Central Sympathetic Nervous System Effects on Cognitive-Motor Performance
Results From a Placebo-Controlled Pharmacological Study
Abstract
Abstract. The intriguing interplay between acute stress physiology and cognitive processes has long been noted. However, while stress-induced release of glucocorticoids has repeatedly been shown to impact brain mechanisms underlying cognition and memory, less experimental research addressed the effects of stress-induced central sympathetic nervous system (SNS) activation on cognitive performance. Moreover, despite the long-standing notion that the way performance is modulated by arousal may crucially depend on task complexity, mechanistic research demonstrating a direct, causal influence of altered SNS activity is scarce. Twelve healthy men participated in a placebo-controlled, pharmacologic dose–response study involving three within-subject assessments (1-week intervals). Subjective and objective indices of SNS activity as well as reaction time (RT) in three different tasks varying in cognitive demand (simple RT, choice RT, and verbal RT in complex mental arithmetic) were assessed during modulation of central SNS tone by intravenous infusions of dexmedetomidine (alpha2-agonist), yohimbine (alpha2-antagonist), and placebo. Cognitive performance was negatively affected by alpha2-agonism in all task conditions. By contrast, administration of yohimbine improved simple RT, while diminishing complex RT, supporting the assumption of a nonlinear way of action depending on task characteristics. Our results highlight the consequences of central (noradrenergic) SNS activation for cognitive-motor performance in RT tasks of varying complexity.
References
1997). Cardiovascular and neuroendocrine adjustment to public speaking and mental arithmetic stressors. Psychophysiology, 34(3), 266–275.
(2003). Arousal, anxiety, and performance: A reexamination of the inverted-U hypothesis. Research Quarterly for Exercise and Sport, 74, 436–444. 10.1080/02701367.2003.10609113
(1991). Discharge of noradrenergic locus coeruleus neurons in behaving rats and monkeys suggests a role in vigilance. Progress in Brain Research, 88, 501–520. 10.1016/S0079-6123(08)63830-3
(2005). An integrative theory of locus coeruleusnorepinephrine function: Adaptive gain and optimal performance. Annual Review of Neuroscience, 28, 403–450. 10.1146/annurev.neuro.28.061604.135709
(2019). Testretest reproducibility of a combined physical and cognitive stressor. Biological Psychology, 148, 107729. 10.1016/j.biopsycho.2019.107729
(2005). The inverted “U-shaped” doseeffect relationships in learning and memory: Modulation of arousal and consolidation. Nonlinearity in Biology, Toxicology, Medicine, 3(1), nonlin-003.01.0. 10.2201/nonlin.003.01.002
(2001). Enhanced memory for emotional material following stress-level cortisol treatment in humans. Psychoneuroendocrinology, 26, 307–317. 10.1016/s0306-4530(00)00058-5
(2008). Neuroscience and hormesis: Overview and general findings. Critical Reviews in Toxicology, 38, 249–252. 10.1080/10408440801981957
(1992). Sympathetic activity is influenced by task difficulty and stress perception during mental challenge in humans. The Journal of Physiology, 454, 373–387. 10.1113/jphysiol.1992.sp019269
(2013). Noradrenergic modulation of cognition: Therapeutic implications. Journal of Psychopharmacology, 27, 694–718. 10.1177/0269881113480988
(2004). Acute stressors and cortisol responses: A theoretical integration and synthesis of laboratory research. Psychological Bulletin, 130, 355–391. 10.1037/0033-2909.130.3.355
(2014). Using Bayes to get the most out of non-significant results. Frontiers in Psychology, 5, 781. 10.3389/fpsyg.2014.00781
(1993). Computer-controlled infusion of intravenous dexmedetomidine hydrochloride in adult human volunteers. Anesthesiology, 78, 821–828. 10.1097/00000542-199305000-00003
(1997). Relating the mechanisms of orienting and alerting. Neuropsychologia, 35, 477–486. 10.1016/s0028-3932(96)00103-0
(1986). Hormonal responses to a graded mental workload. European Journal of Applied Physiology and Occupational Physiology, 55, 339–343. 10.1007/bf00422730
(2008). Arousal and attention: Self-chosen stimulation optimizes cortical excitability and minimizes compensatory effort. Journal of Cognitive Neuroscience, 20, 1443–1453. 10.1162/jocn.2008.20101
(2013). Stress disrupts distractor-based retrieval of SR episodes. Biological Psychology, 93(1), 58–64. 10.1016/j.biopsycho.2013.01.013
(1983). Influence of yohimbine on blood pressure, autonomic reflexes, and plasma catecholamines in humans. Hypertension, 5, 772–778. 10.1161/01.hyp.5.5.772
(1990). Short-term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus. Neuroscience, 37, 367–375. 10.1016/0306-4522(90)90407-u
(1977). Paced auditory serial-addition task: A measure of recovery from concussion. Perceptual and Motor Skills, 44, 367–373. 10.2466/pms.1977.44.2.367
(1994). The effect of d‐amphetamine, clonidine, and yohimbine on human information processing. Psychophysiology, 31, 331–337. 10.1111/j.1469-8986.1994.tb02441.x
(1992). Yohimbine pharmacokinetics and interaction with the sympathetic nervous system in normal volunteers. European Journal of Clinical Pharmacology, 43, 651–656. 10.1007/bf02284967
(1999). Two functionally distinct α2-adrenergic receptors regulate sympathetic neurotransmission. Nature, 402, 181–184. 10.1038/46040
(1936). The cold pressor test for measuring the reactibility of the blood pressure: Data concerning 571 normal and hypertensive subjects. American Heart Journal, 11(1), 1–9. 10.1016/s0002-8703(36)90370-8
(1993). The ‘Trier Social Stress Test’–a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology, 28(12), 76–81. 10.1159/000119004
(1973). Increased turnover of norepinephrine in the rat cerebral cortex during stress: Role of the locus coeruleus. Neuropharmacology, 12, 933–938. 10.1016/0028-3908(73)90024-5
(2010). The effect of exercise-induced arousal on cognitive task performance: A meta-regression analysis. Brain Research, 1341, 12–24. 10.1016/j.brainres.2010.03.091
(1994). Reduced parasympathetic cardiac control in patients with hypertension at rest and under mental stress. American Heart Journal, 127(1), 122–128. 10.1016/0002-8703(94)90517-7
(2020). Disentangling sensorimotor and cognitive cardioafferent effects: A cardiac-cycle-time study on spatial stimulus-response compatibility. Scientific Reports, 10(1), 1–10. 10.1038/s41598-020-61068-1
(1999). Biopharmaceutics and metabolism of yohimbine in humans. European Journal of Pharmaceutical Sciences, 9(1), 79–84. 10.1016/s0928-0987(99)00046-9
(2003). A modified computer version of the Paced Auditory Serial Addition Task (PASAT) as a laboratory-based stressor. The Behavior Therapist, 26, 290–293.
(1975). The cold pressor test and autonomic function: A review and integration. Psychophysiology, 12, 268–282. 10.1111/j.1469-8986.1975.tb01289.x
(2018). Sympathetic arousal, but not disturbed executive functioning, mediates the impairment of cognitive flexibility under stress. Cognition, 174, 94–102. 10.1016/j.cognition.2018.02.004
(1970). Motor performance under stress: A test of the inverted-U hypothesis. Journal of Personality and Social Psychology, 16(1), 29. 10.1037/h0029787
(2004). The physiological experience of the Paced Auditory Serial Addition Task (PASAT): Does the PASAT induce autonomic arousal? Archives of Clinical Neuropsychology, 19, 543–554. 10.1016/j.acn.2003.08.001
(2007). Effects of arterial and cardiopulmonary baroreceptor activation on simple and choice reaction times. Psychophysiology, 44, 874–879. 10.1111/j.1469-8986.2007.00547.x
(2007). Effects of the noradrenergic agonist clonidine on temporal and spatial attention. Psychopharmacology, 193, 261–269. 10.1007/s00213-007-0770-7
(2007). Cardiovascular reactivity to mental stress is not affected by alpha2-adrenoreceptor activation or inhibition. Psychopharmacology, 190, 181–188. 10.1007/s00213-006-0597-7
(2008). Measuring alertness. Annals of the New York Academy of Sciences, 1129(1), 193–199. 10.1196/annals.1417.011
(2016). Orienting of attention: Then and now. The Quarterly Journal of Experimental Psychology, 69, 1864–1875. 10.1080/17470218.2014.937446
(2020). Acute psychological stress promotes general alertness and attentional control processes: An ERP study. Psychophysiology, 57, e13521. 10.1111/psyp.13521
(1993). Baroreceptor stimulation alters cortical activity. Psychophysiology, 30, 322–325. 10.1111/j.1469-8986.1993.tb03359.x
(2002). Stress and memory: Opposing effects of glucocorticoids on memory consolidation and memory retrieval. Neurobiology of Learning and Memory, 78, 578–595. 10.1006/nlme.2002.4080
(2003). Cognitive and psychomotor function in hypoglycemia: Response error patterns and retest reliability. Pharmacology Biochemistry and Behavior, 75, 915–920. 10.1016/s0091-3057(03)00167-9
(1998). Reversal of the sedative and sympatholytic effects of dexmedetomidine with a specific alpha2-adrenoceptor antagonist atipamezole: A pharmacodynamic and kinetic study in healthy volunteers. Anesthesiology, 89, 574–584. 10.1097/00000542-199809000-00005
(2014). Rapid cortisol enhancement of psychomotor and startle reactions to side-congruent stimuli in a focused cross-modal choice reaction time paradigm. European Neuropsychopharmacology, 24, 1828–1835. 10.1016/j.euroneuro.2014.09.002
(2008). Covariance between psychological and endocrine responses to pharmacological challenge and psychosocial stress: A question of timing. Psychosomatic Medicine, 70, 787–796. 10.1097/psy.0b013e3181810658
(2009). Cold pressor stress impairs performance on working memory tasks requiring executive functions in healthy young men. Behavioral Neuroscience, 123, 1066–1075. 10.1037/a0016980
(2009). Cardiac modulation of startle: Effects on eye blink and higher cognitive processing. Brain and Cognition, 71, 265–271. 10.1016/j.bandc.2009.08.002
(2010). Corticosteroids operate as a switch between memory systems. Journal of Cognitive Neuroscience, 22, 1362–1372. 10.1162/jocn.2009.21278
(2016). The effects of acute stress on core executive functions: A meta-analysis and comparison with cortisol. Neuroscience & Biobehavioral Reviews, 68, 651–668. 10.1016/j.neubiorev.2016.06.038
(2016). Effects of acute laboratory stress on executive functions. Frontiers in Psychology, 7, 461. 10.3389/fpsyg.2016.00461
(1987). Peripheral, autonomic regulation of locus coeruleus noradrenergic neurons in brain: Putative implications for psychiatry and psychopharmacology. Psychopharmacology, 92(1), 1–7. 10.1007/bf00215471
(2003). Systemically administered α2-agonist-induced peripheral vasoconstriction in humans. Anesthesiology, 99(1), 65–70. 10.1097/00000542-200307000-00014
(2001). Yohimbine: A clinical review. Pharmacology & Therapeutics, 91, 215–243. 10.1016/s0163-7258(01)00156-5
(2015). The effects of cold pressor-induced pain on PASAT performance. Applied Neuropsychology: Adult, 22, 227–232. 10.1080/23279095.2014.910213
(1994). Yerkes-Dodson: A law for all seasons. Theory & Psychology, 4, 525–547. 10.1177/0959354394044004
(2006). A comprehensive review of the paced auditory serial addition test (PASAT). Archives of Clinical Neuropsychology, 21(1), 53–76.
(1984). Distribution of α2 agonist binding sites in the rat and human central nervous system: Analysis of some functional, anatomic correlates of the pharmacologic effects of clonidine and related adrenergic agents. Brain Research Reviews, 7(1), 69–101. 10.1016/0165-0173(84)90030-4
(2008). Convergent regulation of locus coeruleus activity as an adaptive response to stress. European Journal of Pharmacology, 583(23), 194–203. 10.1016/j.ejphar.2007.11.062
(2017). Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine. Clinical Pharmacokinetics, 56, 893–913. 10.1007/s40262-017-0507-7
(1998). Norepinephrine release in the amygdala after systemic injection of epinephrine or escapable footshock: Contribution of the nucleus of the solitary tract. Behavioral Neuroscience, 112, 1414–1422. 10.1037/0735-7044.112.6.1414
(1908). The relation of strength of stimulus to rapidity of habit‐formation. Journal of Comparative Neurology and Psychology, 18, 459–482. 10.1002/cne.920180503
(1993). Dexmedetomidine decreases cerebral blood flow velocity in humans. Journal of Cerebral Blood Flow & Metabolism, 13, 350–353. 10.1038/jcbfm.1993.45
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