Serotonergic Modulation of Prefrontal Cortex during Negative Feedback in Probabilistic Reversal Learning

This study used functional magnetic resonance imaging to examine the effects of acute tryptophan (TRP) depletion (ATD), a well-recognized method for inducing transient cerebral serotonin depletion, on brain activity during probabilistic reversal learning. Twelve healthy male volunteers received a TRP-depleting drink or a balanced amino-acid drink (placebo) in a double-blind crossover design. At 5 h after drink ingestion, subjects were scanned while performing a probabilistic reversal learning task and while viewing a flashing checkerboard. The probabilistic reversal learning task enabled the separate examination of the effects of ATD on behavioral reversal following negative feedback and negative feedback per se that was not followed by behavioral adaptation. Consistent with previous findings, behavioral reversal was accompanied by significant signal change in the right ventrolateral prefrontal cortex (PFC) and the dorsomedial prefrontal cortex. ATD enhanced reversal-related signal change in the dorsomedial PFC, but did not modulate the ventrolateral PFC response. The ATD-induced signal change in the dorsomedial PFC during behavioral reversal learning extended to trials where subjects received negative feedback but did not change their behavior. These data suggest that ATD affects reversal learning and the processing of aversive signals by modulation of the dorsomedial PFC.

[1]  M. Mishkin,et al.  Limbic lesions and the problem of stimulus--reinforcement associations. , 1972, Experimental neurology.

[2]  G. Biggio,et al.  Rapid depletion of serum tryptophan, brain tryptophan, serotonin and 5-hydroxyindoleacetic acid by a tryptophan-free diet. , 1974, Life sciences.

[3]  I. Lapin,et al.  Effect of serotoninergic drugs on positive and negative reinforcing systems in cats , 1976, Pharmacology Biochemistry and Behavior.

[4]  P. Redgrave,et al.  Potentiation of central reward by localised perfusion of acetylcholine and 5-hydroxytryptamine , 1976, Nature.

[5]  F. Graeff.  Modulation of the brain aversive system by gabaergic and serotonergic mechanisms , 1985, Behavioural Brain Research.

[6]  P. Soubrié.  Reconciling the role of central serotonin neurons in human and animal behavior , 1986, Behavioral and Brain Sciences.

[7]  D. Watson,et al.  Development and validation of brief measures of positive and negative affect: the PANAS scales. , 1988, Journal of personality and social psychology.

[8]  L. Siever,et al.  Serotonergic studies in patients with affective and personality disorders. Correlates with suicidal and impulsive aggressive behavior. , 1989, Archives of general psychiatry.

[9]  J. Deakin.  Depression and 5HT , 1991, International clinical psychopharmacology.

[10]  Alan C. Evans,et al.  Role of the human anterior cingulate cortex in the control of oculomotor, manual, and speech responses: a positron emission tomography study. , 1993, Journal of neurophysiology.

[11]  C. Benkelfat,et al.  Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders. , 1994, Archives of general psychiatry.

[12]  J. T. Coull,et al.  Tryptophan depletion in normal volunteers produces selective impairments in learning and memory , 1994, Neuropharmacology.

[13]  T. Robbins,et al.  Differential Effects of Forebrain 5‐Hydroxytryptamine Depletions on Pavlovian Aversive Conditioning to Discrete and Contextual Stimuli in the Rat , 1995, The European journal of neuroscience.

[14]  B. Sahakian,et al.  Cognitive performance in tests sensitive to frontal lobe dysfunction in the elderly depressed , 1996, Psychological Medicine.

[15]  Peggy Dean,et al.  Mood Response to Acute Tryptophan Depletion in Healthy Volunteers: Sex Differences and Temporal Stability , 1996, Neuropsychopharmacology.

[16]  T. Robbins,et al.  Dissociation in prefrontal cortex of affective and attentional shifts , 1996, Nature.

[17]  T. Robbins,et al.  Abnormal response to negative feedback in unipolar depression: evidence for a diagnosis specific impairment , 1997, Journal of neurology, neurosurgery, and psychiatry.

[18]  KA Smith,et al.  Relapse of depression after rapid depletion of tryptophan , 1997, The Lancet.

[19]  M Diksic,et al.  Differences between males and females in rates of serotonin synthesis in human brain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[20]  M. Raichle,et al.  Subgenual prefrontal cortex abnormalities in mood disorders , 1997, Nature.

[21]  Barry J. Everitt,et al.  Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms , 1997, Psychopharmacology.

[22]  M. Botvinick,et al.  Anterior cingulate cortex, error detection, and the online monitoring of performance. , 1998, Science.

[23]  G. Aghajanian,et al.  5-Hydroxytryptamine-induced excitatory postsynaptic currents in neocortical layer V pyramidal cells: suppression by μ-opiate receptor activation , 1998, Neuroscience.

[24]  C. McDougle,et al.  Tryptophan Depletion During Continuous CSF Sampling in Healthy Human Subjects , 1998, Neuropsychopharmacology.

[25]  J. Sirviö,et al.  Changes in activities of dopamine and serotonin systems in the frontal cortex underlie poor choice accuracy and impulsivity of rats in an attention task , 1998, Neuroscience.

[26]  W. Riedel,et al.  Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation , 1999, Psychopharmacology.

[27]  D Hommer,et al.  Effects of Acute Tryptophan Depletion on Plasma and Cerebrospinal Fluid Tryptophan and 5‐Hydroxyindoleacetic Acid in Normal Volunteers , 1999, Journal of neurochemistry.

[28]  J. Evenden.  Varieties of impulsivity , 1999, Psychopharmacology.

[29]  T. Robbins,et al.  Dissociable Deficits in the Decision-Making Cognition of Chronic Amphetamine Abusers, Opiate Abusers, Patients with Focal Damage to Prefrontal Cortex, and Tryptophan-Depleted Normal Volunteers: Evidence for Monoaminergic Mechanisms , 1999, Neuropsychopharmacology.

[30]  L. Parsons,et al.  Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. , 1999, The American journal of psychiatry.

[31]  J. Sirviö,et al.  The 5-HT2 Receptor Activation Enhances Impulsive Responding Without Increasing Motor Activity in Rats , 2000, Pharmacology Biochemistry and Behavior.

[32]  J. Cohen,et al.  Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. , 2000, Science.

[33]  S. Mobini,et al.  Effects of central 5-hydroxytryptamine depletion on sensitivity to delayed and probabilistic reinforcement , 2000, Psychopharmacology.

[34]  S. Lane,et al.  Fenfluramine effects on impulsivity in a sample of adults with and without history of conduct disorder , 2000, Psychopharmacology.

[35]  T. Robbins,et al.  Probabilistic learning and reversal deficits in patients with Parkinson’s disease or frontal or temporal lobe lesions: possible adverse effects of dopaminergic medication , 2000, Neuropsychologia.

[36]  T. Robbins,et al.  Chemical neuromodulation of frontal-executive functions in humans and other animals , 2000, Experimental Brain Research.

[37]  M Diksic,et al.  Brain Regional alpha-[11C]methyl-L-tryptophan trapping in impulsive subjects with borderline personality disorder. , 2001, The American journal of psychiatry.

[38]  A. Kelley,et al.  Serotonin-Dopamine Interactions in the Control of Conditioned Reinforcement and Motor Behavior , 2001, Neuropsychopharmacology.

[39]  H. Wagner,et al.  Performance feedback deficit in geriatric depression , 2001, Biological Psychiatry.

[40]  Joel Paris,et al.  Brain Regional α-[11C]Methyl-l-Tryptophan Trapping in Impulsive Subjects With Borderline Personality Disorder , 2001 .

[41]  E. Rolls,et al.  Abstract reward and punishment representations in the human orbitofrontal cortex , 2001, Nature Neuroscience.

[42]  T. Robbins,et al.  Decision-making in mania: a PET study. , 2001, Brain : a journal of neurology.

[43]  W. Gehring,et al.  Functions of the Medial Frontal Cortex in the Processing of Conflict and Errors , 2001, The Journal of Neuroscience.

[44]  N. Tzourio-Mazoyer,et al.  Automated Anatomical Labeling of Activations in SPM Using a Macroscopic Anatomical Parcellation of the MNI MRI Single-Subject Brain , 2002, NeuroImage.

[45]  Stephen M Smith,et al.  Fast robust automated brain extraction , 2002, Human brain mapping.

[46]  R. Dolan,et al.  The neural basis of mood-congruent processing biases in depression. , 2002, Archives of general psychiatry.

[47]  E. Walderhaug,et al.  Lowering of serotonin by rapid tryptophan depletion increases impulsiveness in normal individuals , 2002, Psychopharmacology.

[48]  T. Robbins,et al.  Defining the Neural Mechanisms of Probabilistic Reversal Learning Using Event-Related Functional Magnetic Resonance Imaging , 2002, The Journal of Neuroscience.

[49]  Dawn M Eagle,et al.  Deficits in Impulse Control Associated with Tonically-elevated Serotonergic Function in Rat Prefrontal Cortex , 2002, Neuropsychopharmacology.

[50]  T. Robbins,et al.  The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers , 2002, Psychopharmacology.

[51]  K. Braun,et al.  Early social deprivation alters monoaminergic afferents in the orbital prefrontal cortex of octodon degus , 2003, Neuroscience.

[52]  T. Robbins,et al.  Neuropsychological impairment in patients with major depressive disorder: the effects of feedback on task performance , 2003, Psychological Medicine.

[53]  Morten L Kringelbach,et al.  Neural correlates of rapid reversal learning in a simple model of human social interaction , 2003, NeuroImage.

[54]  M. Farah,et al.  Ventromedial frontal cortex mediates affective shifting in humans: evidence from a reversal learning paradigm. , 2003, Brain : a journal of neurology.

[55]  T. Robbins,et al.  Dissociable Contributions of the Orbitofrontal and Infralimbic Cortex to Pavlovian Autoshaping and Discrimination Reversal Learning: Further Evidence for the Functional Heterogeneity of the Rodent Frontal Cortex , 2003, The Journal of Neuroscience.

[56]  Y. P. Liu,et al.  Effects of acute and chronic buspirone on impulsive choice and efflux of 5-HT and dopamine in hippocampus, nucleus accumbens and prefrontal cortex , 2004, Psychopharmacology.

[57]  Matthew Brett,et al.  An Evaluation of the Use of Magnetic Field Maps to Undistort Echo-Planar Images , 2003, NeuroImage.

[58]  H Garavan,et al.  A midline dissociation between error-processing and response-conflict monitoring , 2003, NeuroImage.

[59]  C. Kennedy,et al.  Increases in avoidance responding produced by REM sleep deprivation or serotonin depletion are reversed by administration of 5-hydroxytryptophan , 2003, Behavioural Brain Research.

[60]  P. Cowen,et al.  Tryptophan depletion decreases the recognition of fear in female volunteers , 2003, Psychopharmacology.

[61]  C. Carter,et al.  Tryptophan Depletion Alters the Decision-Making of Healthy Volunteers through Altered Processing of Reward Cues , 2003, Neuropsychopharmacology.

[62]  Arthur W Toga,et al.  Anterior cingulate, gyrus rectus, and orbitofrontal abnormalities in elderly depressed patients: an MRI-based parcellation of the prefrontal cortex. , 2004, The American journal of psychiatry.

[63]  T. Robbins,et al.  Inhibition and the right inferior frontal cortex , 2004, Trends in Cognitive Sciences.

[64]  F. Beslot,et al.  Alpha-lactalbumin-enriched diets enhance serotonin release and induce anxiolytic and rewarding effects in the rat , 2004, Behavioural Brain Research.

[65]  H. Anisman,et al.  Dysregulation in the Suicide Brain: mRNA Expression of Corticotropin-Releasing Hormone Receptors and GABAA Receptor Subunits in Frontal Cortical Brain Region , 2004, The Journal of Neuroscience.

[66]  T. Robbins,et al.  Cognitive Inflexibility After Prefrontal Serotonin Depletion , 2004, Science.

[67]  Jonathan D. Cohen,et al.  Anterior Cingulate Conflict Monitoring and Adjustments in Control , 2004, Science.

[68]  E. Rolls,et al.  Reward-related Reversal Learning after Surgical Excisions in Orbito-frontal or Dorsolateral Prefrontal Cortex in Humans , 2004, Journal of Cognitive Neuroscience.

[69]  T. Robbins,et al.  Region specific changes in forebrain 5-hydroxytryptamine1a and 5-hydroxytryptamine2a receptors in isolation-reared rats: an in vitro autoradiography study , 2004, Neuroscience.

[70]  D. Kupfer,et al.  Anatomic evaluation of the orbitofrontal cortex in major depressive disorder , 2004, Biological Psychiatry.

[71]  R. Pihl,et al.  Tryptophan depletion causes a rapid lowering of mood in normal males , 2004, Psychopharmacology.

[72]  M. Mishkin,et al.  Perseverative interference in monkeys following selective lesions of the inferior prefrontal convexity , 1970, Experimental Brain Research.

[73]  P. Celada,et al.  Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: involvement of serotonin and GABA. , 2004, Cerebral cortex.

[74]  C. McDougle,et al.  Serotonergic mechanisms of cocaine effects in humans , 1995, Psychopharmacology.