The Role Of Serotonergic And Noradrenergic Descending Pathways On Performance-Based Cognitive Functioning At Rest And in Response To Exercise in People With Chronic Whiplash-Associated Disorders: A Randomized Controlled Crossover Study Part 2
Sep 13, 2023
3.4. The Effect of a Single Dose of an SSRI or a Selective NRI on Cognitive Performance in Response to Submaximal Aerobic Exercise in People with CWAD
Based on the interaction effects, no significant differences were revealed between the medication conditions (no medication, Citalopram, Atomoxetine) on cognitive performance in response to a bout of acute submaximal aerobic exercise in people with CWAD (p>0.05). However, when performing pairwise comparisons (pre-post submaximal exercise) within each medication condition, significant improvements in selective attention for Stroop reaction time incongruent (p=0.025, d=−0.70) and choice reaction time for Stroop reaction time congruent (p=0.018, d=−0.92) and category (p=0.012,d=−0.65) were found after exercise for the no medication condition (Figure 3; detailed statistics presented in Table 4).
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In contrast, after intake of Citalopram or Atomoxetine, both selective and sustained attention significantly worsened, and simple (PVT) reaction time significantly increased postexercise (p<0.05) (Figures 3 and 4; Table 4). More specifically, people with CWAD showed significantly decreased accuracy in Stroop reaction time incongruent after the submaximal exercise bout on the Atomoxetine assessment day (p=0.030, d=−0.50). Additionally, participants showed a significantly higher number of lapses during the PVT after exercise compared to the pre-exercise result on the Atomoxetine assessment day (p=0.034, d=0.64) (Figure 4). After intake of Citalopram, Stroop accuracy negative priming significantly worsened after the aerobic exercise (p=0.015, d=−0.65) (Figure 3). Furthermore, after Citalopram intake, simple reaction time significantly increased postexercise, thus sustained attention worsened (p = 0.021, d = 0.53) (Figure 4).
4. Discussion
This innovative study investigated the effects of a single dose of an SSRI and a selective NRI on cognitive performance at rest and in response to exercise in people with CWAD. At rest, the intake of a single dose of Atomoxetine had a positive influence on the results of the Stroop task of only one condition by decreasing the choice reaction time during the Stroop congruent condition compared to the Stroop congruent reaction time measured without Atomoxetine intake (small effect size). The latter finding of improved selective attention is in line with our hypothesis. Nevertheless, Atomoxetine had no significant isolated effect on all other cognitive performance variables in people with CWAD. Furthermore, no significant effects of a single dose of Citalopram on cognitive functioning at rest in people with CWAD could be demonstrated. It is noteworthy that the possible reported side effects of both medications that could influence cognition are drowsiness, sleeping problems, and fatigue [65]. Nonetheless, an acute dose of Citalopram or Atomoxetine did not worsen cognitive performance at rest in people with CWAD compared to the no medication condition. Additionally, levels of fatigue were similar on all assessment days.
It might be possible that activation of noradrenergic transmission pre-exercise and the subsequent increased availability of norepinephrine after Atomoxetine use enhanced selective attention, but further work in this area is necessary. Citalopram intake had no significant isolated effect on cognitive performance, which is by findings in healthy persons [46,66,67].
This study provides the novel insight that the positive effects of a bout of acute aerobic exercise on selective attention and choice reaction time (medium to large effect sizes) could only be detected when no SSRI or selective NRI was taken by people with CWAD. In addition, WAD symptoms, such as pain (based on our previous study [9]) and fatigue, were not exacerbated either immediately or 24 h postexercise.
A positive influence of acute aerobic exercise on cognitive functioning was, on the one hand, hypothesized because this has been demonstrated in patients with chronic fatigue syndrome [68] and healthy people [35,36]. Furthermore, evidence is available in various chronic pain conditions that exercise therapy has a positive effect on cognitive functioning [69–73]. On the other hand, some evidence exists for the worsening of symptoms following physical exertion in women with CWAD [18]. Nevertheless, in a recent study, patients with CWAD did not perceive increased pain sensitivity following aerobic exercise [74].
The mechanisms that could explain the observed beneficial effects of acute aerobic exercise on cognitive functioning are presumed to be driven by physiological responses to exercise. These responses comprise changes in heart rate and plasma catecholamines, increased levels of growth factors such as brain-derived neurotrophic factor (BDNF) [35], and brain neurotransmitters such as norepinephrine, serotonin, and dopamine, mediating the exercise-induced enhancement of cognition [33,34].
The intake of a single dose of Atomoxetine resulted in a worsening of Stroop accuracy reaction time incongruent and more errors of omission during the PVT in response to the acute exercise bout (medium effect size). Similarly, a single dose of Citalopram resulted in a worsening of Stroop accuracy reaction time (negative priming) and gave rise to diminished sustained attention after the exercise compared to the pre-exercise condition (medium effect size). The latter results are not according to our hypotheses. Because changes in, for example, BDNF, serotonin, and norepinephrine levels in response to the exercise performance were not measured, we cannot state which mechanisms accounted for the observed changes in cognitive functioning following the exercise.
Possibly, the acute medication-induced increased levels of serotonin and norepinephrine in the brain had a negative influence on the mediating effect of these monoamines on cognitive performance in response to exercise. On the other hand, it could be that the single acute dose of both centrally acting drugs was not adequate to successfully activate serotonergic and noradrenergic descending pathways in response to exercise and hence, to obtain positive effects on postexercise cognition. Therefore, the present study has limited clinical implications. It can be concluded that clinicians are advised not to use single doses of Citalopram or Atomoxetine to improve cognitive performance at rest or in response to exercise in people with CWAD.
Limitations and Recommendations for Further Research
The following limitations should be taken into account. As we could not demonstrate significant interaction effects, and a small sample size increases the risk of committing a type II error, further research with a larger sample size is warranted before firm conclusions can be drawn.
This study only investigated the effects of a single dose of Citalopram and Atomoxetine in people with CWAD. To ensure peak concentrations at the time of testing, all participants were instructed to take Citalopram (20 mg per os; Citalopram Sandoz®) for four hours and Atomoxetine (40 mg per os; Strattera®) for one and a half hours, respectively, before the scheduled start of their appointment [41,42]. However, people with chronic pain usually take these medications over a long period. Perhaps, these medications should be taken for a longer period before exerting positive effects on the influence that exercise exerts on cognitive functioning. Indeed, the onset of action of Citalopram for depression is approximately 1 to 4 weeks, and the complete response may take 8 to 12 weeks after initiation. Future work should examine whether such long-term administration of Citalopram has different effects, as observed here. Furthermore, this trial is not placebo-controlled. We did not include a condition with a placebo medication which could have been useful to blind participants also for the test day without medication and to enhance insights into underlying mechanisms. Originally, we intended to include a placebo group, but the ethical committee did not allow us to do that.
The improved selective attention combined with the absence of post-exertional aggravation of symptoms in response to the acute aerobic exercise in individuals with CWAD indicates the relevance of further randomized controlled trials to study the effects of graded aerobic exercise therapy on cognitive functioning.
5. Conclusions
In conclusion, a single dose of Atomoxetine improved selective attention only in one Stroop condition, and a single dose of Citalopram did not affect cognitive functioning at rest in people with CWAD. Only without medication intake did selective attention improve in response to exercise, whereas both centrally acting medications worsened cognitive performance in response to a submaximal aerobic exercise bout in people with CWAD. Further research with larger sample sizes is warranted. Examining the influence of the long-term use of selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors on the physiological response to exercise training and subsequent effects on cognitive functioning in people with chronic pain is a future research avenue.
Author Contributions: Conceptualization, J.N., and K.I.; methodology, K.I., I.C., M.M., I.H., and M.D.K.; validation, I.C., J.N., M.M., M.D.K., E.R., E.H., R.P., W.V.B., I.H., and K.I.; formal analysis, M.D.K., I.C., and K.I.; investigation, I.C., J.N., M.M., M.D.K., E.R., E.H., R.P., W.V.B., I.H., and K.I.; resources, I.H., J.N., and K.I.; data curation, K.I.; writing—original draft preparation, I.C., and K.I.; writing—review and editing, I.C., J.N., M.M., M.D.K., E.R., E.H., R.P., W.V.B., I.H. and K.I.; visualization, I.C.; supervision, K.I., and J.N.; project administration, K.I.; funding acquisition, J.N., K.I., and I.H. All authors have read and agreed to the published version of the manuscript.
Funding: This research was partly funded by the Scientific Fund Willy Gepts of the University Hospital Brussels, grant number WFWG-22. Iris Coppieters, a postdoctoral researcher at Vrije Universiteit Brussel, is funded by the Research Foundation Flanders (FWO) [G007217N], Belgium. Eva Huysmans is a PhD research fellow funded by the Research Foundation Flanders (FWO) [1108619N], Belgium. Roselien Pas and Emma Rheel are funded by a Chair awarded by the Berekuyl Academy/European College for Decongestive Lymphatic Therapy, the Netherlands, to the Vrije Universiteit Brussel, Belgium. Wouter Van Bogaert is funded by the Agency for Innovation by Science and Technology (IWT)—Applied Biomedical Research Program (TBM) [150180].
Institutional Review Board Statement: The research protocol was approved by the Ethics Committee of the University Hospital Brussels/Vrije Universiteit Brussel and complied with the Declaration of Helsinki. The study drugs were produced according to the Good Manufacturing Practice. All participants were thoroughly informed about the study procedures and signed a consent form before study enrolment. This study was registered with ClinicalTrials.gov (Identifier No. NCT01601912).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: Please contact the corresponding author to obtain the research data. All requests for obtaining the research data will be considered by the research team.
Acknowledgments: The authors would like to thank Menno Franken and Elien Vanderlinden for their assistance with data collection. The authors would like to thank Roos Colman and Wilfried Cools for their assistance with statistical data analyses.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
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