Reinforcement ambiguity and novelty do not account for transitive inference deficits in schizophrenia.

The capacity for transitive inference (TI), a form of relational memory organization, is impaired in schizophrenia patients. In order to disambiguate deficits in TI from the effects of ambiguous reinforcement history and novelty, 28 schizophrenia and 20 nonpsychiatric control subjects were tested on newly developed TI and non-TI tasks that were matched on these 2 variables. Schizophrenia patients performed significantly worse than controls on the TI task but were able to make equivalently difficult nontransitive judgments as well as controls. Neither novelty nor reinforcement ambiguity accounted for the selective deficit of the patients on the TI task. These findings implicate a disturbance in relational memory organization, likely subserved by hippocampal dysfunction, in the pathophysiology of schizophrenia.

[1]  Stephan Heckers,et al.  Impaired hippocampal recruitment during normal modulation of memory performance in schizophrenia , 2003, Biological Psychiatry.

[2]  H. Fukuzako,et al.  Reduction in hippocampal formation volume is caused mainly by its shortening in chronic schizophrenia: Assessment by MRI , 1996, Biological Psychiatry.

[3]  F. Benes,et al.  Evidence for altered trisynaptic circuitry in schizophrenic hippocampus , 1999, Biological Psychiatry.

[4]  R. Kahn,et al.  Modulating sensorimotor gating in healthy volunteers: the effects of desipramine and haloperidol , 2004, Psychiatry Research.

[5]  T. Goldberg,et al.  Thought Disorder in Schizophrenia: A Reappraisal of Older Formulations and an Overview of Some Recent Studies , 2000 .

[6]  N. Alpert,et al.  Impaired recruitment of the hippocampus during conscious recollection in schizophrenia , 1998, Nature Neuroscience.

[7]  T. Goldberg,et al.  Forms of memory failure in schizophrenia , 1991, Schizophrenia Research.

[8]  William B Levy,et al.  Relational learning with and without awareness: Transitive inference using nonverbal stimuli in humans , 2001, Memory & cognition.

[9]  Patrice Boyer,et al.  Hippocampal abnormalities and memory deficits: New evidence of a strong pathophysiological link in schizophrenia , 2007, Brain Research Reviews.

[10]  William B. Levy,et al.  When logic fails: Implicit transitive inference in humans , 2005, Memory & cognition.

[11]  B. Bogerts,et al.  Basal Ganglia and Limbic System Pathology in Schizophrenia: A Morphometric Study of Brain Volume and Shrinkage , 1985 .

[12]  R. Kahn,et al.  Memory impairment in schizophrenia: a meta-analysis. , 1999, The American journal of psychiatry.

[13]  L. C. Bidwell,et al.  Differential activation patterns of occipital and prefrontal cortices during motion processing: Evidence from normal and schizophrenic brains , 2008, Cognitive, affective & behavioral neuroscience.

[14]  B. Turetsky,et al.  Event-related fMRI of frontotemporal activity during word encoding and recognition in schizophrenia. , 2004, The American journal of psychiatry.

[15]  H. Eichenbaum,et al.  Conservation of hippocampal memory function in rats and humans , 1996, Nature.

[16]  U. Grenander,et al.  Hippocampal morphometry in schizophrenia by high dimensional brain mapping. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[17]  H. Holcomb,et al.  Probing the human hippocampus using rCBF: Contrasts in schizophrenia , 2001, Hippocampus.

[18]  R. Bilder,et al.  The Frontal Lobes and Hierarchical Organization of Cognitive Control , 2019, The Frontal Lobes Revisited.

[19]  M. W. Brown,et al.  Novel spatial arrangements of familiar visual stimuli promote activity in the rat hippocampal formation but not the parahippocampal cortices: a c-fos expression study , 2004, Neuroscience.

[20]  A. Dale,et al.  Functional–Anatomic Study of Episodic Retrieval II. Selective Averaging of Event-Related fMRI Trials to Test the Retrieval Success Hypothesis , 1998, NeuroImage.

[21]  A. Schene,et al.  Long-term memory deficits in schizophrenia: primary or secondary dysfunction? , 2003, Neuropsychology.

[22]  R. Gur,et al.  Neuropsychological function in schizophrenia. Selective impairment in memory and learning. , 1991, Archives of general psychiatry.

[23]  Jason P. Mitchell,et al.  Multiple routes to memory: Distinct medial temporal lobe processes build item and source memories , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Joseph T. Coyle,et al.  The Glutamatergic Dysfunction Hypothesis for Schizophrenia , 1996, Harvard review of psychiatry.

[25]  J. Lisman,et al.  The Hippocampal-VTA Loop: Controlling the Entry of Information into Long-Term Memory , 2005, Neuron.

[26]  F. Benes,et al.  Reduced neuronal size in posterior hippocampus of schizophrenic patients. , 1991, Schizophrenia bulletin.

[27]  S. Heckers,et al.  Neuroimaging of declarative memory in schizophrenia. , 2001, Scandinavian journal of psychology.

[28]  Ira Driscoll,et al.  Damage to the hippocampal formation does not disrupt representational flexibility as measured by a novelty transfer test. , 2004, Behavioral neuroscience.

[29]  D. Senitz,et al.  A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. , 1999, Biological psychiatry.

[30]  F M Miezin,et al.  Activation of the hippocampus in normal humans: a functional anatomical study of memory. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[31]  R. Gur,et al.  Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. , 1994, Archives of general psychiatry.

[32]  Michael D. Nelson,et al.  Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging : A meta-analytic study , 1998 .

[33]  J. Donoghue,et al.  Frontal and parietal lobe activation during transitive inference in humans. , 2002, Cerebral cortex.

[34]  S. Lal,et al.  Cognitive and clinical moderators of recognition memory in schizophrenia: a meta-analysis , 2005, Schizophrenia Research.

[35]  Roberto Cabeza,et al.  Neural Correlates of Relational Memory: Successful Encoding and Retrieval of Semantic and Perceptual Associations , 2005, The Journal of Neuroscience.

[36]  S. Woods,et al.  Chlorpromazine equivalent doses for the newer atypical antipsychotics. , 2003, The Journal of clinical psychiatry.

[37]  H. Barbas,et al.  Topographically specific hippocampal projections target functionally distinct prefrontal areas in the rhesus monkey , 1995, Hippocampus.

[38]  S. Arnold,et al.  Further Evidence of Abnormal Cytoarchitecture of the Entorhinal Cortex in Schizophrenia Using Spatial Point Pattern Analyses , 1997, Biological Psychiatry.

[39]  L. Davachi Item, context and relational episodic encoding in humans , 2006, Current Opinion in Neurobiology.

[40]  J. Ehrhardt,et al.  Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging. , 1994, Science.

[41]  D. Barch,et al.  Working and long-term memory deficits in schizophrenia: is there a common prefrontal mechanism? , 2002, Journal of abnormal psychology.

[42]  Stephan Heckers,et al.  Hippocampal and parahippocampal volumes in schizophrenia: a structural MRI study. , 2006, Schizophrenia bulletin.

[43]  R. Murray,et al.  Meta-analysis of regional brain volumes in schizophrenia. , 2000, The American journal of psychiatry.

[44]  F. Benes,et al.  Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics. , 1986, Archives of general psychiatry.

[45]  B. Bogerts,et al.  Cell loss in the hippocampus of schizophrenics , 2004, European archives of psychiatry and neurological sciences.

[46]  A. Meyer-Lindenberg,et al.  Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. , 2005, Archives of general psychiatry.

[47]  Charan Ranganath,et al.  Medial Temporal Lobe Activity Predicts Successful Relational Memory Binding , 2008, The Journal of Neuroscience.

[48]  Ellen Perecman,et al.  The frontal lobes revisited. , 1987 .

[49]  Jeffrey A. Lieberman,et al.  Hippocampus-amygdala volumes and psychopathology in chronic schizophrenia , 1993, Biological Psychiatry.

[50]  M E Shenton,et al.  Scoring manual for the Thought Disorder Index. , 1986, Schizophrenia bulletin.

[51]  M. Leboyer,et al.  Conscious and subliminal conflicts in normal subjects and patients with schizophrenia: The role of the anterior cingulate , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[52]  R. Coppola,et al.  Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. , 2000, Cerebral cortex.

[53]  J. Trojanowski,et al.  Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions. , 1995, The American journal of psychiatry.

[54]  R. Habib,et al.  Activation of midbrain structures by associative novelty and the formation of explicit memory in humans. , 2004, Learning & memory.

[55]  S. Heckers,et al.  Neuroimaging studies of the hippocampus in schizophrenia , 2001, Hippocampus.

[56]  D. Weinberger,et al.  A connectionist approach to the prefrontal cortex. , 1993, The Journal of neuropsychiatry and clinical neurosciences.

[57]  S. Heckers,et al.  Hippocampal activation during transitive inference in humans , 2004, Hippocampus.

[58]  H. Eichenbaum,et al.  From Conditioning to Conscious Recollection , 2001 .

[59]  D. Schacter,et al.  Functional–Anatomic Study of Episodic Retrieval Using fMRI I. Retrieval Effort versus Retrieval Success , 1998, NeuroImage.

[60]  M. Buchsbaum,et al.  Biologic heterogeneity and psychiatrict research. Platelet MAO activity as a case study. , 1979, Archives of general psychiatry.

[61]  I. Fuentes,et al.  Intellectual functioning and memory deficits in schizophrenia. , 2007, Comprehensive psychiatry.

[62]  Kristen M. Haut,et al.  The Influence of Encoding Strategy on Episodic Memory and Cortical Activity in Schizophrenia , 2005, Biological Psychiatry.

[63]  R. Kikinis,et al.  Amygdala–hippocampal shape differences in schizophrenia: the application of 3D shape models to volumetric MR data , 2002, Psychiatry Research: Neuroimaging.

[64]  K. Hugdahl,et al.  Sensitivity and Specificity of Memory Dysfunction in Schizophrenia: A Comparison With Major Depression , 2003, Journal of clinical and experimental neuropsychology.

[65]  A. Baddeley,et al.  Memory in schizophrenia: What is impaired and what is preserved? , 1993, Neuropsychologia.

[66]  R. Bilder,et al.  Morphologic Markers of Neurodevelopmental Paths to Schizophrenia , 1991 .

[67]  M. LeMay,et al.  Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study. , 1992, The New England journal of medicine.

[68]  John M. Davis Dose equivalence of the anti-psychotic drugs , 1974 .

[69]  T. Crow,et al.  Estimated neuronal populations and volumes of the hippocampus and its subfields in schizophrenia. , 2002, The American journal of psychiatry.

[70]  D. Levy,et al.  Transitive inference in schizophrenia: impairments in relational memory organization , 2004, Schizophrenia Research.

[71]  Howard Chertkow,et al.  rCBF to the hippocampal complex covaries with superior semantic memory retrieval , 2007, Behavioural Brain Research.

[72]  H. Nyman Neuropsychological function in schizophrenia , 2002, European Psychiatry.

[73]  Kaj Blennow,et al.  The synaptic-vesicle-specific proteins rab3a and synaptophysin are reduced in thalamus and related cortical brain regions in schizophrenic brains , 1999, Schizophrenia Research.

[74]  R. Buckner,et al.  THE COGNITIVE NEUROSCIENCE OF REMEMBERING , 2001 .

[75]  L. Squire,et al.  Simple and associative recognition memory in the hippocampal region. , 2001, Learning & memory.

[76]  David A Lewis,et al.  Schizophrenia as a disorder of neurodevelopment. , 2002, Annual review of neuroscience.

[77]  J. Piaget Judgement and Reasoning in the Child , 1962 .

[78]  Matthias Nagel,et al.  Different extraretinal neuronal mechanisms of smooth pursuit eye movements in schizophrenia: An fMRI study , 2007, NeuroImage.

[79]  M. Weissman,et al.  Best estimate of lifetime psychiatric diagnosis: a methodological study. , 1982, Archives of general psychiatry.

[80]  A. Alavi,et al.  Frontotemporal cerebral blood flow change during executive and declarative memory tasks in schizophrenia: a positron emission tomography study. , 1998, Neuropsychology.

[81]  W. Scoville,et al.  LOSS OF RECENT MEMORY AFTER BILATERAL HIPPOCAMPAL LESIONS , 1957, Journal of neurology, neurosurgery, and psychiatry.

[82]  A. Alavi,et al.  Effect of schizophrenia on frontotemporal activity during word encoding and recognition: a PET cerebral blood flow study. , 2001, The American journal of psychiatry.

[83]  R. McCarley,et al.  MRI anatomy of schizophrenia , 1999, Biological Psychiatry.

[84]  F. Benes,et al.  GABAergic Interneurons: Implications for Understanding Schizophrenia and Bipolar Disorder , 2001, Neuropsychopharmacology.

[85]  H. Eichenbaum,et al.  The hippocampus and memory for orderly stimulus relations. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[86]  L. Squire,et al.  Medial Temporal Lobe Amnesia: Gradual Acquisition of Factual Information by Nondeclarative Memory , 2002, The Journal of Neuroscience.

[87]  R Tandon,et al.  Superior temporal gyrus in schizophrenia: a volumetric magnetic resonance imaging study , 2000, Schizophrenia Research.

[88]  Jeffrey A. Lieberman,et al.  Anterior hippocampal volume reductions predict frontal lobe dysfunction in first episode schizophrenia , 1995, Schizophrenia Research.

[89]  Paul J. Harrison,et al.  Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia , 2001, Hippocampus.

[90]  J. Sweeney,et al.  The entorhinal cortex in first-episode psychotic disorders: a structural magnetic resonance imaging study. , 2004, The American journal of psychiatry.

[91]  D. Levy,et al.  Conceptual combination in schizophrenia: Contrasting property and relational interpretations , 2007, Journal of Neurolinguistics.

[92]  F. Benes,et al.  Differences in the subregional and cellular distribution of GABAA receptor binding in the hippocampal formation of schizophrenic brain , 1996, Synapse.

[93]  Y. Hirayasu,et al.  Localized volume reduction in prefrontal, temporolimbic, and paralimbic regions in schizophrenia: an MRI parcellation study , 2004, Psychiatry Research: Neuroimaging.

[94]  G. A. Miller,et al.  A specific test of hippocampal deficit in schizophrenia. , 2005, Behavioral neuroscience.

[95]  D. Shohamy,et al.  Integrating Memories in the Human Brain: Hippocampal-Midbrain Encoding of Overlapping Events , 2008, Neuron.

[96]  N. Alpert,et al.  Functional imaging of memory retrieval in deficit vs nondeficit schizophrenia. , 1999, Archives of general psychiatry.

[97]  O. Krastoshevsky,et al.  Hippocampal Contributions to Episodic Encoding : Insights From Relational and Item-Based Learning , 2002 .

[98]  William L. Gross,et al.  An fMRI Analysis of the Human Hippocampus: Inference, Context, and Task Awareness , 2006, Journal of Cognitive Neuroscience.

[99]  M. First,et al.  Structured clinical interview for DSM-IV axis II personality disorders : SCID-II , 1997 .

[100]  F. Benes,et al.  The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects , 2001, Biological Psychiatry.

[101]  J BELBEY,et al.  What is schizophrenia? , 1982, Schizophrenia bulletin.

[102]  Hans-Jochen Heinze,et al.  Human Hippocampal and Parahippocampal Activity during Visual Associative Recognition Memory for Spatial and Nonspatial Stimulus Configurations , 2003, The Journal of Neuroscience.

[103]  D. Javitt,et al.  Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia , 2008, Trends in Neurosciences.

[104]  T. Schneider-Axmann,et al.  Entorhinal cortex pre-alpha cell clusters in schizophrenia: quantitative evidence of a developmental abnormality , 2000, Biological Psychiatry.

[105]  N. Cohen From Conditioning to Conscious Recollection Memory Systems of the Brain. Oxford Psychology Series, Volume 35. , 2001 .

[106]  D. Titone,et al.  The role of awareness and working memory in human transitive inference , 2008, Behavioural Processes.

[107]  M. Miller,et al.  Hippocampal deformities in schizophrenia characterized by high dimensional brain mapping. , 2002, The American journal of psychiatry.

[108]  R. Greene Circuit analysis of NMDAR hypofunction in the hippocampus, in vitro, and psychosis of schizophrenia † , 2001, Hippocampus.

[109]  K. Holyoak,et al.  A System for Relational Reasoning in Human Prefrontal Cortex , 1999 .

[110]  G. Reynolds,et al.  Deficit and hemispheric asymmetry of GABA uptake sites in the hippocampus in schizophrenia , 1990, Biological Psychiatry.

[111]  B. Bogerts,et al.  Limbic pathology in schizophrenia: The entorhinal region—a morphometric study , 1988, Biological Psychiatry.

[112]  S. Mednick Developmental Neuropathology of Schizophrenia , 1991, NATO ASI Series.

[113]  M. Miller,et al.  Statistical Analysis of Hippocampal Asymmetry in Schizophrenia , 2001, NeuroImage.

[114]  Michael J. Frank,et al.  Transitivity, flexibility, conjunctive representations, and the hippocampus. II. A computational analysis , 2003, Hippocampus.

[115]  J. Olney,et al.  Glutamate receptor dysfunction and schizophrenia. , 1995, Archives of general psychiatry.

[116]  Alison R Preston,et al.  Hippocampal contribution to the novel use of relational information in declarative memory , 2004, Hippocampus.

[117]  W. A. Phillips,et al.  Where the rubber meets the road: The importance of implementation , 2003, Behavioral and Brain Sciences.

[118]  S. Heckers,et al.  Impaired hippocampal function during the detection of novel words in schizophrenia , 2004, Biological Psychiatry.

[119]  B T Hyman,et al.  Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia. , 1991, Archives of general psychiatry.

[120]  R. Heinrichs,et al.  Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. , 1998, Neuropsychology.

[121]  D. Lewis,et al.  Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. , 2000, Archives of general psychiatry.

[122]  H. Berenbaum,et al.  Cognitive impairments associated with formal thought disorder in people with schizophrenia. , 2002, Journal of abnormal psychology.

[123]  Larry R Squire,et al.  Declarative Memory, Awareness, and Transitive Inference , 2005, The Journal of Neuroscience.

[124]  Benjamin W. H. Lim,et al.  Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars , 2007, Proceedings of the National Academy of Sciences.

[125]  J. Krystal,et al.  NMDA receptor regulation of memory and behavior in humans , 2001, Hippocampus.

[126]  Philip S. Holzman,et al.  Assessing schizophrenic thinking : a clinical and research instrument for measuring thought disorder , 1979 .

[127]  H. Eichenbaum,et al.  The medial temporal lobe and recognition memory. , 2007, Annual review of neuroscience.