Abstract
The default mode network (DMN) plays a central role in intrinsic thought processes. Altered DMN connectivity has been linked to diminished cerebral serotonin synthesis. Diminished brain serotonin synthesis is further associated with a lack of impulse control and various psychiatric disorders. Here, we investigated the serotonergic modulation of intrinsic functional connectivity (FC) within the DMN in healthy adult females, controlling for the menstrual cycle phase. Eighteen healthy women in the follicular phase (aged 20–31 years) participated in a double-blind controlled cross-over study of serotonin depletion. Acute tryptophan depletion (ATD) and a balanced amino acid load (BAL), used as the control condition, were applied on two separate days of assessment. Neural resting state data using functional magnetic resonance imaging (fMRI) and individual trait impulsivity scores were obtained. ATD compared with BAL significantly reduced FC with the DMN in the precuneus (associated with self-referential thinking) and enhanced FC with the DMN in the frontal cortex (associated with cognitive reasoning). Connectivity differences with the DMN between BAL and ATD in the precentral gyrus were significantly correlated with the magnitude of serotonin depletion. Right medial frontal gyrus and left superior frontal gyrus connectivity differences with the DMN were inversely correlated with trait impulsivity. These findings partially deviate from previous findings obtained in males and underline the importance of gender-specific studies and controlling for menstrual cycle to further elucidate the mechanism of ATD-induced changes within intrinsic thought processes.
Similar content being viewed by others
References
Anticevic A, Cole MW, Murray JD et al (2012) The role of default network deactivation in cognition and disease. Trends Cogn Sci 16:584–592. doi:10.1016/j.tics.2012.10.008
Barbey AK, Koenigs M, Grafman J (2013) Dorsolateral prefrontal contributions to human working memory. Cortex 49:1195–1205. doi:10.1016/j.cortex.2012.05.022
Biskup CS, Sánchez CL, Arrant A et al (2012) Effects of acute tryptophan depletion on brain serotonin function and concentrations of dopamine and norepinephrine in C57BL/6 J and BALB/cJ mice. PLoS One 7:e35916. doi:10.1371/journal.pone.0035916
Biskup C, Helmbold K, Baurmann D et al (2015a) Linking amino acids and brain function: serotonergic modulation of resting state default mode network connectivity in young patients with ADHD after dietary tryptophan depletion
Biskup CS, Gaber T, Helmbold K et al (2015b) Amino acid challenge and depletion techniques in human functional neuroimaging studies. Amino Acids 47(4):651–683. doi:10.1007/s00726-015-1919-z (Epub 2015 Mar 15)
Brown SM, Manuck SB, Flory JD, Hariri AR (2006) Neural basis of individual differences in impulsivity: contributions of corticolimbic circuits for behavioral arousal and control. Emotion 6(2):239–245
Carhart-Harris RL, Erritzoe D, Williams T et al (2012) Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci USA 109:2138–2143. doi:10.1073/pnas.1119598109
Cavanna AE, Trimble MR (2006) The precuneus: a review of its functional anatomy and behavioural correlates. Brain 129:564–583. doi:10.1093/brain/awl004
Chan RCK, Shum D, Toulopoulou T, Chen EYH (2008) Assessment of executive functions: review of instruments and identification of critical issues. Arch Clin Neuropsychol 23:201–216. doi:10.1016/j.acn.2007.08.010
Crawford JR, Henry JD (2004) The positive and negative affect schedule (PANAS): construct validity, measurement properties and normative data in a large non-clinical sample. Br J Clin Psychol 43:245–265
Crockett MJ, Clark L, Robbins TW (2009) Reconciling the role of serotonin in behavioral inhibition and aversion : acute tryptophan depletion abolishes punishment-induced inhibition in humans. Clin Neurosci 29:11993–11999. doi:10.1523/JNEUROSCI.2513-09.2009
Demisch L, Kewitz A, Schmeck K (2002) Methodology of rapid tryptophan depletion (RTD): impact of gender and body weight. Eur Arch Psychiatry Clin Neurosci 1:252
Dingerkus VLS, Gaber TJ, Helmbold K et al (2012) Acute tryptophan depletion in accordance with body weight: influx of amino acids across the blood-brain barrier. J Neural Transm 119:1037–1045. doi:10.1007/s00702-012-0793-z
Etkin A, Egner T, Kalisch R (2012) Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn Sci 15:85–93. doi:10.1016/j.tics.2010.11.004
Eysenck SBG, Pearson PR, Easting G, Allsopp JF (1985) Age norms for impulsiveness, venturesomeness and empathy in adults. J Individ Differ 6:613–619
Fornito A, Harrison BJ, Zalesky A, Simons JS (2012) Competitive and cooperative dynamics of large-scale brain functional networks supporting recollection. Proc Natl Acad Sci USA 109:12788–12793. doi:10.1073/pnas.1204185109
Fox MD, Snyder AZ, Vincent JL et al (2005) The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci USA 102:9673–9678. doi:10.1073/pnas.0504136102
Fransson P (2005) Spontaneous low-frequency BOLD signal fluctuations: an fMRI investigation of the resting-state default mode of brain function hypothesis. Hum Brain Mapp 26:15–29. doi:10.1002/hbm.20113
Gaber TJ, Dingerkus VL, Crockett MJ, Bubenzer-Busch S et al (2015) Studying the effects of dietary body weight-adjusted acute tryptophan depletion on punishment-related behavioral inhibition. Food Nutr Res 11(59):28443. doi:10.3402/fnr.v59.28443
Goldberg II, Harel M, Malach R (2006) When the brain loses its self: prefrontal inactivation during sensorimotor processing. Neuron 50:329–339. doi:10.1016/j.neuron.2006.03.015
Greicius MD, Krasnow B, Reiss AL, Menon V (2003) Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci USA 100:253–258. doi:10.1073/pnas.0135058100
Helmbold K, Bubenzer S, Dahmen B et al (2013) Influence of acute tryptophan depletion on verbal declarative episodic memory in young adult females. Amino Acids 45:1207–1219. doi:10.1007/s00726-013-1582-1
Helmbold K, Zvyagintsev M, Dahmen B et al (2015) Effects of serotonin depletion on punishment processing in the orbitofrontal and anterior cingulate cortices of healthy women. Eur Neuropsychopharmacol 25(6):846–856. doi:10.1016/j.euroneuro.2015.02.007
Hildebrand P, Königschulte W, Gaber TJ, Bubenzer-Busch S et al (2015) Effects of dietary tryptophan and phenylalanine-tyrosine depletion on phasic alertness in healthy adults—a pilot study. Food Nutr Res. 59:26407. doi:10.3402/fnr.v59.26407
Kewitz A (2002) Biochemische Untersuchungen zur Optimierung des “‘Rapid Tryptophan Depletion-Test’” (RTD)—Eine physiologische Methode zur akuten Verminderung der zentralnervösen Serotonin-Synthese in der psychobiologischen Forschung. Doctoral Thesis, Johann Wolfgang Goethe University of Frankfurt, Germany
Kötting WF, Bubenzer S, Helmbold K et al (2012) Effects of tryptophan depletion on reactive aggression and aggressive decision-making in young people with ADHD. Acta Psychiatr Scand 128:114–123. doi:10.1111/acps.12001
Kringelbach ML, Radcliffe J (2005) The human orbitofrontal cortex: linking reward to hedonic experience. Nat Rev Neurosci 6(9):691–702. doi:10.1038/nrn1747
Kunisato Y, Okamoto Y, Okada G et al (2011) Modulation of default-mode network activity by acute tryptophan depletion is associated with mood change: a resting state functional magnetic resonance imaging study. Neurosci Res 69:129–134. doi:10.1016/j.neures.2010.11.005
Lasiuk GC, Hegadoren KM (2007) The effects of estradiol on central serotonergic systems and its relationship to mood in women. Biol Res Nurs 9:147–160. doi:10.1177/1099800407305600
Lee MA, Meltzer HY (2001) 5-HT(1A) receptor dysfunction in female patients with schizophrenia. Biol Psychiatry 50:758–766
Lemogne C, Delaveau P, Freton M et al (2012) Medial prefrontal cortex and the self in major depression. J Affect Disord 136:e1–e11. doi:10.1016/j.jad.2010.11.034
Lis E, Greenfield B, Henry M et al (2007) Neuroimaging and genetics of borderline personality disorder: a review. J Psychiatry Neurosci 32:162–173
Margraf J (1994) Mini-DIPS. Diagnostisches Kurz-Interview bei psychischen Störungen. Springer, Berlin
Margraf J, Schneider S, Ehlers A (2008) Diagnostisches Interview bei psychischen Störungen (DIPS). Springer, Berlin
Mason MF, Norton MI, Van Horn JD et al (2007) Wandering minds: the default network and stimulus-independent thought. NIHPA Author Manuscr 315:393–395
Metzak PD, Riley JD, Wang L et al (2012) Decreased efficiency of task-positive and task-negative networks during working memory in schizophrenia. Schizophr Bull (Bp) 38:803–813. doi:10.1093/schbul/sbq154
Mischel W, Shoda Y, Smith RE (2004) Introduction to personality: toward an integration. Wiley, New York
Moja EA, Stoff DM, Gessa GL et al (1988) Decrease in plasma tryptophan after tryptophan-free amino acid mixtures in man. Life Sci 42:1551–1556
Oldfield RC (1971) The assessment and analysis of handedness: the edinburgh inventory. Neuropsychologia 9:97–113
O’Neill A, D’Souza A, Samson AC et al (2015) Dysregulation between emotion and theory of mind networks in borderline personality disorder. Psy Res 231(1):25–32. doi:10.1016/j.pscychresns.2014.11.002
Pardridge WM (1983) Brain metabolism: a perspective from the blood-brain barrier. Physiol Rev 63:1481–1535
Petersen N, Kilpatrick LA, Goharzad A, Cahill L (2014) Oral contraceptive pill use and menstrual cycle phase are associated with altered resting state functional connectivity. Neuroimage 90:24–32. doi:10.1016/j.neuroimage.2013.12.016
Raichle ME, Macleod AM, Snyder AZ et al (2001) A default mode of brain function. PNAS 98:676–682
Rolls ET (1996) The orbitofrontal cortex. Philosophical transactions of the Royal Society of London Series B. Biol Sci 351:1433–1443. doi:10.1098/rstb.1996.0128 (discussion 1443–4)
Sánchez S, Sánchez C, Paredes SD et al (2008) Circadian variations of serotonin in plasma and different brain regions of rats. Mol Cell Biol 317:105–111. doi:10.1007/s11010-008-9836-z
Sánchez CL, Biskup CS, Herpertz S, Gaber TJ et al (2015a) The role of serotonin (5-HT) in behavioral control: findings from animal research and clinical implications. Int J Neuropsychopharmacol 19(18):10. doi:10.1093/ijnp/pyv050 (pii: pyv050)
Sánchez CL, Van Swearingen AE, Arrant AE, Biskup CS et al (2015b) Simplified dietary acute tryptophan depletion: effects of a novel amino acid mixture on the neurochemistry of C57BL/6 J mice. Food Nutr Res 59:27424. doi:10.3402/fnr.v59.27424
Scharinger C, Rabl U, Kasess CH et al (2014) Platelet serotonin transporter function predicts default-mode network activity. PLoS One 9:e92543. doi:10.1371/journal.pone.0092543
Scherpiet S, Herwig U, Opialla S, Scheerer H et al (2015) Reduced neural differentiation between self-referential cognitive and emotional processes in women with borderline personality disorder. Psychiatry Res 233(3):314–323. doi:10.1016/j.pscychresns.2015.05.008
Schmitt JAJ, Wingen M, Ramaekers JG et al (2006) Serotonin and human cognitive performance. Curr Pharm Des 12:2473–2486
Schmitz TW, Kawahara-Baccus TN, Johnson SC (2004) Metacognitive evaluation, self-relevance, and the right prefrontal cortex. Neuroimage 22:941–947. doi:10.1016/j.neuroimage.2004.02.018
Schneider FC, Royer A, Grosselin A et al (2011) Modulation of the default mode network is task-dependant in chronic schizophrenia patients. Schizophr Res 125:110–117. doi:10.1016/j.schres.2010.11.013
Schoenbaum G, Takahashi Y, Liu T-L, McDannald MA (2011) Does the orbitofrontal cortex signal value? Ann N Y Acad Sci 1239:87–99. doi:10.1111/j.1749-6632.2011.06210.x
Sebastian A, Jung P, Krause-Utz A et al (2014) Frontal dysfunctions of impulse control—a systematic review in borderline personality disorder and attention-deficit/hyperactivity disorder. Front Hum Neurosci 8:698. doi:10.3389/fnhum.2014.00698
Smith QR, Momma S, Aoyagi M, Rapoport SI (1987) Kinetics of neutral amino acid transport across the blood-brain barrier. J Neurochem 49:1651–1658
Soloff PH, Chiappetta L, Mason NS, Becker C, Price JC (2014) Effects of serotonin-2A receptor binding and gender on personality traits and suicidal behavior in borderline personality disorder. Psychiatry Res 30;222(3):140–8. doi: 10.1016/j.pscychresns.2014.03.008
Van de Ven V, Wingen M, Kuypers KPC et al (2013) Escitalopram decreases cross-regional functional connectivity within the default-mode network. PLoS One 8:e68355. doi:10.1371/journal.pone.0068355
Van Wingen GA, Tendolkar I, Urner M et al (2013) Short-term antidepressant administration reduces default mode and task-positive network connectivity in healthy individuals during rest. Neuroimage 88C:47–53. doi:10.1016/j.neuroimage.2013.11.022
Vincent JL, Snyder AZ, Fox MD et al (2006) Coherent spontaneous activity identifies a hippocampal-parietal memory network. J Neurophysiol 96:3517–3531. doi:10.1152/jn.00048.2006
Weiß RH (2006) Grundintelligenztest Skala 2—Revision CFT 20-R [Culture fair intelligence test scale 2—Revision]. Hogrefe, Göttingen
Wihlbäck A-C, Sundström Poromaa I, Bixo M et al (2004) Influence of menstrual cycle on platelet serotonin uptake site and serotonin2A receptor binding. Psychoneuroendocrinology 29:757–766
Zepf FD, Poustka F (2008) 5-HT functioning and aggression in children with ADHD and disruptive behaviour disorders. Hum Psychopharmacol Clin Exper 23:438
Zepf FD, Stewart RM (2015) Inflammation, immunity and suicidality: a potential role for autoantibodies against neurotransmitters and antiphospholipid syndrome? Acta Psychiatr Scand. doi:10.1111/acps.12508
Zepf FD, Hood S, Guillemin GJ (2015) Food and your mood: nutritional psychiatry. Lancet Psychiatry 2(7):e19. doi:10.1016/S2215-0366(15)00241-2
Acknowledgments
We would like to thank the participants for their support. We would also like to thank Theodor Schmitt for his support in conducting the measurements and the Brain Imaging Facility of the Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at the RWTH Aachen University, Germany for further support in fMRI measurement and analysis.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding for this study was provided by the START research funding scheme of the RWTH Aachen University Hospital, Germany. The funder had no role in the study design, in the collection, analysis and interpretation of data, in writing the report, or in the decision to submit the paper for publication.
KH, MZ, TJG, MC, BD, SB, MK, AE, KK and UH do not have any real or potential conflicts of interest and have not received any travel support or honoraria from a commercial business. BHD serves as an advisory board member for Eli Lilly and Company and received research support from Vifor Pharma Ltd. In the past six years, FDZ was the recipient of an unrestricted award donated by the American Psychiatric Association (APA), the American Psychiatric Institute for Research and Education (APIRE), and AstraZeneca (the Young Minds in Psychiatry Award). He has also received research support from the German Federal Ministry for Economics and Technology, the European Union (EU), the German Society for Social Pediatrics and Adolescent Medicine, the Paul and Ursula Klein Foundation, the Dr. August Scheidel Foundation and the IZKF of RWTH Aachen University and a travel stipend donated by the GlaxoSmithKline Foundation. He is the recipient of an unrestricted educational grant, travel support and speaker honoraria from Shire Pharmaceuticals, Germany, as well as of editorial fees from Co-Action Publishing (Sweden). In addition, he has received support from the Raine Foundation for Medical Research (Raine Visiting Professorship). The other authors have nothing to disclose or report.
Additional information
Handling Editor: N. Singewald.
Rights and permissions
About this article
Cite this article
Helmbold, K., Zvyagintsev, M., Dahmen, B. et al. Serotonergic modulation of resting state default mode network connectivity in healthy women. Amino Acids 48, 1109–1120 (2016). https://doi.org/10.1007/s00726-015-2137-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-015-2137-4