The primary findings of this study were an impairment of attentional performance (TAP) during the seated position and a reduction of executive function (Stroop) while upright in patients with PoTS compared with HCs. Only a few studies have investigated cognitive dysfunction in PoTS, even though many patients with PoTS report cognitive problems in routine clinical examinations [
6,
8,
11]. The results of the TAP in seated patients with PoTS compared with HCs provide further evidence that patients with PoTS show selective cognitive impairment of attentional performance, even during minimal orthostatic stress (sitting). This result is especially interesting in the context of the LPS as a measure of general cognitive ability, which showed no difference between patients with PoTS and HCs. Impaired attention in patients with PoTS was found in other studies in a seated position using Ruff 2 + 7 Speed Test [
3], WAIS-III digits forward [
8], ADHD subscales [
18] and CANTAB [
41], and also while standing using CogState [
8,
9] and TAP subtest for sustained attention [
11]. In contrast, recent research found no differences in tonic alertness using the TAP in supine and passive upright positions; however, the sample size was small (PoTS
n = 8, only neuropathic PoTS) [
42]. Patients scored worse than HCs for Stroop in the upright position and deteriorated from supine to the upright (upright and upright legs crossed) positions. In the supine position, where orthostatic stress is reduced to a minimum, no differences in cognitive tests were detected between PoTS and HCs. This validates the hypothesis that orthostatic stress itself impairs executive function in patients with PoTS. These findings are in line with results found in previous research: describing normal executive function in the supine position but an impairment during active standing [
9] and in the seated position using Stroop and Trail Making Test B [
3]. In line with previous results [
9], our results show a moderately positive correlation between impaired attention (TAP) and executive functioning (Stroop). There was a positive correlation between Stroop U and TAP in the HC group, but not in the PoTS group. As Stroop and TAP both require executive control [
43], we would have expected the tests to correlate as seen in the HC group, if standing did not have any impact on executive control. On the other hand, for Stroop S (supine) we found a positive correlation with TAP in both the PoTS and the HC group. In recent research, “sustained attention” was tested with the TAP in the supine position and at 60° head-up tilt during, before, and after water ingestion. There was more cognitive impairment during head-up tilt in patients with PoTS (more omissions in the TAP), which also indicates a decrease in working memory [
11]. A positive effect on working memory was shown previously using intake of water to reduce orthostatic symptoms [
11,
42]. It must be mentioned that in their study, cognitive performance was tested during passive tilt testing, whereas in our study, patients performed active standing, which pre-activates the leg muscle pump as described above. Thus, all these data support the hypothesis that cognitive impairment in PoTS is not a global problem caused by the disease itself, but a functional deficit induced by orthostatic stress, which might alter cerebral perfusion or central neurometabolic mechanisms. A second important finding was that leg crossing did not improve executive function in patients with PoTS. Crossing the legs increases the venous return and improves cerebral perfusion, but also reduces the balance compared with standing. A situation with an increasing need to maintain balance might result in impaired cognition [
44]. Interestingly, the significant difference that exists between PoTS and HCs in the upright posture is no longer detectable in the ULC posture. While the performance in Stroop worsened on average from U to ULC in the HCs, in patients with PoTS, the performance in Stroop improved during ULC, considering the absolute values. However, the change is very small, and it should be interpreted with caution. For further studies we would suggest reducing orthostatic stress by other methods, e.g., using compression garments that reduce orthostatic symptoms without affecting balance.
Although the effect of NE, not only on orthostatic symptoms such as tachycardia, palpitations and tremor, but also on cognitive dysfunction in patients with PoTS, has been extensively discussed in the literature, there is little research and evidence to date. Thus, in this study, one finding was that NE levels were elevated in both the supine and upright positions, similar to previous research [
11], indicating an overactivity of the sympathetic nervous system in patients with PoTS compared with HCs. Moreover, there was a negative correlation between the degree of NE rise and Stroop performance while upright. In our study, we can exclude an effect of stress during the cognitive test on NE release because cognitive testing and NE testing were not performed at the same time, as recorded in another study [
11]. An excessive NE rise in the PoTS group might negatively influence cognition, either by the central effects of NE itself or more profound symptoms during standing, as described previously [
11]. In contrast, an association between plasma levels of NE and impaired cognition was not found, but their cognitive tests were performed in the seated position [
3]. In our sample, TAP median values, which were also tested in a seated position, did not correlate with NE responses.
We observed higher depression and anxiety scores using the BDI-II and BAI for patients with PoTS than for HCs. There was a positive correlation between BAI and BDI-II scores and NE increase. The symptoms listed in the BAI include both psychological and somatic symptoms, such as tremor, palpitation, sleep problems and fatigue, which are very common in PoTS and may be a symptom of the hyperadrenergic state and the disease itself, but not of a depressive or anxiety disorder. Only two of our patients had a prior diagnosis of depression, and none had anxiety. These results show that the scores alone must be interpreted with caution [
3,
45], especially in patients with PoTS, because PoTS symptoms can mimic symptoms of depression or anxiety. Patients with higher NE levels might score higher in the BAI due to more somatic symptoms caused by PoTS. As symptoms of PoTS are phenomenologically different from symptoms of panic disorder or anxiety, these diseases must be clinically distinguished [
46] to avoid misinterpretation of PoTS as an anxiety disorder.
Study limitations
A limitation of this study is the small study group; thus, further studies should include more patients to reach good power. Moreover, a selection bias cannot be ruled out because in this centre specializing in autonomic disorders, people with less symptom burden may be under represented. Thus, our results are not representative of the overall PoTS population. Second, cognitive tests of the assessment battery did not cover all aspects of cognition, and the TAP was not performed in the standing position due to practical reasons, so the comparison with other studies is limited. To counteract the potential bias caused by practice effects on the results, we randomized the order of positions in which the participants performed the task (S, U, ULC). Thus, any practice effect that may have occurred would be evenly distributed across all the different orders, minimizing its impact on the overall results. This was done both for the PoTS and control groups to ensure that any differences observed between the two groups were solely due to group affiliation (PoTS versus control) and not due to the influence of practice effects. We cannot exclude that a longer standing time with e.g., higher heart rate, lower blood pressure or reduced intracerebral blood flow might influence cognition as well. Interestingly, we started the runs always with the Stroop tests and this was the only test where we found significant differences between the PoTS and the HC group in the main cognition. Thus, one might assume that not the standing time itself, but the upright posture alone may be the important factor. For further studies it might be interesting to test if the standing time has any influence on cognition itself.