The role of hippocampus in the pathophysiology of bipolar disorder

Bipolar disorder (BD) is thought to be associated with abnormalities within discrete brain regions associated with emotional regulation, particularly in fronto-limbic-subcortical circuits. Several reviews have addressed the involvement of the prefrontal cortex in the pathophysiology of BD, whereas little attention has been given to the role of the hippocampus. This study critically reviews data from brain imaging, postmortem, neuropsychological, and preclinical studies, which suggested hippocampal abnormalities in BD. Most of the structural brain imaging studies did not find changes in hippocampal volume in BD, although a few studies suggested that anatomical changes might be restricted to the psychotic, pediatric, or unmedicated BD subgroups. Functional imaging studies showed abnormal brain activation in the hippocampus and its closely related regions during emotional, attentional, and memory tasks. This is consistent with neuropsychological findings that revealed a wide range of cognitive disturbances during acute mood episodes and a significant impairment in declarative memory during remission. Postmortem studies indicate abnormal glutamate and GABA transmission in the hippocampus of BD patients, whereas data from preclinical studies suggest that the regulation of hippocampal plasticity and survival might be associated with the therapeutic effects of mood stabilizers. In conclusion, the available evidence suggests that the hippocampus plays an important role in the pathophysiology of BD.

[1]  J. Deakin,et al.  NMDA receptor subunit NRI and postsynaptic protein PSD-95 in hippocampus and orbitofrontal cortex in schizophrenia and mood disorder , 2005, Schizophrenia Research.

[2]  S. Schulz,et al.  Hippocampal CA1 Pyramidal Cell Size is Reduced in Bipolar Disorder , 2007, Cellular and Molecular Neurobiology.

[3]  Tyrone D. Cannon,et al.  The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. , 2001, Bipolar disorders.

[4]  L. Selemon,et al.  Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder , 2001, Biological Psychiatry.

[5]  J. Price,et al.  Glial reduction in the subgenual prefrontal cortex in mood disorders. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Paul J. Harrison,et al.  Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs , 2000, Molecular Psychiatry.

[7]  F. Benes,et al.  Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. , 2002, Archives of general psychiatry.

[8]  R. Stern,et al.  Differential Impact of Executive Dysfunction on Verbal List Learning and Story Recall , 2000, The Clinical neuropsychologist.

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

[10]  Michael Marriott,et al.  Lower hippocampal volume in patients suffering from depression: a meta-analysis. , 2004, The American journal of psychiatry.

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

[12]  R. El-Mallakh,et al.  Glial cell number and neuron/glial cell ratios in postmortem brains of bipolar individuals. , 2006, Journal of affective disorders.

[13]  C. Bown,et al.  Attenuation of N-methyl-d-aspartate-mediated cytoplasmic vacuolization in primary rat hippocampal neurons by mood stabilizers , 2003, Neuroscience.

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

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

[16]  S. Rauch,et al.  Episodic memory impairment in bipolar disorder and obsessive-compulsive disorder: the role of memory strategies. , 2004, Bipolar disorders.

[17]  Jun-Feng Wang,et al.  Immunoreactivity of 43 kDa growth-associated protein is decreased in post mortem hippocampus of bipolar disorder and schizophrenia. , 2007, Neuroscience letters.

[18]  John Suckling,et al.  Explicit and Implicit Facial Affect Recognition in Manic and Depressed States of Bipolar Disorder: A Functional Magnetic Resonance Imaging Study , 2006, Biological Psychiatry.

[19]  D. Glahn,et al.  Sources of declarative memory impairment in bipolar disorder: mnemonic processes and clinical features. , 2006, Journal of psychiatric research.

[20]  Eric J. Nestler,et al.  Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus , 2000, The Journal of Neuroscience.

[21]  S. Fatemi,et al.  Altered levels of the synaptosomal associated protein SNAP-25 in hippocampus of subjects with mood disorders and schizophrenia , 2001, Neuroreport.

[22]  B. Sahakian,et al.  Cognitive impairment in remission in bipolar affective disorder , 2000, Psychological Medicine.

[23]  L. Young,et al.  Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate , 2007, Neuroscience.

[24]  Mark A Frye,et al.  Principal components of the beck depression inventory and regional cerebral metabolism in unipolar and bipolar depression , 2002, Biological Psychiatry.

[25]  D. Chuang,et al.  Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: An essential step for neuroprotection against glutamate excitotoxicity , 2002, Neuropharmacology.

[26]  Guang Chen,et al.  Mood Stabilizer Valproate Promotes ERK Pathway-Dependent Cortical Neuronal Growth and Neurogenesis , 2004, The Journal of Neuroscience.

[27]  R. Dingledine,et al.  Long-term depression in hippocampal interneurons: joint requirement for pre- and postsynaptic events. , 1999, Science.

[28]  G. MacQueen,et al.  G Protein‐Coupled Cyclic AMP Signaling in Postmortem Brain of Subjects with Mood Disorders , 1999, Journal of neurochemistry.

[29]  H. Manji,et al.  The Role of the Extracellular Signal-Regulated Kinase Signaling Pathway in Mood Modulation , 2003, The Journal of Neuroscience.

[30]  R. Robinson,et al.  SPECT findings in patients with primary mania. , 1993, The Journal of neuropsychiatry and clinical neurosciences.

[31]  J. Barendregt,et al.  Global burden of disease , 1997, The Lancet.

[32]  Glenda M MacQueen,et al.  Bilateral Hippocampal Volume Increase in Patients with Bipolar Disorder and Short-term Lithium Treatment , 2008, Neuropsychopharmacology.

[33]  J. Coyle,et al.  Finding the Intracellular Signaling Pathways Affected by Mood Disorder Treatments , 2003, Neuron.

[34]  S. Holland,et al.  A Preliminary fMRI Study of Sustained Attention in Euthymic, Unmedicated Bipolar Disorder , 2004, Neuropsychopharmacology.

[35]  M. Phillips,et al.  Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression , 2004, Biological Psychiatry.

[36]  H. Yokoo,et al.  Lithium: potential therapeutics against acute brain injuries and chronic neurodegenerative diseases. , 2005, Journal of pharmacological sciences.

[37]  Paul J. Harrison,et al.  The neuropathology of primary mood disorder. , 2002, Brain : a journal of neurology.

[38]  R. Morris,et al.  Glucocorticoids, hippocampal corticosteroid receptor gene expression and antidepressant treatment: relationship with spatial learning in young and aged rats , 1995, Neuroscience.

[39]  Alessandro Bertolino,et al.  Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging , 2003, Biological Psychiatry.

[40]  S. Fatemi,et al.  Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression , 2000, Molecular Psychiatry.

[41]  C. McBain,et al.  Long-Term Potentiation in Distinct Subtypes of Hippocampal Nonpyramidal Neurons , 1996, The Journal of Neuroscience.

[42]  B. Frey,et al.  Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania. , 2006, Life sciences.

[43]  N. Uranova,et al.  Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium , 2004, Schizophrenia Research.

[44]  R. Duman,et al.  Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[45]  Y. Okamoto,et al.  Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain , 2001, Psychopharmacology.

[46]  G. Rajkowska,et al.  Depression: What We can Learn from Postmortem Studies , 2003, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[47]  L. Frank,et al.  Hippocampal and cortical place cell plasticity: Implications for episodic memory , 2006, Hippocampus.

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

[49]  E. Maguire,et al.  The Human Hippocampus and Spatial and Episodic Memory , 2002, Neuron.

[50]  E. Castrén,et al.  Is mood chemistry? , 2005, Nature Reviews Neuroscience.

[51]  H. Manji,et al.  The Anticonvulsants Lamotrigine, Riluzole, and Valproate Differentially Regulate AMPA Receptor Membrane Localization: Relationship to Clinical Effects in Mood Disorders , 2007, Neuropsychopharmacology.

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

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

[54]  Gin S Malhi,et al.  An emotional Stroop functional MRI study of euthymic bipolar disorder. , 2005, Bipolar disorders.

[55]  M. Atmaca,et al.  Hippocampal 1H MRS in first-episode bipolar I patients , 2006, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[56]  F. Benes,et al.  A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives , 1998, Biological Psychiatry.

[57]  R. Parsey,et al.  Regional brain gray matter volume differences in patients with bipolar disorder as assessed by optimized voxel-based morphometry , 2004, Biological Psychiatry.

[58]  B. Dean,et al.  Changes in hippocampal GABAA receptor subunit composition in bipolar 1 disorder. , 2005, Brain research. Molecular brain research.

[59]  R G Robinson,et al.  Cognitive impairment in the euthymic phase of chronic unipolar depression. , 1997, The Journal of nervous and mental disease.

[60]  Stephen M Strakowski,et al.  Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder. , 2002, The American journal of psychiatry.

[61]  Bruce S. McEwen,et al.  Stress and hippocampal plasticity: implications for the pathophysiology of affective disorders , 2001, Human psychopharmacology.

[62]  S. Holland,et al.  Abnormal FMRI brain activation in euthymic bipolar disorder patients during a counting Stroop interference task. , 2005, The American journal of psychiatry.

[63]  R. Sapolsky.  Why Stress Is Bad for Your Brain , 1996, Science.

[64]  S. Rauch,et al.  Neurobiology of emotion perception I: the neural basis of normal emotion perception , 2003, Biological Psychiatry.

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

[66]  G. Buzsáki,et al.  Interneurons of the hippocampus , 1998, Hippocampus.

[67]  G F Mason,et al.  Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments , 2002, Molecular Psychiatry.

[68]  Barry Halliwell,et al.  Oxidative stress and neurodegeneration: where are we now? , 2006, Journal of neurochemistry.

[69]  B. Dean,et al.  Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder , 2007, Brain Research.

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

[71]  S. Rauch,et al.  Impaired Recruitment of the Dorsolateral Prefrontal Cortex and Hippocampus During Encoding in Bipolar Disorder , 2006, Biological Psychiatry.

[72]  Subhash Aryal,et al.  Neurocognitive function in unmedicated manic and medicated euthymic pediatric bipolar patients. , 2006, The American journal of psychiatry.

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

[74]  D. Amaral,et al.  Hippocampal‐neocortical interaction: A hierarchy of associativity , 2000, Hippocampus.

[75]  I. Fujita,et al.  Neuronal mechanisms of selectivity for object features revealed by blocking inhibition in inferotemporal cortex , 2000, Nature Neuroscience.

[76]  B. Frey,et al.  Effects of lithium and valproate on amphetamine-induced oxidative stress generation in an animal model of mania. , 2006, Journal of psychiatry & neuroscience : JPN.

[77]  J. Price,et al.  Low glial numbers in the amygdala in major depressive disorder , 2002, Biological Psychiatry.

[78]  H. Manji,et al.  The Anti-Apoptotic, Glucocorticoid Receptor Cochaperone Protein BAG-1 Is a Long-Term Target for the Actions of Mood Stabilizers , 2005, The Journal of Neuroscience.

[79]  David J Kupfer,et al.  Neuropsychologic impairments in bipolar and unipolar mood disorders on the CANTAB neurocognitive battery , 2000, Biological Psychiatry.

[80]  D. Rubinow,et al.  Impaired recognition of affect in facial expression in depressed patients , 1992, Biological Psychiatry.

[81]  C. Konradi,et al.  Hippocampal neurons in schizophrenia , 2002, Journal of Neural Transmission.

[82]  M. Herman,et al.  Neuritic pathology is lacking in the entorhinal cortex, subiculum and hippocampus in middle-aged adults with schizophrenia, bipolar disorder or unipolar depression , 2002, Acta Neuropathologica.

[83]  M. Webster,et al.  Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium , 2004, Molecular Psychiatry.

[84]  R. Feiwell,et al.  Lower concentration of hippocampal N-acetylaspartate in familial bipolar I disorder. , 2003, The American journal of psychiatry.

[85]  B. Frey,et al.  Effects of lithium and valproate on serum and hippocampal neurotrophin-3 levels in an animal model of mania. , 2008, Journal of psychiatric research.

[86]  B. McEwen,et al.  Stress-induced structural remodeling in hippocampus: prevention by lithium treatment. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[87]  S. Rauch,et al.  Neurobiology of emotion perception II: implications for major psychiatric disorders , 2003, Biological Psychiatry.

[88]  D. Glahn,et al.  Patterns of memory impairment in bipolar disorder and unipolar major depression , 2006, Psychiatry Research.

[89]  G Buzsáki,et al.  Functions for interneuronal nets in the hippocampus. , 1997, Canadian journal of physiology and pharmacology.

[90]  H. Lôo.  [On bipolar disorder]. , 2008, L'Encephale.

[91]  Jun-Feng Wang,et al.  Chronic Treatment with Mood Stabilizers Lithium and Valproate Prevents Excitotoxicity by Inhibiting Oxidative Stress in Rat Cerebral Cortical Cells , 2005, Biological Psychiatry.

[92]  H. Thoenen,et al.  GABAergic Stimulation Regulates the Phenotype of Hippocampal Interneurons through the Regulation of Brain-Derived Neurotrophic Factor , 1996, Neuron.

[93]  B. Frey,et al.  Lithium increases nerve growth factor levels in the rat hippocampus in an animal model of mania , 2006, Behavioural pharmacology.

[94]  D. Chuang,et al.  Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[95]  G. Rajkowska,et al.  Enhancement of Hippocampal Neurogenesis by Lithium , 2000, Journal of neurochemistry.

[96]  J. Noga,et al.  A volumetric magnetic resonance imaging study of monozygotic twins discordant for bipolar disorder , 2001, Psychiatry Research: Neuroimaging.

[97]  David J Kupfer,et al.  The increasing medical burden in bipolar disorder. , 2005, JAMA.

[98]  J. Meador-Woodruff,et al.  Abnormal Glutamate Receptor Expression in the Medial Temporal Lobe in Schizophrenia and Mood Disorders , 2007, Neuropsychopharmacology.

[99]  E. Bramon,et al.  Regional brain morphometry in patients with schizophrenia or bipolar disorder and their unaffected relatives. , 2006, The American journal of psychiatry.

[100]  D. Glahn,et al.  Declarative memory impairment in pediatric bipolar disorder. , 2005, Bipolar disorders.

[101]  P. Brambilla,et al.  Stress and hippocampal abnormalities in psychiatric disorders , 2004, European Neuropsychopharmacology.

[102]  S. Strakowski,et al.  Changes in Gray Matter Volume in Patients with Bipolar Disorder , 2005, Biological Psychiatry.

[103]  R. Cabeza,et al.  Cognitive neuroscience of emotional memory , 2006, Nature Reviews Neuroscience.

[104]  A. Mackinnon,et al.  Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder. , 2003, Bipolar disorders.

[105]  Stephan Heckers,et al.  Molecular evidence for mitochondrial dysfunction in bipolar disorder. , 2004, Archives of general psychiatry.

[106]  J. Kleinman,et al.  Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia , 2002, Molecular Psychiatry.

[107]  G. Evan,et al.  A matter of life and cell death. , 1998, Science.

[108]  S. Rauch,et al.  Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder. , 2005, The American journal of psychiatry.

[109]  Caleb M. Adler,et al.  Voxel-Based Study of Structural Changes in First-Episode Patients with Bipolar Disorder , 2007, Biological Psychiatry.

[110]  James C. Ehrhardt,et al.  Subcortical and temporal structures in affective disorder and schizophrenia: A magnetic resonance imaging study , 1992, Biological Psychiatry.

[111]  J. Mann,et al.  The functional neuroanatomy of mood disorders. , 1997, Journal of psychiatric research.

[112]  H. Manji,et al.  Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. , 2001, Psychopharmacology bulletin.

[113]  H. Eichenbaum.  A cortical–hippocampal system for declarative memory , 2000, Nature Reviews Neuroscience.

[114]  B. Ravnkilde,et al.  Hippocampal volume and depression: a meta-analysis of MRI studies. , 2004, The American journal of psychiatry.

[115]  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.

[116]  Mark S. Cohen,et al.  Blunted Activation in Orbitofrontal Cortex During Mania: A Functional Magnetic Resonance Imaging Study , 2005, Biological Psychiatry.

[117]  Alan D. Lopez.  THE GLOBAL BURDEN OF DISEASE 1990-2020 , 2001 .

[118]  Paul J. Harrison,et al.  Reduced spinophilin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: molecular evidence for a pathology of dendritic spines. , 2004, The American journal of psychiatry.

[119]  D. Ruano,et al.  Native gamma-aminobutyric acid type A receptors from rat hippocampus, containing both alpha 1 and alpha 5 subunits, exhibit a single benzodiazepine binding site with alpha 5 pharmacological properties. , 1999, The Journal of pharmacology and experimental therapeutics.

[120]  B. Kaang,et al.  Lithium enhances long‐term potentiation independently of hippocampal neurogenesis in the rat dentate gyrus , 2003, Journal of neurochemistry.

[121]  J. Potash,et al.  Hippocampal and ventricular volumes in psychotic and nonpsychotic bipolar patients compared with schizophrenia patients and community control subjects: A pilot study , 2005, Biological Psychiatry.

[122]  H. Jakob,et al.  Prenatal disturbances of nerve cell migration in the entorhinal region: a common vulnerability factor in functional psychoses? , 2005, Journal of Neural Transmission / General Section JNT.

[123]  R. Burke,et al.  The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia , 2006, Molecular Psychiatry.

[124]  Kiralee M. Hayashi,et al.  Three-Dimensional Mapping of Hippocampal Anatomy in Unmedicated and Lithium-Treated Patients with Bipolar Disorder , 2008, Neuropsychopharmacology.

[125]  K. Anand,et al.  Is hippocampal atrophy a future drug target? , 2007, Medical hypotheses.

[126]  S. Kish,et al.  Reduced [3H]Cyclic AMP Binding in Postmortem Brain from Subjects with Bipolar Affective Disorder , 1997, Journal of neurochemistry.

[127]  M S Mega,et al.  The limbic system: an anatomic, phylogenetic, and clinical perspective. , 1997, The Journal of neuropsychiatry and clinical neurosciences.

[128]  G. Rosoklija,et al.  Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders: preliminary findings. , 2000, Archives of general psychiatry.

[129]  T. Robbins,et al.  Emotional bias and inhibitory control processes in mania and depression , 1999, Psychological Medicine.

[130]  J. Warsh,et al.  cAMP-Dependent protein kinase (PKA) subunit mRNA levels in postmortem brain from patients with bipolar affective disorder (BD). , 2003, Brain research. Molecular brain research.

[131]  Eduard Vieta,et al.  Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. , 2004, The American journal of psychiatry.

[132]  H. Son,et al.  Lithium selectively increases neuronal differentiation of hippocampal neural progenitor cells both in vitro and in vivo , 2004, Journal of neurochemistry.

[133]  R. Duman,et al.  Antidepressants and neuroplasticity. , 2002, Bipolar disorders.

[134]  G. Parker,et al.  Cognitive generation of affect in bipolar depression: an fMRI study , 2004, The European journal of neuroscience.

[135]  E T Bullmore,et al.  Behavioural and neurocognitive responses to sad facial affect are attenuated in patients with mania , 2004, Psychological Medicine.

[136]  M. Atmaca,et al.  Hippocampal 1H MRS in patients with bipolar disorder taking valproate versus valproate plus quetiapine , 2006, Psychological Medicine.

[137]  K. Krishnan,et al.  Hippocampal volume measurement in older adults with bipolar disorder. , 2004, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[138]  John A. Rice,et al.  The long-term natural history of the weekly symptomatic status of bipolar I disorder. , 2002, Archives of general psychiatry.

[139]  C. Konradi,et al.  Decrease in creatine kinase messenger RNA expression in the hippocampus and dorsolateral prefrontal cortex in bipolar disorder. , 2006, Bipolar disorders.

[140]  B. McEwen.  Stress and hippocampal plasticity. , 1999, Annual review of neuroscience.

[141]  L. Altshuler,et al.  MRI-based measurements of temporal lobe and ventricular structures in patients with bipolar I and bipolar II disorders. , 2000, Journal of affective disorders.

[142]  R Kawashima,et al.  Hypoperfusion in the limbic system and prefrontal cortex in depression: SPECT with anatomic standardization technique. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[143]  Katharina Henke,et al.  Glucocorticoid‐induced impairment of declarative memory retrieval is associated with reduced blood flow in the medial temporal lobe , 2003, The European journal of neuroscience.

[144]  S. Kish,et al.  Increased Cyclic AMP‐Dependent Protein Kinase Activity in Postmortem Brain from Patients with Bipolar Affective Disorder , 1999, Journal of neurochemistry.