Neuron Numbers and Volume of the Amygdala in Subjects Diagnosed with Bipolar Disorder or Schizophrenia

BACKGROUND Growing evidence supports a pivotal role for the amygdala in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ). However, the occurrence of morphologic changes in the amygdala is currently controversial. METHODS Total number and numeric density of neurons, neuronal somata size, and volume of the lateral (LN), basal (BN), accessory basal (ABN), and cortical (CO) nuclei of the amygdala were measured in 12 normal control, 10 BD, and 16 SZ subjects. RESULTS In BD subjects, reductions of total numbers (41.1%; p = .01) and numeric densities of neurons (14.5%, p = .01), as well as volume (29.0%; p = .01), were detected in LN. Density of neurons was also decreased in ABN of the same subjects (20.8%; p = .0005). These changes were not related to antipsychotics or lithium salt exposure. In SZ subjects, a decrease of total numbers of neurons was detected in LN (23.6%; p = .04). This effect was no longer significant once exposure to antipsychotics was taken into account. CONCLUSIONS These findings offer structural evidence for an involvement of the amygdala in BD. Consequent loss of amygdalar function may account for abnormalities in emotion processing typical of BD subjects. In contrast, changes in SZ were limited and may have been induced by pharmacologic treatment.

[1]  W. Stigelman,et al.  Goodman and Gilman's the Pharmacological Basis of Therapeutics , 1986 .

[2]  Bonaventura Cavalieri,et al.  Geometria degli indivisibili , 1966 .

[3]  Joseph E LeDoux Emotion Circuits in the Brain , 2000 .

[4]  J. Gore,et al.  Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder. , 2003, Archives of general psychiatry.

[5]  D. Kupfer,et al.  MRI investigation of temporal lobe structures in bipolar patients. , 2003, Journal of psychiatric research.

[6]  Joseph E LeDoux The Emotional Brain, Fear, and the Amygdala , 2003, Cellular and Molecular Neurobiology.

[7]  R. Coggeshall,et al.  Methods for determining numbers of cells and synapses: A case for more uniform standards of review , 1996, The Journal of comparative neurology.

[8]  B. Steinhoff,et al.  Amygdala lesion in temporal lobe epilepsy subjects impairs associative learning of emotional facial expressions , 2001, Neuropsychologia.

[9]  R. Carletti,et al.  Down‐regulation of amygdala preprotachykinin A mRNA but not 3H‐SP receptor binding sites in subjects affected by mood disorders and schizophrenia , 2005, The European journal of neuroscience.

[10]  Edward T. Bullmore,et al.  Hippocampus and amygdala volumes in schizophrenia and other psychoses in the Northern Finland 1966 birth cohort , 2005, Schizophrenia Research.

[11]  C. Harmer,et al.  Enhanced recognition of disgust in bipolar illness , 2002, Biological Psychiatry.

[12]  J. Hedreen Lost caps in histological counting methods , 1998, The Anatomical record.

[13]  A. Sampson,et al.  Decreased somal size of deep layer 3 pyramidal neurons in the prefrontal cortex of subjects with schizophrenia. , 2001, Archives of general psychiatry.

[14]  A. Vita,et al.  Brain morphology in first-episode schizophrenia: A meta-analysis of quantitative magnetic resonance imaging studies , 2006, Schizophrenia Research.

[15]  Marcus E Raichle,et al.  Glucose metabolism in the amygdala in depression: Relationship to diagnostic subtype and plasma cortisol levels , 2002, Pharmacology Biochemistry and Behavior.

[16]  Sabine Landau,et al.  Evidence for orbitofrontal pathology in bipolar disorder and major depression, but not in schizophrenia. , 2005, Bipolar disorders.

[17]  H. Soininen,et al.  Distribution of parvalbumin‐immunoreactive cells and fibers in the human amygdaloid complex , 1995, The Journal of comparative neurology.

[18]  J. Kleinman,et al.  Reduced glucocorticoid and estrogen receptor alpha messenger ribonucleic acid levels in the amygdala of patients with major mental illness , 2004, Biological Psychiatry.

[19]  Andreas A. Ioannides,et al.  Real-time neural activity and connectivity in healthy individuals and schizophrenia patients , 2004, NeuroImage.

[20]  Eric Halgren,et al.  Emotional neurophysiology of the amygdala within the context of human cognition. , 1992 .

[21]  W. Drevets Prefrontal Cortical‐Amygdalar Metabolism in Major Depression , 1999, Annals of the New York Academy of Sciences.

[22]  A. Sampson,et al.  Pyramidal cell size reduction in schizophrenia: evidence for involvement of auditory feedforward circuits , 2004, Biological Psychiatry.

[23]  E. Leibenluft,et al.  Frontotemporal alterations in pediatric bipolar disorder: results of a voxel-based morphometry study. , 2005, Archives of general psychiatry.

[24]  D. Amaral,et al.  Organization of the intrinsic connections of the monkey amygdaloid complex: Projections originating in the lateral nucleus , 1998, The Journal of comparative neurology.

[25]  R. Bentall,et al.  Social cognition and the manic defense: attributions, selective attention, and self-schema in bipolar affective disorder. , 1999, Journal of abnormal psychology.

[26]  H. Gundersen Stereology of arbitrary particles * , 1986, Journal of microscopy.

[27]  G. Paxinos,et al.  Atlas of the Human Brain , 2000 .

[28]  D. Amaral,et al.  Stereological estimation of the number of neurons in the human amygdaloid complex , 2005, The Journal of comparative neurology.

[29]  F. Yasuno,et al.  Decreased 5-HT1A receptor binding in amygdala of schizophrenia , 2004, Biological Psychiatry.

[30]  J. Kleinman,et al.  Alterations in TRH receptors in temporal lobe of schizophrenics: A quantitative autoradiographic study , 1994, Synapse.

[31]  Nicholas Lange,et al.  Two-dimensional versus three-dimensional cell counting: a practical perspective , 2001, Trends in Neurosciences.

[32]  J. Price,et al.  Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes , 2004, Biological Psychiatry.

[33]  V. Howard,et al.  Unbiased Stereology: Three-Dimensional Measurement in Microscopy , 1998 .

[34]  J. Aggleton,et al.  Amnesia and recognition memory: A re-analysis of psychometric data , 1996, Neuropsychologia.

[35]  A. Reiss,et al.  Reduced amygdalar gray matter volume in familial pediatric bipolar disorder. , 2005, Journal of the American Academy of Child and Adolescent Psychiatry.

[36]  B. Bogerts,et al.  Volume deficits of subcortical nuclei in mood disorders , 2005, European Archives of Psychiatry and Clinical Neuroscience.

[37]  G. Halliday,et al.  Clinical correlates of selective pathology in the amygdala of patients with Parkinson's disease. , 2002, Brain : a journal of neurology.

[38]  R. Kerwin,et al.  Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. , 2001, Archives of general psychiatry.

[39]  Israel Liberzon,et al.  Neural Response to Emotional Salience in Schizophrenia , 2005, Neuropsychopharmacology.

[40]  S. Stahl,et al.  Emotion processing, the amygdala, and outcome in schizophrenia , 2005, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[41]  G. Bartzokis,et al.  An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia , 2000, Biological Psychiatry.

[42]  Michael Davis,et al.  The amygdala: vigilance and emotion , 2001, Molecular Psychiatry.

[43]  R. Scott,et al.  Altered gene expression in the amygdala in schizophrenia: Up-regulation of genes located in the cytomatrix active zone , 2006, Molecular and Cellular Neuroscience.

[44]  H. Gundersen,et al.  The efficiency of systematic sampling in stereology — reconsidered , 1999, Journal of microscopy.

[45]  J. Feighner,et al.  Diagnostic criteria for use in psychiatric research. , 1972, Archives of general psychiatry.

[46]  Patricia Desmond,et al.  Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals. , 2006, Archives of general psychiatry.

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

[48]  E. Halgren,et al.  Mental phenomena evoked by electrical stimulation of the human hippocampal formation and amygdala. , 1978, Brain : a journal of neurology.

[49]  L. Goodman,et al.  The Pharmacological Basis of Therapeutics , 1941 .

[50]  B. Everitt,et al.  Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex , 2002, Neuroscience & Biobehavioral Reviews.

[51]  David G. Amaral,et al.  Stereological Analysis of Amygdala Neuron Number in Autism , 2006, The Journal of Neuroscience.

[52]  T. Crow,et al.  Amygdala volume in schizophrenia: post-mortem study and review of magnetic resonance imaging findings. , 2002, The British journal of psychiatry : the journal of mental science.

[53]  René S. Kahn,et al.  Strange feelings: Do amygdala abnormalities dysregulate the emotional brain in schizophrenia? , 2005, Progress in Neurobiology.

[54]  Christopher S von Bartheld,et al.  Differential tissue shrinkage and compression in the z-axis: implications for optical disector counting in vibratome-, plastic- and cryosections , 2003, Journal of Neuroscience Methods.

[55]  John P. Aggleton,et al.  The amygdala: Neurobiological aspects of emotion, memory, and mental dysfunction. , 1992 .

[56]  G. Pearlson,et al.  Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder , 1997, Biological Psychiatry.

[57]  Stephan Heckers,et al.  Increased medial temporal lobe activation during the passive viewing of emotional and neutral facial expressions in schizophrenia , 2006, Schizophrenia Research.

[58]  S. Strakowski,et al.  Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorder. , 2004, Bipolar disorders.

[59]  H J Gundersen,et al.  Non‐uniform systematic sampling in stereology* , 2000, Journal of microscopy.

[60]  R. Isaacson The Limbic System , 1974, Springer US.

[61]  E. Bora,et al.  Evidence for theory of mind deficits in euthymic patients with bipolar disorder , 2005, Acta psychiatrica Scandinavica.

[62]  S. Haber,et al.  Amygdaloid projections to ventromedial striatal subterritories in the primate , 2002, Neuroscience.

[63]  M. Keshavan,et al.  Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder , 2004, Biological Psychiatry.

[64]  G. Reynolds Increased concentrations and lateral asymmetry of amygdala dopamine in schizophrenia , 1983, Nature.

[65]  B. Pakkenberg,et al.  Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. , 1990, Archives of general psychiatry.

[66]  A. Chiba,et al.  The amygdala and emotion , 1996, Current Opinion in Neurobiology.

[67]  S. Strakowski,et al.  Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. , 1999, Archives of general psychiatry.

[68]  M. Gitlin Treatment-resistant bipolar disorder , 2006, Molecular Psychiatry.

[69]  N. Fox,et al.  Affect-modulated startle in adults with childhood-onset depression: Relations to bipolar course and number of lifetime depressive episodes , 2005, Psychiatry Research.

[70]  S. Lawrie,et al.  Brain abnormality in schizophrenia , 1998, British Journal of Psychiatry.

[71]  S. Strakowski,et al.  The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings , 2005, Molecular Psychiatry.

[72]  William D S Killgore,et al.  fMRI during affect discrimination in bipolar affective disorder. , 2000, Bipolar disorders.

[73]  David C. Alsop,et al.  Brain Activation during Facial Emotion Processing , 2002, NeuroImage.

[74]  D. Amaral,et al.  Projections from the lateral, basal, and accessory basal nuclei of the amygdala to the entorhinal cortex in the macaque monkey , 2002, Hippocampus.

[75]  A. Pitkänen,et al.  Projections from the lateral, basal and accessory basal nuclei of the amygdala to the perirhinal and postrhinal cortices in rat. , 2001, Cerebral cortex.

[76]  O. Shirakawa,et al.  Isotype-Specific G Protein Abnormalities in the Left Superior Temporal Cortex and Limbic Structures of Patients with Chronic Schizophrenia , 1998, Biological Psychiatry.

[77]  Mark S. Cohen,et al.  Increased amygdala activation during mania: a functional magnetic resonance imaging study. , 2005, The American journal of psychiatry.

[78]  M. Frye,et al.  Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder , 2001, Biological Psychiatry.

[79]  P. Holland,et al.  Amygdala circuitry in attentional and representational processes , 1999, Trends in Cognitive Sciences.

[80]  D. Amaral,et al.  Topographic organization of projections from the amygdala to the visual cortex in the macaque monkey , 2003, Neuroscience.