surveys will take approximately 60 minutes to complete.