Skip to main content
SpringerLink
Log in

Effect of acute tryptophan depletion on pre-frontal engagement

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Background

Serotonin is known to modulate cognitive functioning and has been implicated in the cognitive deficits associated with affective disorders. The present study examined regional brain activation during two tasks that are known to engage the pre-frontal cortex and are performed poorly by patients with depression and bipolar disorder. We tested the hypothesis that acute tryptophan depletion (ATD) would attenuate pre-frontal activation during both tasks.

Materials and methods

Ten healthy right-handed volunteers were studied using functional MRI whilst performing a 2-back verbal working memory task and a phonological verbal fluency task. Subjects were studied in two separate sessions, after either a tryptophan-free or a balanced amino acid drink, in a double-blind design. Task performance and mood were measured online.

Results

Relative to sham depletion, ATD attenuated activation in the right superior frontal gyrus during the 2-back task and in the medial frontal gyrus and precuneus during the verbal fluency task. ATD lowered total plasma tryptophan by 79% but had no significant effect on either task performance or mood.

Conclusions

The engagement of pre-frontal cortex during verbal working memory and verbal fluency tasks is significantly modulated by central serotonergic activity. The different location of these modulatory effects within the frontal cortex may reflect the engagement of distinct cognitive processes by the respective tasks.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Adler CM, Holland SK, Schmithorst V, Tuchfarber MJ, Strakowski SM (2004) Changes in neuronal activation in patients with bipolar disorder during performance of a working memory task. Bipolar Disord 6:540–549

    Article  PubMed  Google Scholar 

  • Ahveninen J, Kahkonen S, Pennanen S, Liesivuori J, Ilmoniemi RJ, Jaaskelainen IP (2002) Tryptophan depletion effects on EEG and MEG responses suggest serotonergic modulation of auditory involuntary attention in humans. Neuroimage 16:1052–1061

    Article  PubMed  Google Scholar 

  • Annet M (1970) A classification of hand preference by association analysis. Br J Psychol 61:303–321

    Google Scholar 

  • Barch DM, Sheline YI, Csernansky JG, Snyder AZ (2003) Working memory and prefrontal cortex dysfunction: specificity to schizophrenia compared with major depression. Biol Psychiatry 53:376–384

    Article  PubMed  Google Scholar 

  • Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961) An inventory for measuring depression. Arch Gen Psychiatry 4:561–571

    PubMed  CAS  Google Scholar 

  • Benton A, Hamsher K, Sivan AB (1994) Multilingual aphasia examination, 3rd edn. IA: AJA Associates

  • Biggio G, Fadda F, Fanni P, Tagliamonte A, Gessa GL (1974) Rapid depletion of serum tryptophan, brain tryptophan, serotonin and 5-hydroxyindoleacetic acid by a tryptophan-free diet. Life Sci 14:1321–1329

    Article  PubMed  CAS  Google Scholar 

  • Bond A, Lader M (1974) The use of analogue scales in rating subjectsive feelings. Br J Med Psychol 47:211–218

    Google Scholar 

  • Bond A, Lader M (1986) A method to elicit aggressive feelings and behaviour via provocation. Biol Psychol 22:69–79

    Article  PubMed  CAS  Google Scholar 

  • Brammer MJ, Bullmore ET, Simmons A, Williams SC, Grasby PM, Howard RJ, Woodruff PW, Rabe-Hesketh S (1997) Generic brain activation mapping in functional magnetic resonance imaging: a nonparametric approach. Magn Reson Imaging 15:763–770

    Article  PubMed  CAS  Google Scholar 

  • Breakspear M, Brammer MJ, Bullmore ET, Das P, Williams LM (2004) Spatiotemporal wavelet resampling for functional neuroimaging data. Hum Brain Mapp 23:1–25

    Article  PubMed  Google Scholar 

  • Bremner JD, Innis RB, Salomon RM, Staib LH, Ng CK, Miller HL, Bronen RA, Krystal JH, Duncan J, Rich D, Price LH, Malison R, Dey H, Soufer R, Charney DS (1997) Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse. Arch Gen Psychiatry 54:364–374

    PubMed  CAS  Google Scholar 

  • Bullmore ET, Brammer MJ, Rabe-Hesketh S, Curtis VA, Morris RG, Williams SC, Sharma T, McGuire PK (1999) Methods for diagnosis and treatment of stimulus-correlated motion in generic brain activation studies using fMRI. Hum Brain Mapp 7:38–48

    Article  PubMed  CAS  Google Scholar 

  • Buss A, Durkee A (1957) An inventory for assessing different kinds of hostility. J Consult Psychol 21:343–349

    Article  PubMed  CAS  Google Scholar 

  • Callicott C, Thomas JM, Goode AW (1999) The magnetization transfer characteristics of human breast tissues: an in vitro NMR study. Phys Med Biol 44:1147–1154

    Article  PubMed  CAS  Google Scholar 

  • Carpenter LL, Anderson GM, Pelton GH, Gudin JA, Kirwin PD, Price LH, Heninger GR, McDougle CJ (1998) Tryptophan depletion during continuous CSF sampling in healthy human subjects. Neuropsychopharmacology 19:26–35

    Article  PubMed  CAS  Google Scholar 

  • Cleare A, Bond A (1995) The effect of tryptophan depletion and enhancement on subjective and behavioral aggression in normal male subjects. Psychopharmacology

  • Cohen JD, Forman S, Braver T, Casey B, Servan-Schreiber D, Noll D (1994) Activation of the prefrontal cortex in a non-spatial working memory task with functional MRI. Human Brain Mapping 1:293–304

    Article  Google Scholar 

  • Curtis VA, Bullmore ET, Brammer MJ, Wright IC, Williams SC, Morris RG, Sharma TS, Murray RM, McGuire PK (1998) Attenuated frontal activation during a verbal fluency task in patients with schizophrenia. Am J Psychiatry 155:1056–1063

    PubMed  CAS  Google Scholar 

  • Dixon T, Kravariti E, Frith C, Murray RM, McGuire PK (2004) Effect of symptoms on executive function in bipolar illness. Psychol Med 34:811–821

    Article  PubMed  CAS  Google Scholar 

  • Ellenbogen MA, Young SN, Dean P, Palmour RM, Benkelfat C (1996) Mood response to acute tryptophan depletion in healthy volunteers: sex differences and temporal stability. Neuropsychopharmacology 15:465–474

    Article  PubMed  CAS  Google Scholar 

  • Ellis KA, Nathan PJ (2001) The pharmacology of human working memory. Int J Neuropsychopharmacol 4:299–313

    Article  PubMed  CAS  Google Scholar 

  • Evers EA, Cools R, Clark L, van der Veen FM, Jolles J, Sahakian BJ, Robbins TW (2005) Serotonergic modulation of prefrontal cortex during negative feedback in probabilistic reversal learning. Neuropsychopharmacology 30:1138–1147

    Article  PubMed  CAS  Google Scholar 

  • First M, Spitzer R, Gibbon M, Williams J (1995) Structured clinical interview for DSM-IV axis I disorders. New York State Psychiatric Institute, Biometric Research, New York State Psychiatric Institute, Biometric Research

  • Fletcher P, Frith C, Grasby P, Friston K, Dolan R (1996) Local and distributed effects of apomorphine on fronto-temporal function in acute unmedicated schizophrenia. J Neurosci 16:7055–7062

    Google Scholar 

  • Fossati P, Amar G, Raoux N, Ergis AM, Allilaire JF (1999) Executive functioning and verbal memory in young patients with unipolar depression and schizophrenia. Psychiatry Res 89:171–187

    Article  PubMed  CAS  Google Scholar 

  • Friman O, Borga M, Lundberg P, Knutsson H (2003) Adaptive analysis of fMRI data. Neuroimage 19:837–845

    Article  PubMed  Google Scholar 

  • Friston KJ, Holmes AP, Worsley KJ (1999) How many subjects constitute a study? Neuroimage 10:1–5

    Article  PubMed  CAS  Google Scholar 

  • Fu CH, Morgan K, Suckling J, Williams SC, Andrew C, Vythelingum GN, McGuire PK (2002) A functional magnetic resonance imaging study of overt letter verbal fluency using a clustered acquisition sequence: greater anterior cingulate activation with increased task demand. Neuroimage 17:871–879

    Article  PubMed  Google Scholar 

  • Fuster J (1995) Memory in the cerebral cortex. MIT Press, Cambridge, MA

    Google Scholar 

  • Gallagher P, Massey AE, Young AH, McAllister-Williams RH (2003) Effects of acute tryptophan depletion on executive function in healthy male volunteers. BMC Psychiatry 3:10

    Article  PubMed  Google Scholar 

  • Graeff FG, Guimaraes FS, De Andrade TG, Deakin JF (1996) Role of 5-HT in stress, anxiety, and depression. Pharmacol Biochem Behav 54:129–141

    Article  PubMed  CAS  Google Scholar 

  • Hanson KL, Luciana M (2004) Neurocognitive function in users of MDMA: the importance of clinically significant patterns of use. Psychol Med 34:229–246

    Article  PubMed  Google Scholar 

  • Harvey PO, Fossati P, Pochon JB, Levy R, Lebastard G, Lehericy S, Allilaire JF, Dubois B (2005) Cognitive control and brain resources in major depression: an fMRI study using the n-back task. Neuroimage 26:860–869

    Article  PubMed  Google Scholar 

  • Henry J, Crawford JR (2005) A meta-analytic review of verbal fluency deficits in depression. J Clin Exp Neuropsychol 27:78–101

    Article  PubMed  Google Scholar 

  • Honey GD, Bullmore ET, Sharma T (2000) Prolonged reaction time to a verbal working memory task predicts increased power of posterior parietal cortical activation. Neuroimage 12:495–503

    Article  PubMed  CAS  Google Scholar 

  • Horacek J, Zavesicka L, Tintera J, Dockery C, Platilova V, Kopecek M, Spaniel F, Bubenikova V, Hoschl C (2005) The effect of tryptophan depletion on brain activation measured by functional magnetic resonance imaging during the stroop test in healthy subjects. Physiol Res 54:235–244

    PubMed  CAS  Google Scholar 

  • Hughes JH, Gallagher P, Stewart ME, Matthews D, Kelly TP, Young AH (2003) The effects of acute tryptophan depletion on neuropsychological function. J Psychopharmacol 17:300–309

    Article  PubMed  CAS  Google Scholar 

  • Keating J, Dractu L, Lader M, Sherwood R (1993) Measurement of plasma serotonin by high-performance liquid chromatography with electrochemical detection as an index of the in vivo activity of fluvoxamine. J Chromatogr 615:237–242

    Article  PubMed  CAS  Google Scholar 

  • Landro NI, Stiles TC, Sletvold H (2001) Neuropsychological function in nonpsychotic unipolar major depression. Neuropsychiatry Neuropsychol Behav Neurol 14:233–240

    Google Scholar 

  • Luciana M, Collins PF, Depue RA (1998) Opposing roles for dopamine and serotonin in the modulation of human spatial working memory functions. Cereb Cortex 8:218–226

    Article  PubMed  CAS  Google Scholar 

  • Lurito JT, Kareken DA, Lowe MJ, Chen SH, Mathews VP (2000) Comparison of rhyming and word generation with FMRI. Hum Brain Mapp 10:99–106

    Article  PubMed  CAS  Google Scholar 

  • Marek GJ, Aghajanian GK (1998) The electrophysiology of prefrontal serotonin systems: therapeutic implications for mood and psychosis. Biol Psychiatry 44:1118–1127

    Article  PubMed  CAS  Google Scholar 

  • Moja EA, Cipolla P, Castoldi D, Tofanetti O (1989) Dose–response decrease in plasma tryptophan and in brain tryptophan and serotonin after tryptophan-free amino acid mixtures in rats. Life Sci 44:971–976

    Article  PubMed  CAS  Google Scholar 

  • Monks PJ, Thompson JM, Bullmore ET, Suckling J, Brammer MJ, Williams SC, Simmons A, Giles N, Lloyd AJ, Harrison CL, Seal M, Murray RM, Ferrier IN, Young AH, Curtis VA (2004) A functional MRI study of working memory task in euthymic bipolar disorder: evidence for task-specific dysfunction. Bipolar Disord 6:550–564

    Article  PubMed  Google Scholar 

  • Morris JS, Smith KA, Cowen PJ, Friston KJ, Dolan RJ (1999) Covariation of activity in habenula and dorsal raphe nuclei following tryptophan depletion. Neuroimage 10:163–172

    Article  PubMed  CAS  Google Scholar 

  • Murphy FC, Smith KA, Cowen PJ, Robbins TW, Sahakian BJ (2002) The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers. Psychopharmacology (Berl) 163:42–53

    Article  CAS  Google Scholar 

  • Nelson HE, Willison J (1991) National Adult Reading Scale (NART), 2nd edn. Windsor, UK

  • Nishizawa S, Benkelfat C, Young S, Leyton M (1997) Differences between males and females in rates of serotonin synthesis in the human brain. Proc Natl Acad Sci USA 94:5308–5313

    Article  PubMed  CAS  Google Scholar 

  • Okada G, Okamoto Y, Morinobu S, Yamawaki S, Yokota N (2003) Attenuated left prefrontal activation during a verbal fluency task in patients with depression. Neuropsychobiology 47:21–26

    Article  PubMed  CAS  Google Scholar 

  • Park SB, Coull JT, McShane RH, Young AH, Sahakian BJ, Robbins TW, Cowen PJ (1994) Tryptophan depletion in normal volunteers produces selective impairments in learning and memory. Neuropharmacology 33:575–588

    Article  PubMed  CAS  Google Scholar 

  • Passingham R, Chen Y, Thaler D (1989) Supplementary motor cortex and self-initiated movement. Japan Scientific Sources Press

  • Patton J, Stanford M, Barrat E (1995) Factor structure of the Barrat impulsiveness scale. J Clin Psychol 51:768–774

    Article  PubMed  CAS  Google Scholar 

  • Paus T (2001) Primate anterior cingulate cortex: where motor control, drive and cognition interface. Nat Rev Neurosci 2:417–424

    Article  PubMed  CAS  Google Scholar 

  • Poeggel G, Nowicki L, Braun K (2003) Early social deprivation alters monoaminergic afferents in the orbital prefrontal cortex of Octodon degus. Neuroscience 116:617–620

    Article  PubMed  CAS  Google Scholar 

  • Preece MA, Dalley JW, Theobald DE, Robbins TW, Reynolds GP (2004) Region specific changes in forebrain 5-hydroxytryptamine1A and 5-hydroxytryptamine2A receptors in isolation-reared rats: an in vitro autoradiography study. Neuroscience 123:725–732

    Article  PubMed  CAS  Google Scholar 

  • Puig MV, Artigas F, Celada P (2005) Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: involvement of serotonin and GABA. Cereb Cortex 15:1–14

    Article  PubMed  Google Scholar 

  • Reilly JG, McTavish SF, Young AH (1997) Rapid depletion of plasma tryptophan: a review of studies and experimental methodology. J Psychopharmacol 11:381–392

    Article  PubMed  CAS  Google Scholar 

  • Richter-Levin G, Segal M 1989) Spatial performance is severely impaired in rats with combined reduction of serotonergic and cholinergic transmission. Brain Res 477:404–407

    Article  PubMed  CAS  Google Scholar 

  • Riedel W (2004) Cognitive changes after acute tryptophan depletion: what can they tell us? Psychol Med 34:3–8

    Article  PubMed  Google Scholar 

  • Riedel WJ, Klaassen T, Deutz NE, van Someren A, van Praag HM (1999) Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation. Psychopharmacology (Berl) 141:362–369

    Article  CAS  Google Scholar 

  • Robbins TW (2000) Chemical neuromodulation of frontal-executive functions in humans and other animals. Exp Brain Res 133:130–138

    Article  PubMed  CAS  Google Scholar 

  • Rubia K, Lee F, Cleare A, Tunstall N, Fu CH, Brammer MJ, McGuire PK (2005) Tryptophan depletion reduces right inferior prefrontal activation during response inhibition in fast event related fMRI. Psychopharmacology (Berl) 179:791–803

    Article  CAS  Google Scholar 

  • Schlosser R, Hutchinson M, Joseffer S, Rusinek H, Saarimaki A, Stevenson J, Dewey SL, Brodie JD (1998) Functional magnetic resonance imaging of human brain activity in a verbal fluency task. J Neurol Neurosurg Psychiatry 64:492–498

    Article  PubMed  CAS  Google Scholar 

  • Siegel RK (1985) LSD hallucinations: from ergot to electric kool-aid. J Psychoactive Drugs 17:247–256

    PubMed  CAS  Google Scholar 

  • Smith EE, Jonides J (1998) Neuroimaging analyses of human working memory. Proc Natl Acad Sci USA 95:12061–12068

    Article  PubMed  CAS  Google Scholar 

  • Smith K, Clifford E, Hockney R, Clark D, Cowen PJ (1997) Effect of tryptophan depletion on mood in male and female volunteers: a pilot study. Hum Psychopharmacol 12:111–117

    Article  CAS  Google Scholar 

  • Smith EE, Jonides J, Marshuetz C, Koeppe RA (1998) Components of verbal working memory: evidence from neuroimaging. Proc Natl Acad Sci USA 95:876–882

    Article  PubMed  CAS  Google Scholar 

  • Talairach J, Tournoux PA (1998) A co-planar stereotoxic atlas of the human brain. Thieme, Stuttgart

  • Williams GV, Rao SG, Goldman-Rakic PS (2002) The physiological role of 5-HT2A receptors in working memory. J Neurosci 22:2843–2854

    PubMed  CAS  Google Scholar 

  • Yatham LN, Liddle PF, Shiah IS, Lam RW, Adam MJ, Zis AP, Ruth TJ (2001) Effects of rapid tryptophan depletion on brain 5-HT(2) receptors: a PET study. Br J Psychiatry 178:448–453

    Article  PubMed  CAS  Google Scholar 

  • Young S, Tourjman S, Teff K (1988) The effect of lowering plasma tryptophan on food selection in normal males. Pharmacol Biochem Behav 31:149–152

    Article  PubMed  CAS  Google Scholar 

  • Yurgelun-Todd DA, Waternaux CM, Cohen BM, Gruber SA, English CD, Renshaw PF (1996) Functional magnetic resonance imaging of schizophrenic patients and comparison subjects during word production. Am J Psychiatry 153:200–205

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Psychological Medicine P067, Institute of Psychiatry, De Crespigny Park, SE5 8AF, London, UK

    Paul P. Allen, Anthony J. Cleare, Francis Lee, Paolo Fusar-Poli, Nigel Tunstall, Cynthia H. Y. Fu & Philip K. McGuire

  2. Brain Image Analysis Unit, Deparment of Biostatistics and Computing, King’s College London, Institute of Psychiatry, De Crespigny Park, SE5 8AF, London, UK

    Micheal J. Brammer

  3. Department of Psychobehavioural Sciences, Cascina Cravino, Via Bassi 7, University of Pavia, Pavia, Italy

    Paolo Fusar-Poli

Authors
  1. Paul P. Allen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony J. Cleare
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francis Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paolo Fusar-Poli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nigel Tunstall
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cynthia H. Y. Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Micheal J. Brammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Philip K. McGuire
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul P. Allen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Allen, P.P., Cleare, A.J., Lee, F. et al. Effect of acute tryptophan depletion on pre-frontal engagement. Psychopharmacology 187, 486–497 (2006). https://doi.org/10.1007/s00213-006-0444-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-006-0444-x

Keywords

Search

Navigation