Amygdala in Bipolar Disorder -- Neurotransmitter.net

(Updated 8/25/04)

Anand A, Shekhar A.
Brain imaging studies in mood and anxiety disorders: special emphasis on the amygdala.
Ann N Y Acad Sci. 2003 Apr;985:370-88.
"Human studies attempting to elucidate brain functioning in health and disease are crucial for our understanding of neuropsychiatric disorders. In the past, scientists relied heavily on neurological lesion studies to understand the functional roles of brain areas. In the last few decades, brain imaging research has made it possible to investigate the molecular and synaptic neuronal events as well as the functioning of neuronal networks in vivo, in patients with neuropsychiatric illnesses. In this context, the functional role of the amygdala has been a focus of neuroimaging studies by leading researchers. Several of these researchers presented papers at a conference, entitled The Amygdala in Brain Function: Basic and Clinical Approaches, that provided the basis for this volume. These papers follow this review in the current volume. The present paper briefly summarizes the highlights of the different presentations, focusing on the functional diversity of the amygdala and its role in different neuropsychiatric disorders; reviews the various brain imaging technologies currently available; and discusses the major findings on the pathophysiology and treatment of depression, bipolar disorder, and anxiety disorders." [Abstract]

Brambilla P, Harenski K, Nicoletti M, Sassi RB, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC.
MRI investigation of temporal lobe structures in bipolar patients.
J Psychiatr Res. 2003 Jul-Aug;37(4):287-95.
"Previous anatomical MRI studies have suggested abnormalities in amygdala volumes in bipolar disorder, whereas hippocampus, temporal lobe (TL), and superior temporal gyri (STG) measures have been reported to be normal. This study further investigated the existence of anatomical abnormalities in these brain structures in bipolar subjects, to attempt to replicate previously reported findings. Twenty-four DSM-IV bipolar patients (mean age+/-S.D.=35+/-10 years) and 36 healthy controls (mean age+/-S.D.=37+/-10 years) were studied. 3D SPGR images were obtained with a 1.5T-GE Signa magnet (TR=25 ms, TE=5 ms, FOV=24 cm, slice-thickness=1.5 mm, matrix-size=256 x 192). Volumetric measurements of TL, hippocampus, amygdala, and STG were performed blindly, with a semi-automated software. Bipolar patients had significantly larger left amygdala volumes compared with controls (mean volumes+/-S.D.=2.57+/-0.69 vs. 2.17+/-0.58 ml, respectively; ANCOVA, age, gender, ICV as covariates; F=4.42, df=1/55, P=0.04). The volumes of the other temporal lobe structures did not differ significantly between the two groups (ANCOVA, age, gender, and ICV as covariates, P>0.05). Our findings of enlarged left amygdala in bipolar patients are in agreement with prior MRI studies, suggesting that abnormalities in this brain structure may be implicated in pathophysiology of the illness. Longitudinal studies in high-risk offspring and first-episode patients will be needed to examine whether such abnormalities precede the appearance of symptoms, or whether they may appear subsequently as a result of illness course." [Abstract]

Drevets WC, Price JL, Bardgett ME, Reich T, Todd RD, Raichle ME.
Glucose metabolism in the amygdala in depression: relationship to diagnostic subtype and plasma cortisol levels.
Pharmacol Biochem Behav 2002 Mar;71(3):431-47
"In a previous positron emission tomography (PET) study of major depression, we demonstrated that cerebral blood flow was increased in the left amygdala in unipolar depressives with familial pure depressive disease (FPDD) relative to healthy controls [J. Neurosci. 12 (1992) 3628.]. These measures were obtained from relatively low-resolution PET images using a stereotaxic method based upon skull X-ray landmarks. The current experiments aimed to replicate and extend these results using higher-resolution glucose metabolism images and magnetic resonance imaging (MRI)-based region-of-interest (ROI) analysis. The specificity of this finding to FPDD was also investigated by assessing depressed samples with bipolar disorder (BD-D) and depression spectrum disease (DSD). Finally, the relationship between amygdala metabolism and plasma cortisol levels obtained during the scanning procedure was assessed. Glucose metabolism was measured using PET and 18F-fluorodeoxyglucose (18FDG) in healthy control (n=12), FPDD (n=12), DSD (n=9) and BD-D (n=7) samples in the amygdala and the adjacent hippocampus. The left amygdala metabolism differed across groups (P<.001), being increased in both the FPDD and BD-D groups relative to the control group. The left amygdala metabolism was positively correlated with stressed plasma cortisol levels in both the unipolar (r=.69; P<.005) and the bipolar depressives (r=0.68;.1<P<.05). In contrast, neither significant main effects of diagnosis nor significant relationships with plasma cortisol were evident in post hoc analyses of metabolism in the right amygdala or the hippocampus. Preliminary assessment of BD subjects imaged during remission suggested that amygdala metabolism is also elevated in remitted subjects who are not taking mood-stabilizing drugs, but within the normal range in subjects taking mood stabilizers. These data confirm our previous finding that neurophysiological activity is abnormally increased in FPDD, and extend it to BD-D. These abnormalities were not accounted for by spilling in of radioactivity from the adjacent hippocampus. The correlation between left amygdala metabolism and stressed plasma cortisol levels may conceivably reflect either the effect of amygdala activity on corticotropin-releasing hormone (CRH) secretion or the effect of cortisol on amygdala function." [Abstract]

Altshuler LL, Bartzokis G, Grieder T, Curran J, Jimenez T, Leight K, Wilkins J, Gerner R, Mintz J.
An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia.
Biol Psychiatry 2000 Jul 15;48(2):147-62
"BACKGROUND: Hippocampal atrophy has been described in postmortem and magnetic resonance imaging studies of schizophrenia. The specificity of this finding to schizophrenia remains to be determined. The neuropathology of bipolar disorder is understudied, and temporal lobe structures have only recently been evaluated. METHODS: Twenty-four bipolar, 20 schizophrenic, and 18 normal comparison subjects were evaluated using magnetic resonance brain imaging. Image data were acquired using a three-dimensional spoiled GRASS sequence, and brain images were reformatted in three planes. Temporal lobe structures including the amygdala, hippocampus, parahippocampus, and total temporal lobe were measured to obtain volumes for each structure in the three subject groups. Severity of symptoms in both patient groups was assessed at the time the magnetic resonance images were obtained. RESULTS: Hippocampal volumes were significantly smaller in the schizophrenic group than in both bipolar and normal comparison subjects. Further, amygdala volumes were significantly larger in the bipolar group than in both schizophrenic and normal comparison subjects. CONCLUSIONS: The results suggest differences in affected limbic structures in patients with schizophrenia and bipolar disorder. These specific neuroanatomic abnormalities may shed light on the underlying pathophysiology and presentation of the two disorders." [Abstract]

Blumberg HP, Kaufman J, Martin A, Whiteman R, Zhang JH, Gore JC, Charney DS, Krystal JH, Peterson BS.
Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder.
Arch Gen Psychiatry. 2003 Dec;60(12):1201-8.
"BACKGROUND: The purported functions of medial temporal lobe structures suggest their involvement in the pathophysiology of bipolar disorder (BD). Previous reports of abnormalities in the volume of the amygdala and hippocampus in patients with BD have been inconsistent in their findings and limited to adult samples. Appreciation of whether volumetric abnormalities are early features of BD or whether the abnormalities represent neurodegenerative changes associated with illness duration is limited by the paucity of data in juvenile samples. OBJECTIVE: To investigate amygdala and hippocampal volume in adults and adolescents with BD.Setting and PARTICIPANTS: Subjects included 36 individuals (14 adolescents and 22 adults) in outpatient treatment for BD type I at a university hospital or Veterans Affairs medical center or in the surrounding community, and 56 healthy comparison subjects (23 adolescents and 33 adults).Design and MAIN OUTCOME MEASURES: Amygdala and hippocampal volumes were defined and measured on high-resolution anatomic magnetic resonance imaging scans. We used a mixed-model, repeated-measures statistical analysis to compare amygdala and hippocampal volumes across groups while covarying for total brain volume, age, and sex. Potential effects of illness features were explored, including rapid cycling, medication, alcohol or other substance dependence, duration, and mood state. RESULTS: For both the amygdala and hippocampal regions, we found an overall significant volume reduction in the BD compared with the control group (P<.0001). Amygdala volume reductions (15.6%) were highly significant (P<.0001). We observed a nonsignificant trend (P =.054) toward reductions in hippocampal volumes of lesser magnitude (5.3%). Effects of illness features were not detected. CONCLUSIONS: These results suggest that BD is associated with decreased volumes of medial temporal lobe structures, with greater effect sizes in the amygdala than in the hippocampus. These abnormalities are likely manifested early in the course of illness, as they affected adolescent and adult subjects similarly in this sample." [Abstract]

Ketter TA, Kimbrell TA, George MS, Dunn RT, Speer AM, Benson BE, Willis MW, Danielson A, Frye MA, Herscovitch P, Post RM.
Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder.
Biol Psychiatry 2001 Jan 15;49(2):97-109
"BACKGROUND: Functional brain imaging studies in unipolar and secondary depression have generally found decreased prefrontal cortical activity, but in bipolar disorders findings have been more variable. METHODS: Forty-three medication-free, treatment-resistant, predominantly rapid-cycling bipolar disorder patients and 43 age- and gender-matched healthy control subjects had cerebral glucose metabolism assessed using positron emission tomography and fluorine-18-deoxyglucose. RESULTS: Depressed bipolar disorder patients compared to control subjects had decreased global, absolute prefrontal and anterior paralimbic cortical, and increased normalized subcortical (ventral striatum, thalamus, right amygdala) metabolism. Degree of depression correlated negatively with absolute prefrontal and paralimbic cortical, and positively with normalized anterior paralimbic subcortical metabolism. Increased normalized cerebello-posterior cortical metabolism was seen in all patient subgroups compared to control subjects, independent of mood state, disorder subtype, or cycle frequency. CONCLUSIONS: In bipolar depression, we observed a pattern of prefrontal hypometabolism, consistent with observations in primary unipolar and secondary depression, suggesting this is part of a common neural substrate for depression independent of etiology. In contrast, the cerebello-posterior cortical normalized hypermetabolism seen in all bipolar subgroups (including euthymic) suggests a possible congenital or acquired trait abnormality. The degree to which these findings in treatment-resistant, predominantly rapid-cycling patients pertain to community samples remains to be established." [Abstract]

Strakowski SM, DelBello MP, Sax KW, Zimmerman ME, Shear PK, Hawkins JM, Larson ER.
Brain magnetic resonance imaging of structural abnormalities in bipolar disorder.
Arch Gen Psychiatry 1999 Mar;56(3):254-60
"BACKGROUND: The neuropathogenesis of bipolar disorder remains poorly described. Previous work suggests that patients with bipolar disorder may have abnormalities in neural pathways that are hypothesized to modulate human mood states. We examined differences in brain structural volumes associated with these pathways between patients with bipolar disorder hospitalized with mania and healthy community volunteers. METHODS: Twenty-four patients with bipolar disorder and mania were recruited from hospital admission records. Twenty-two healthy volunteers were recruited from the community who were similar to the patients in age, sex, race, height, handedness, and education. All subjects were scanned using a 3-dimensional radio-frequency-spoiled Fourier acquired steady state acquisition sequence on a 1.5-T magnetic resonance imaging scanner. Scans were analyzed using commercial software. Prefrontal, thalamic, hippocampal, amygdala, pallidal, and striatal volumetric measurements were compared between the 2 groups. RESULTS: Patients with bipolar disorder demonstrated a significant (A = 0.64; F6,37 = 3.4; P = .009) overall difference in structural volumes in these regions compared with controls. In particular, the amygdala was enlarged in the patients. Brain structural volumes were not significantly associated with duration of illness, prior medication exposure, number of previous hospital admissions, or duration of substance abuse. Separating patients into first-episode (n = 12) and multiple-episode (n = 12) subgroups revealed no significant differences in any structure (P>.10). CONCLUSION: Patients with bipolar disorder exhibit structural abnormalities in neural pathways thought to modulate human mood." [Abstract]

Benes FM, Berretta S.
GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder.
Neuropsychopharmacology 2001 Jul;25(1):1-27
"A core component to corticolimbic circuitry is the GABAergic interneuron. Neuroanatomic studies conducted over the past century have demonstrated several subtypes of interneuron defined by characteristic morphological appearances in Golgi-stained preparations. More recently, both cytochemical and electrophysiological techniques have defined various subtypes of GABA neuron according to synaptic connections, electrophysiological properties and neuropeptide content. These cells provide both inhibitory and disinhibitory modulation of cortical and hippocampal circuits and contribute to the generation of oscillatory rhythms, discriminative information processing and gating of sensory information within the corticolimbic system. All of these functions are abnormal in schizophrenia. Recent postmortem studies have provided consistent evidence that a defect of GABAergic neurotransmission probably plays a role in both schizophrenia and bipolar disorder. Many now believe that such a disturbance may be related to a perturbation of early development, one that may result in a disturbance of cell migration and the formation of normal lamination. The ingrowth of extrinsic afferents, such as the mesocortical dopamine projections, may "trigger" the appearance of a defective GABA system, particularly under stressful conditions when the modulation of the dopamine system is likely to be altered. Based on the regional and subregional distribution of changes in GABA cells in schizophrenia and bipolar disorder, it has been postulated that the basolateral nucleus of the amygdala may contribute to these abnormalities through an increased flow of excitatory activity. By using "partial" modeling, changes in the GABA system remarkably similar to those seen in schizophrenia and bipolar disorder have been induced in rat hippocampus. In the years to come, continued investigations of the GABA system in rodent, primate and human brain and the characterization of changes in specific phenotypic subclasses of interneurons in schizophrenia and bipolar disorder will undoubtedly provide important new insights into how the integration of this transmitter system may be altered in neuropsychiatric disease." [Abstract]

Malhi GS, Lagopoulos J, Ward PB, Kumari V, Mitchell PB, Parker GB, Ivanovski B, Sachdev P.
Cognitive generation of affect in bipolar depression: an fMRI study.
Eur J Neurosci. 2004 Feb;19(3):741-54.
"Individuals with bipolar disorder manifest the full spectrum of emotions ranging from depression to mania. In attempting to understand the functional substrates of mood we attempted to identify brain regions associated with the cognitive generation of affect in bipolar depressed patients. We therefore examined ten depressed female subjects with bipolar affective disorder, and ten age-matched and sex-matched healthy comparison subjects using functional magnetic resonance imaging (fMRI) while viewing alternating blocks of captioned pictures designed to evoke negative, positive or no affective change. The activation paradigm involved the presentation of the same visual materials over three experiments alternating (experiment 1) negative and reference; (experiment 2) positive and reference and (experiment 3) positive and negative captioned pictures. The stimuli produced activation in both patients and comparison subjects in brain regions previously implicated in the generation and modulation of affect, in particular the prefrontal and anterior cingulate cortices. The activation in patients, when compared with healthy subjects, involved additional subcortical regions, in particular the amygdala, thalamus, hypothalamus and medial globus pallidus. Patients and comparison subjects displayed differential sensitivity to affective change with negative (experiment 1) and positive (experiment 2) affect induction producing converse patterns of activation. We conclude that bipolar depressed patients perhaps recruit additional subcortical limbic systems for emotional evaluation and this may reflect state-related or trait-related dysfunction. The differential patterns of activation inform us about bipolar depression and have potential diagnostic and therapeutic significance." [Abstract]
Yurgelun-Todd DA, Gruber SA, Kanayama G, Killgore WD, Baird AA, Young AD.
fMRI during affect discrimination in bipolar affective disorder.
Bipolar Disord 2000 Sep;2(3 Pt 2):237-48
"OBJECTIVE: It has been hypothesized that disturbances in affect may represent distinct etiologic factors for bipolar affective disorder. The neural mechanisms mediating affective processes and their relationship to brain development and the pathophysiology of bipolar affective disorder remain to be clarified. Recent advances in neuroimaging techniques have made possible the non-invasive examination of specific brain regions during cortical challenge paradigms. This study reports findings based on fMRI data acquired during fearful and happy affect recognition paradigms in patients with bipolar affective disorder and in healthy adult subjects. METHODS: Prior to the scan, subjects were instructed to view the stimuli and to identify the type of facial expression presented. Echo planar scanning was performed on a 1.5 Tesla scanner which had been retrofitted with a whole body echo planar coil, using a head coil. RESULTS: The data indicate that in adult subjects with bipolar affective disorder, there is a reduction in dorsolateral prefrontal cortex activation and an increase in amygdalar activation in response to fearful facial affect. In a healthy comparison group, signal intensity changes were not found in these regions. In addition, although the patients with bipolar affective disorder completed the task demands, they demonstrated an impaired ability to correctly identify fearful facial affect but not the happy facial affect displayed. CONCLUSION: These findings are consistent with the hypothesis that in some patients with bipolar affective disorder, there may be a reduction of frontal cortical function which may be associated with affective as well as attentional processing deficits." [Abstract]
Drevets WC.
Prefrontal cortical-amygdalar metabolism in major depression.
Ann N Y Acad Sci 1999 Jun 29;877:614-37
"Functional neuroimaging studies of the anatomical correlates of familial major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of resting blood flow (BF) and glucose metabolism in depression in the amygdala and the orbital and medial prefrontal cortical (PFC) areas that are extensively connected with the amygdala. The amygdala metabolism in MDD and BD is positively correlated with both depression severity and "stressed" plasma cortisol concentrations measured during scanning. During antidepressant drug treatment, the mean amygdala metabolism decreases in treatment responders, and the persistence of elevated amygdala metabolism during remission is associated with a high risk for the development of depressive relapse. The orbital C metabolism is also abnormally elevated during depression, but is negatively correlated with both depression severity and amygdala metabolism, suggesting that this structure may be activated as a compensatory mechanism to modulate amygdala activity or amygdala-driven emotional responses. The posterior orbital C and anterior cingulate C ventral to the genu of the corpus callosum (subgenual PFC) have more recently been shown in morphometric MRI and/or post mortem histopathological studies to have reduced grey matter volume and reduced glial cell numbers (with no equivalent loss of neurons) in familial MDD and BD. These data suggest a neural model in which dysfunction of limbic PFC structures impairs the modulation of the amygdala, leading to abnormal processing of emotional stimuli. Antidepressant drugs may compensate for this dysfunction by inhibiting pathological limbic activity." [Abstract]
DelBello MP, Zimmerman ME, Mills NP, Getz GE, Strakowski SM
Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorder.
Bipolar Disord. 2004 Feb;6(1):43-52.
OBJECTIVES: Few studies have examined the abnormalities that underlie the neuroanatomy of bipolar disorder in youth. The aim of this study was to evaluate brain regions that are thought to modulate mood utilizing quantitative analyses of thin-slice magnetic resonance imaging (MRI) scans of adolescents with bipolar disorder. We hypothesized that adolescents with bipolar disorder would exhibit abnormalities in brain regions that are involved in the regulation of mood including the amygdala, globus pallidus, caudate, putamen, and thalamus. METHODS: Bipolar adolescents (n = 23) and healthy subjects (n = 20) matched for age, race, sex, socioeconomic status, IQ, education and Tanner stage, were evaluated using the Washington University at St Louis Kiddie-Schedule for Affective Disorders and Schizophrenia (WASH-U K-SADS). Contiguous 1 mm axial T1-weighted MRI slices were obtained using a GE 1.5 T MR scanner. Regions of interest (ROI) included total cerebral volume, amygdala, globus pallidus, caudate, putamen, and thalamus. RESULTS: Total cerebral volume was smaller in bipolar adolescents than in healthy adolescents. A MANCOVA revealed a significant group difference in overall ROI volumes after adjusting for total cerebral volume. Specifically, adolescents with bipolar disorder exhibited smaller amygdala and enlarged putamen compared with healthy subjects. CONCLUSIONS: Our findings indicate that adolescents with bipolar disorder exhibit abnormalities in some of the brain regions that are thought to be involved in the regulation of mood. Additional structural and functional neuroimaging investigations of children, adolescents, and adults with bipolar disorder are necessary to clarify the role of these brain regions in the neurophysiology of adolescent bipolar disorder. [Abstract]
Strakowski SM, Adler CM, DelBello MP.
Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder?
Bipolar Disord 2002 Apr;4(2):80-8
"The authors reviewed magnetic resonance imaging volumetric imaging results in major mood disorders, particularly comparing similarities and differences from studies of bipolar disorder and unipolar major depression. Abnormalities of cerebral brain regions appear inconsistently in mood disorders and, when present, typically consist of decreased frontal or prefrontal cortical volumes in both unipolar depression and bipolar disorder. In contrast, subcortical and medial temporal abnormalities are more commonly observed and are different between these two major classes of affective illness. Specifically, whereas structural enlargement of the basal ganglia and amygdala have been observed in bipolar disorder, in unipolar depression, these structures appear to be smaller in patients than healthy subjects. These findings suggest that affective illnesses may share in common an underdeveloped or atrophied prefrontal region, leading to loss of cortical modulation of limbic emotional networks. The effect of this loss results in unipolar depression or cycling (mania with depression) depending on the abnormalities of the subcortical structures involved. The cerebellum may also play a role in the presentation of mood disorders. This hypothesis remains speculative as much more research is needed to specifically examine how morphometric brain abnormalities translate into the neurophysiologic deficits that produce mood disorders." [Abstract]
Kennedy SH, Javanmard M, Vaccarino FJ.
A review of functional neuroimaging in mood disorders: positron emission tomography and depression.
Can J Psychiatry 1997 Jun;42(5):467-75
"OBJECTIVE: To examine the progress of positron emission tomography (PET) as a tool for understanding the psychobiology of mood disorders, particularly major depression and bipolar disorder. METHOD: Review of the literature on functional imaging of mood disorders. RESULTS: Functional imaging techniques have been used in psychiatric research as a noninvasive method to study the behaviour and function of the brain. Techniques used so far have involved the manipulation of emotion in healthy volunteers, the evaluation of depressed (unipolar and bipolar as well as secondary depression), manic, and normal subjects under resting and various activation conditions, such as cognitive activation, acute pharmacological challenge, and chronic thymoleptic treatments. As a result, functional imaging studies tend to support abnormalities in specific frontal and limbic regions. CONCLUSION: Different PET methods demonstrate consistent abnormalities in the prefrontal, cingulate, and amygdala regions. These findings are in agreement with past animal and clinical anatomical correlates of mood and emotions." [Abstract]

Hurd YL.
Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex.
Mol Psychiatry 2002;7(1):75-81
"The dynorphin system has been associated with the regulation of mood. The expression of the prodynorphin mRNA was currently studied in the amygdaloid complex, a brain region critical for emotional processing, in subjects (14-15 per group) diagnosed with major depression, bipolar disorder, or schizophrenia and compared to normal controls. In situ hybridization histochemistry was used to characterize the anatomical distribution and expression levels of the prodynorphin mRNA within the amygdaloid complex. High prodynorphin mRNA levels were expressed in the parvicellular division of the accessory basal, posterior cortical, periamygdaloid cortex, and amygdalohippocampal area in normal subjects. Individuals with major depression had significantly reduced (41-68%) expression of the prodynorphin mRNA in the accessory basal (both parvicellular and magnocellular divisions; P < 0.01) and amygdalohippocampal area (P < 0.001) as compared to controls. The bipolar disorder group also showed a significant reduction (37-38%, P < 0.01) of the mRNA expression levels in the amygdalohippocampal area and in the parvicellular division of the accessory basal. No other amygdala nuclei studied showed any significant differences for the prodynorphin mRNA levels measured in the major depression and bipolar disorder subjects. Additionally, the prodynorphin mRNA expression levels did not differ significantly between the schizophrenic and normal control subjects in any of the amygdala areas examined. These findings indicate specific prodynorphin amygdala impairment in association with mood disorder." [Abstract]
Bowley MP, Drevets WC, Ongur D, Price JL.
Low glial numbers in the amygdala in major depressive disorder.
Biol Psychiatry. 2002 Sep 1;52(5):404-12.
"BACKGROUND: Functional imaging studies implicate the prefrontal cortex and amygdala in major depressive disorder and bipolar disorder, and glial decreases have been reported in the prefrontal cortex. Here, glia and neurons were counted in the amygdala and entorhinal cortex in major depressive disorder, bipolar disorder, and control cases. METHODS: Tissue blocks from major depressive disorder (7), bipolar disorder (10), and control (12) cases, equally divided between right and left, were cut into 50 microm sections and stained with the Nissl method. One major depressive disorder and all but two bipolar disorder cases had been treated with lithium or valproate. Neurons and glia were counted using stereological methods. RESULTS: Glial density and the glia/neuron ratio were substantially reduced in the amygdala in major depressive disorder cases. The reduction was mainly accounted for by counts in the left hemisphere. No change was found in neurons. Average glia measures were not reduced in bipolar disorder cases; however, bipolar disorder cases not treated with lithium or valproate had significant glial reduction. Similar but smaller changes were found in the entorhinal cortex. CONCLUSIONS: Glia are reduced in the amygdala in major depressive disorder, especially on the left side. The results suggest that lithium and valproate may moderate the glial reduction." [Abstract]
Hamidi M, Drevets WC, Price JL
Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes.
Biol Psychiatry. 2004 Mar 15;55(6):563-9.
BACKGROUND: A previous study reported reductions in glial density and glia/neuron ratio in the amygdala of individuals with major depressive disorder (MDD), without a change in neuronal density. It is not known, however, whether this glial loss is due to astrocytes, oligodendrocytes, or microglia. METHODS: Tissue samples, equally from the right and left hemispheres, were obtained from subjects diagnosed with MDD (n = 8), bipolar disorder (BD) (n = 9), or no psychiatric disorders (n = 10). Sections were stained immunohistochemically for S-100beta (for astrocytes) and human leukocyte antigen (for microglia), and with the Nissl method. In Nissl-stained sections, oligodendrocytes have more compact, darker-stained nuclei, whereas astrocytes and microglia have larger, lighter-stained nuclei, with more granular chromatin. Neurons are larger, with a nucleolus and stained cytoplasm. The density of glia was determined with stereologic methods. RESULTS: The density of total glia and oligodendrocytes in the amygdala was significantly lower in MDD than in control subjects, but not significantly lower in BD compared with control subjects. The decreases were largely accounted for by differences in the left hemisphere. There was no significant decrease in astrocyte or microglia density in MDD or BD subjects. CONCLUSIONS: The glial cell reduction previously found in the amygdala in MDD is primarily due to oligodendrocytes. [Abstract]
Young LT, Bezchlibnyk YB, Chen B, Wang JF, MacQueen GM
Amygdala cyclic adenosine monophosphate response element binding protein phosphorylation in patients with mood disorders: effects of diagnosis, suicide, and drug treatment.
Biol Psychiatry. 2004 Mar 15;55(6):570-7.
BACKGROUND: Signal transduction abnormalities have been identified in patients with bipolar (BD) and major depressive (MDD) disorders and are targets for lithium and antidepressant drugs. A key downstream target for signal transduction pathways is the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Therefore, we measured the levels of phosphorylated CREB (pCREB) in the amygdala, a region critical to emotional processing and important in the pathophysiology of both BD and MDD. METHODS: Human postmortem amygdala sections were generously provided by the Stanley Foundation Neuropathology Consortium. Samples consisted of subjects with MDD, BD, schizophrenia (SCZ), and nonpsychiatric-nonneurologic comparison subjects (n = 15 per group). Levels of pCREB were measured by immunohistochemistry, relative to total cell number. RESULTS: There were no differences between diagnostic groups--control subjects and subjects with BD, MDD, or SCZ--but increased numbers of pCREB stained cells were found in several amygdalar nuclei in subjects who had died by suicide. In contrast, patients treated with lithium at the time of death had significantly lower pCREB levels in the same region. CONCLUSIONS: These results suggest that CREB activity may be an important factor in the neurobiology of suicide and the well-documented antisuicidal effect of lithium. [Abstract]

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Recent Amygdala in Bipolar Disorder Research
1) Pavuluri MN, Herbener ES, Sweeney JA
Affect regulation: a systems neuroscience perspective.
Neuropsychiatr Dis Treat. 2005 Mar;1(1):9-15.
OBJECTIVE: TO INTEGRATE: (1) the neuroanatomical model of affect regulation; (2) a functional model of affect regulation; and (3) the evolving picture of affect dysregulation as exemplified by bipolar disorder. METHODOLOGY: A computerized search for articles on related topics was augmented by additional selected studies. RESULTS: Subdivision between the orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) is defined by distinct cytoarchitecture, corticocortical and subcortical connectivity, and function. The hierarchical relationship between OFC and amygdala is not resolved. Positive and negative emotions appear to have differential effect on cognitive ability. It is possible that cognitive and affective stimuli activate DLPFC and OFC respectively in a see-saw like manner. This complementary activation may be out of sync in disease models. CONCLUSION: IT IS CRITICAL TO ACCOUNT FOR: (1) differential anatomy and corresponding functions of various parts of the prefrontal cortex as opposed to treating it as a single entity; (2) complexity of clinical presentation of bipolar disorder that involves affect dysregulation, cognitive erosion, and motoric disinhibition in functional imaging studies; and (3) the mutual influence of affect and cognition. Future studies focusing on pharmacological effects using functional magnetic neuroimaging techniques will inform us if the affective circuitry dysfunction is reversible, and if so, what are the predictors of response. [PubMed Citation] [Order full text from Infotrieve]

2) Kauer-Sant'anna M, Yatham LN, Tramontina J, Weyne F, Cereser KM, Gazalle FK, Andreazza AC, Santin A, Quevedo J, Izquierdo I, Kapczinski F
Emotional memory in bipolar disorder.
Br J Psychiatry. 2008 Jun;192:458-63.
BACKGROUND: Cognitive impairment has been well documented in bipolar disorder. However, specific aspects of cognition such as emotional memory have not been examined. AIMS: To investigate episodic emotional memory in bipolar disorder, as indicated by performance on an amygdala-related cognitive task. METHOD: Twenty euthymic patients with bipolar disorder and 20 matched controls were recruited. Participants were shown a slide show of an emotionally neutral story, or a closely matched emotionally arousing story. One week later, participants were assessed on a memory-recall test. RESULTS: In contrast with the pattern observed in controls, patients with bipolar disorder had no enhancement of memory for the emotional content of the story (F=14.7, d.f.=1,36, P<0.001). The subjective perception of the emotional impact of the emotional condition was significantly different from that of the neutral condition in controls but not in people with bipolar disorder. CONCLUSIONS: Our data suggest that the physiological pattern of enhanced memory retrieval for emotionally bound information is blunted in bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

3) Szily E, K�ri S
Emotion-related brain regions.
Ideggyogy Sz. 2008 Mar 30;61(3-4):77-86.
Converging data from human functional imaging in healthy subjects, neuropsychological studies of brain-damaged patients, and non-human neurophysiology indicate that emotional processing is linked to anatomically distinct and well-defined brain regions. A main characteristic of emotion-related brain regions (orbitofrontal cortex, anterior cingulated cortex, amygdala, insula) is their reciprocal anatomical connectivity with each other as well as with neuromodulatory systems (e.g., serotonergic dorsal raphe, cholinergic nucleus basalis of Meynert, and dopaminergic ventral tegmentum) and with other brain areas involved in sensory, motor, and cognitive functions. These structures mediate the representation of stimulus values, the affect-leaden enhancement of sensory processing, and the predictions of values associated with actions in order to bias decision-making in uncertain situations. In this review, we discuss new results from the functional neuroanatomy of these brain circuits and outline their significance in the emergence of various psychopathological phenomena. [PubMed Citation] [Order full text from Infotrieve]

4) Doty TJ, Payne ME, Steffens DC, Beyer JL, Krishnan KR, Labar KS
Age-dependent reduction of amygdala volume in bipolar disorder.
Psychiatry Res. 2008 May 30;163(1):84-94.
The amygdala is hypothesized to play a critical role in mood regulation, yet its involvement in bipolar disorder remains unclear. The aim of the present study was to compare measurements of amygdala volumes in a relatively large sample of bipolar disorder patients and healthy controls ranging in age from 18 to 49 years. Subjects comprised 54 adult patients meeting DSM-IV criteria for bipolar disorder and 41 healthy controls matched for age, sex, and education. Magnetic resonance imaging (1.5 T) was performed to obtain volumetric measurements of the amygdala using a manual region-of-interest tracing method with software that allowed simultaneous visualization of the amygdala in three orthogonal planes. The anterior head of the hippocampus was removed in the sagittal plane prior to amygdala volumetry measurement. Multiple regression analysis was computed on amygdala volume measurements as a function of diagnosis, age, sex, and cerebral volume. Bipolar patients showed an age-related reduction of amygdala volume, but controls did not. Among bipolar subjects, amygdala volume was unrelated to medication history. There were no significant hemispheric or sex interactions with the main effects. Results support a role for amygdala dysfunction in bipolar disorder which appears most robustly in older relative to younger adult patients. Differential aging effects in bipolar disorder may compromise amygdala integrity and contribute to mood dysregulation. [PubMed Citation] [Order full text from Infotrieve]

5) Chang KD, Wagner C, Garrett A, Howe M, Reiss A
A preliminary functional magnetic resonance imaging study of prefrontal-amygdalar activation changes in adolescents with bipolar depression treated with lamotrigine.
Bipolar Disord. 2008 May;10(3):426-31.
OBJECTIVES: Hypotheses regarding mood dysregulation in bipolar disorder (BD) have centered on limbic overactivity with relative prefrontal underactivity during mood episodes. Therefore, we hypothesized that adolescents with bipolar depression successfully treated with lamotrigine would show decreases in amygdalar activation, and increases in prefrontal activation. METHODS: Eight adolescents with BD underwent functional magnetic resonance imaging (fMRI) at baseline and after eight weeks of lamotrigine treatment. Blocks of negatively and neutrally valenced emotional pictures were presented during scanning, and subjects were asked to rate how each picture made them feel. Activation in bilateral amygdalae and dorsolateral prefrontal cortices (DLPFC) for negative minus neutral pictures was correlated with Children's Depression Rating Scale (CDRS) scores. RESULTS: Mean (SD) CDRS scores decreased significantly, from 53.0 (10.6) at baseline to 26.3 (5.3) at Week 8. This clinical improvement was correlated with decreased right amygdalar activation (r = 0.91, p = 0.002). At Week 8, but not baseline, CDRS score was positively correlated with bilateral amygdalar activation (r = 0.85, p = 0.007). DLPFC activation was not correlated with change in CDRS score. CONCLUSIONS: These preliminary results indicate that adolescents with BD treated with lamotrigine demonstrated less amygdalar activation when viewing negative stimuli as depressive symptoms improved. Larger controlled studies are needed to confirm these findings. [PubMed Citation] [Order full text from Infotrieve]

6) Bearden CE, Soares JC, Klunder AD, Nicoletti M, Dierschke N, Hayashi KM, Narr KL, Brambilla P, Sassi RB, Axelson D, Ryan N, Birmaher B, Thompson PM
Three-dimensional mapping of hippocampal anatomy in adolescents with bipolar disorder.
J Am Acad Child Adolesc Psychiatry. 2008 May;47(5):515-25.
OBJECTIVE: Early-onset bipolar disorder is thought to be a particularly severe variant of the illness. Continuity with the adult form of illness remains unresolved, but preliminary evidence suggests similar biological underpinnings. Recently, we observed localized hippocampal decreases in unmedicated adults with bipolar disorder that were not detectable with conventional volumetric measures. Using the same three-dimensional mapping methods, we sought to investigate whether a similar pattern exists in adolescents with bipolar disorder. METHOD: High-resolution brain magnetic resonance images were acquired from 16 adolescents meeting DSM-IV criteria for bipolar disorder (mean age 15.5 +/- 3.4 years, 50% female) and 20 demographically matched, typically developing control subjects. Three-dimensional parametric mesh models of the hippocampus were created from manual tracings of the hippocampal formation. RESULTS: Controlling for total brain volume, total hippocampal volume was significantly smaller in adolescent patients with bipolar disorder relative to controls (by 9.2%). Statistical mapping results, confirmed by permutation testing, revealed significant localized deformations in the head and tail of the left hippocampus in adolescents with bipolar disorder, relative to normal controls. In addition, there was a significant positive correlation between hippocampal size and age in patients with bipolar disorder, whereas healthy controls showed an inverse relation. DISCUSSION: Localized hippocampal deficits in adolescent patients with bipolar disorder suggest a possible neural correlate for memory deficits observed in this illness. Moreover, age-related increases in hippocampal size in patients with bipolar disorder, not observed in healthy controls, may reflect abnormal developmental mechanisms in bipolar disorder. This possibility must be confirmed by longitudinal studies. [PubMed Citation] [Order full text from Infotrieve]

7) Singh MK, Delbello MP, Adler CM, Stanford KE, Strakowski SM
Neuroanatomical characterization of child offspring of bipolar parents.
J Am Acad Child Adolesc Psychiatry. 2008 May;47(5):526-31.
OBJECTIVE: To examine structural differences in selected anterior limbic brain regions between at-risk children of parents with bipolar I disorder and children with healthy parents. We hypothesized that at-risk (AR) children would exhibit abnormalities in brain regions that are involved in mood regulation. METHOD: Children (8-12 years old) of parents with bipolar I disorder (AR children, n = 21) and of parents without any DSM-IV Axis I disorder (healthy controls, n = 24) were evaluated using diagnostic assessments and brain magnetic resonance imaging. Morphometric analyses were used to examine group differences in the prefrontal cortical, thalamic, striatal, and amygdalar volumes. RESULTS: Nine (43%) of the AR children met DSM-IV-TR criteria for a nonbipolar mood disorder at the time of assessment. AR and healthy control children did not demonstrate statistically significant differences across regions of interest (Wilks lambda =.86, F4,39 = 1.64, p = .18; effect size, f = 0.19). Post hoc analyses of covariance showed the largest relative effect size was contributed by the prefrontal cortex (f = 0.26). CONCLUSIONS: Eight- to 12-year-old children with a familial risk for mania do not exhibit any statistically significant volumetric differences in the prefrontal cortex, thalamus, striatum, or amygdala as compared with age-matched children of parents without any psychopathology. Longitudinal studies examining whether structural changes over time may be associated with vulnerability for developing subsequent bipolar disorder are needed to clarify the underlying pathophysiology of this disorder. [PubMed Citation] [Order full text from Infotrieve]

8) Ladouceur CD, Almeida JR, Birmaher B, Axelson DA, Nau S, Kalas C, Monk K, Kupfer DJ, Phillips ML
Subcortical gray matter volume abnormalities in healthy bipolar offspring: potential neuroanatomical risk marker for bipolar disorder?
J Am Acad Child Adolesc Psychiatry. 2008 May;47(5):532-9.
OBJECTIVE: A growing number of structural neuroimaging studies have shown that bipolar disorder (BD) is associated with gray matter (GM) volume abnormalities in brain regions known to support affect regulation. The goal of this study was to examine whole-brain regional GM volume in healthy bipolar offspring (HBO) relative to age-matched controls to identify possible structural abnormalities that may be associated with risk for BD. METHOD: Participants were 20 youths (8-17 years old) with at least one parent diagnosed with BD, and 22 age-matched healthy individuals. All of them were free of Axis I diagnoses. High-resolution magnetic resonance imaging structural images were acquired using a 3-T Siemens scanner. Voxel-based morphometric analyses were conducted using SPM5. RESULTS: Relative to controls, HBO had significantly increased GM volume in left parahippocampal/hippocampal gyrus (p <.05 corrected), following whole-brain analyses. This increase was correlated with puberty but not age in HBO. Region-of-interest analyses on the amygdala and orbitomedial prefrontal cortex did not yield any significant group differences after conducting small volume correction. CONCLUSIONS: The pattern of increased GM volume in parahippocampal/hippocampal gyrus in HBO suggests a potential marker for risk for BD. It can also be considered as a potential neuroprotective marker for the disorder because HBO were free of current psychopathology. Prospective studies examining the relationship between changes in GM volume in these regions and subsequent development of BD in HBO will allow us to elucidate further the role of this region in either conferring risk for or protecting against the development of BD. [PubMed Citation] [Order full text from Infotrieve]

9) Trantham-Davidson H, Vazdarjanova A, Dai R, Terry A, Bergson C
Up-regulation of calcyon results in locomotor hyperactivity and reduced anxiety in mice.
Behav Brain Res. 2008 Jun 3;189(2):244-9.
Gene linkage and association studies have implicated the region of chromosome 10q containing the calcyon locus with attention deficit hyperactivity disorder (ADHD), bipolar disorder, and schizophrenia susceptibility. In addition, levels of calcyon protein and transcripts are also significantly increased in postmortem tissue from schizophrenic brains. But whether altered calcyon expression might be part of the disease etiology or merely a patho-physiological side effect is not known. To begin to address this issue, we generated a transgenic mouse line (Cal(OE)) using the human calcyon cDNA in which calcyon expression is up-regulated in a number of forebrain structures including the hippocampus, prefrontal cortex (PFC), striatum, and amygdala. Compared to control littermates, the Cal(OE) mice display a range of abnormal behaviors including spontaneous hyperactivity, reduced anxiety, and/or impaired restraint (harm avoidance) that would indicate that calcyon up-regulation leads to deficits in control over behavioral output. [PubMed Citation] [Order full text from Infotrieve]

10) Pavuluri MN, O'Connor MM, Harral EM, Sweeney JA
An fMRI study of the interface between affective and cognitive neural circuitry in pediatric bipolar disorder.
Psychiatry Res. 2008 Apr 15;162(3):244-55.
The pathophysiology of pediatric bipolar disorder (PBD) impacts both affective and cognitive brain systems. Understanding disturbances in the neural circuits subserving these abilities is critical for characterizing developmental aberrations associated with the disorder and developing improved treatments. Our objective is to use functional neuroimaging with pediatric bipolar disorder patients employing a task that probes the functional integrity of attentional control and affect processing. Ten euthymic unmedicated pediatric bipolar patients and healthy controls matched for age, sex, race, socioeconomic status, and IQ were scanned using functional magnetic resonance imaging. In a pediatric color word matching paradigm, subjects were asked to match the color of a word with one of two colored circles below. Words had a positive, negative or neutral emotional valence, and were presented in 30-s blocks. In the negative affect condition, relative to the neutral condition, patients with bipolar disorder demonstrated greater activation of bilateral pregenual anterior cingulate cortex and left amygdala, and less activation in right rostral ventrolateral prefrontal cortex (PFC) and dorsolateral PFC at the junction of the middle frontal and inferior frontal gyri. In the positive affect condition, there was no reduced activation of PFC or increased amygdala activation. The pattern of reduced activation of ventrolateral PFC and greater amygdala activation in bipolar children in response to negative stimuli suggests both disinhibition of emotional reactivity in the limbic system and reduced function in PFC systems that regulate those responses. Higher cortical cognitive areas such as the dorsolateral PFC may also be adversely affected by exaggerated emotional responsivity to negative emotions. This pattern of functional alteration in affective and cognitive circuitry may contribute to the reduced capacity for affect regulation and behavioral self-control in pediatric bipolar disorder. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

11) Konarski JZ, McIntyre RS, Kennedy SH, Rafi-Tari S, Soczynska JK, Ketter TA
Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder.
Bipolar Disord. 2008 Feb;10(1):1-37.
BACKGROUND: As patients with mood disorders manifest heterogeneity in phenomenology, pathophysiology, etiology, and treatment response, a biological classification of mental disease is urgently needed to advance research. Patient and methodological variability complicates the comparison of neuroimaging study results and limits heuristic model development and a biologically-based diagnostic schema. OBJECTIVE: We have critically reviewed and compared the magnetic resonance neuroimaging literature to determine the degree and directionality of volumetric changes in brain regions putatively implicated in the pathophysiology of major depressive disorder (MDD) versus bipolar disorder (BD). METHODS: A total of 140 published magnetic resonance imaging investigations evaluating subjects with BD or MDD were selected to provide a summary and interpretation of volumetric neuroimaging results in MDD and BD. Further commentary on the pathophysiological implications, and putative cellular and pharmacological mechanisms, is also provided. RESULTS: While whole brain volumes of patients with mood disorders do not differ from those of healthy controls, regional deficits in the frontal lobe, particularly in the anterior cingulate and the orbitofrontal cortex, appear to consistently differentiate subjects with mood disorders from the general population. Preliminary findings also suggest that subcortical structures, particularly the striatum, amygdala, and hippocampus, may be differentially affected in MDD and BD. CONCLUSIONS: Structural neuroimaging studies have consistently identified regional abnormalities in subjects with mood disorders. Future studies should strive to definitively establish the influence of age and medication. [PubMed Citation] [Order full text from Infotrieve]

12) Foland LC, Altshuler LL, Sugar CA, Lee AD, Leow AD, Townsend J, Narr KL, Asuncion DM, Toga AW, Thompson PM
Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium.
Neuroreport. 2008 Jan 22;19(2):221-4.
Previous structural neuroimaging studies of bipolar disorder have reported conflicting findings in limbic structures. Medication heterogeneity of patient samples may have contributed to these inconsistencies. Using structural magnetic resonance imaging we assessed whether lithium treatment was associated with differences in amygdala and hippocampal volumes in a sample of bipolar adults. A total of 49 magnetic resonance imaging scans were collected from patients who were currently treated with or without lithium. Amygdala and hippocampal volumes were analyzed using tensor-based morphometry. Statistical between-group comparisons of deformation maps showed that patients treated with lithium exhibited significantly increased volumes of the amygdala and hippocampus compared with patients who were not taking lithium. Our findings may help to explain previous inconsistencies in the bipolar literature. [PubMed Citation] [Order full text from Infotrieve]

13) Rich BA, Fromm SJ, Berghorst LH, Dickstein DP, Brotman MA, Pine DS, Leibenluft E
Neural connectivity in children with bipolar disorder: impairment in the face emotion processing circuit.
J Child Psychol Psychiatry. 2008 Jan;49(1):88-96.
BACKGROUND: Pediatric bipolar disorder (BD), a highly debilitating illness, is characterized by amygdala abnormalities, i.e., volume reduction and hyperactivation during face processing. Evidence of perturbed amygdala functional connectivity with other brain regions would implicate a distributed neural circuit in the pathophysiology of BD, and would further elucidate the neural mechanisms associated with BD face emotion misinterpretation. METHODS: Thirty-three BD and 24 healthy age, gender, and IQ-matched subjects completed a functional magnetic resonance imaging (fMRI) task of face emotion identification in which attention was directed to emotional (hostility, fearfulness) and nonemotional (nose width) aspects of faces. Voxel-wise analyses examined whole brain functional connectivity with the left amygdala. RESULTS: Compared to healthy subjects, BD subjects had significantly reduced connectivity between the left amygdala and two regions: right posterior cingulate/precuneus and right fusiform gyrus/parahippocampal gyrus. Deficits were evident regardless of mood state and comorbid diagnoses. CONCLUSIONS: BD youth exhibit deficient connectivity between the amygdala and temporal association cortical regions previously implicated in processing facial expressions and social stimuli. In conjunction with previously documented volumetric and functional perturbations in these brain regions, dysfunction in this distributed neural circuit may begin to clarify the pathophysiology of the face emotion misperceptions and social deficits seen in BD youth. [PubMed Citation] [Order full text from Infotrieve]

14) Foland LC, Altshuler LL, Bookheimer SY, Eisenberger N, Townsend J, Thompson PM
Evidence for deficient modulation of amygdala response by prefrontal cortex in bipolar mania.
Psychiatry Res. 2008 Jan 15;162(1):27-37.
Several studies have implicated the involvement of two major components of emotion regulatory networks, the ventrolateral prefrontal cortex (VLPFC) and amygdala, in the pathophysiology of bipolar disorder. In healthy subjects, the VLPFC has been shown to negatively modulate amygdala response when subjects cognitively evaluate an emotional face by identifying and labeling the emotion it expresses. The current study used such a paradigm to assess whether the strength of this modulation was altered in bipolar subjects when manic. During functional magnetic resonance imaging (fMRI), nine manic subjects with bipolar I disorder and nine healthy subjects either named the emotion shown in a face by identifying one of two words that correctly expressed the emotion (emotion labeling task) or matched the emotion shown in a face to one of two other faces (emotion perception task). The degree to which the VLPFC regulated amygdala response during these tasks was assessed using a psychophysiological interaction (PPI) analysis. Compared with healthy subjects, manic patients had a significantly reduced VLPFC regulation of amygdala response during the emotion labeling task. These findings, taken in context with previous fMRI studies of bipolar mania, suggest that reductions in inhibitory frontal activity in these patients may lead to an increased reactivity of the amygdala. [PubMed Citation] [Order full text from Infotrieve]

15) Frazier JA, Hodge SM, Breeze JL, Giuliano AJ, Terry JE, Moore CM, Kennedy DN, Lopez-Larson MP, Caviness VS, Seidman LJ, Zablotsky B, Makris N
Diagnostic and sex effects on limbic volumes in early-onset bipolar disorder and schizophrenia.
Schizophr Bull. 2008 Jan;34(1):37-46.
OBJECTIVE: The limbic structures in early-onset schizophrenia-spectrum illness (SZ) and bipolar disorder (BPD) were studied to discern patterns associated with diagnosis and sex. METHODS: Thirty-five youths with DSM-IV BPD without psychosis, 19 with BPD with psychosis, 20 with SZ, and 29 healthy controls (HC), similar in age (6-17 years) and sex, underwent structured and clinical interviews, neurological examination, and cognitive testing. Structural magnetic resonance images (MRIs) were acquired on a 1.5 Tesla, General Electric Signa Scanner. Differences in subcortical brain volumes, including the amygdala and hippocampus, were evaluated using two-way (diagnosis, sex) univariate analyses covarying for total cerebral volume and age. RESULTS: Youth with SZ and BPD showed no differences in amygdala and hippocampal volumes. However, boys with SZ had smallest left amygdala and girls with BPD had the smallest left hippocampal volumes. In exploratory analyses, SZ showed reduced thalamic volumes bilaterally and both BPD groups had larger right nucleus accumbens (NA) volumes relative to HC. CONCLUSION: There were no limbic volumetric differences between BPD and SZ. However, there were diagnosis-by-sex interactions in the amygdala and hippocampus, structures that are rich in sex hormone receptors. In addition, smaller thalamus was associated with SZ while larger right NA volumes were most related to BPD. This study underscores the importance of assessing diagnostic effects and sex effects on the brain in future studies and provides evidence that boys and girls with SZ and BPD may have differential patterns of neuropathology associated with disease expression. [PubMed Citation] [Order full text from Infotrieve]

16) Lagopoulos J, Malhi GS
A functional magnetic resonance imaging study of emotional Stroop in euthymic bipolar disorder.
Neuroreport. 2007 Oct 8;18(15):1583-7.
Bipolar disorder is regarded as a disorder of mood and initial studies have focused on structural abnormalities in limbic networks, known to subserve mood. More recently, functional imaging studies allude to affect processing deficits, which may involve frontostriatal networks. This study sought to explore disturbances in networks involved in the processing of negative affect in euthymic bipolar patients. We used simultaneous functional magnetic resonance imaging and galvanic skin responsivity to explore disturbances in these networks. When processing negative affect, controls recruited a distributed subcortical-prefrontal network. In contrast, patients could only activate a subcortical network that included the amygdala and hippocampus. This study provides evidence for a disconnection in the transfer of information within frontostriatal networks in bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

17) Puskas L, Puskas N, Malobabić S, Krivokuća D, Stanković G, Radonjić V
[Characteristics of galanin and vasoactive intestinal peptide immunoreactivity in the rat amygdala complex]
Med Pregl. 2007 Jan-Feb;60(1-2):19-24.
INTRODUCTION: Morphological features and morphometric parameters of galanin (GAL) and vasoactive intestinal peptide (VIP) immunoreactive neurons and neuronal fibres were studied in all nuclei of adult male rat amygdala. MATERIAL AND METHODS: After perfusion and fixation, rat brains were immunohistochemically stained with antibodies against GAL and VIP and then visualized by avidin-biotin-peroxidase complex. RESULTS AND DISCUSSION: The greatest number of galanin-immunoreactive neurons were identified in the medial part of the central nucleus and in the dorsal part of the medial nucleus. In the first case, most neurons were bipolar (37%), and in the second, they were ovoid (45%). GAL-immunoreactive fibers were identified in the medial nucleus, "bed nucleus" of the accessory olfactory tract, fiontal cortical nucleus, amygdalo-hippocampal area and basolateral nucleus. VIP-immunoreactive neurons were diffusely distributed in more nuclei than the previous, mostly in the lateral, basolateral, and basomedial nucleus. They were mostly ovoid (40%). VIP-immunoreactive fibers were observed in the lateral part oJ'the central nucleus, while long and radially oriented fibers were present in the frontal and dorsal cortical nucleus. CONCLUSION: By distribution analysis of GAL and VIP immunoreactive neurons and fibers, and according to literature data, it can be assumed that the medial part of the central nucleus receives VIP fibers from other parts of the amygdaloid body, and then sends GAL fibers to the medial nucleus. [PubMed Citation] [Order full text from Infotrieve]

18) Lowe XR, Lu X, Marchetti F, Wyrobek AJ
The expression of Troponin T1 gene is induced by ketamine in adult mouse brain.
Brain Res. 2007 Oct 12;1174:7-17.
The glutamatergic system has been implicated in neuropsychiatric disorders, such as schizophrenia, bipolar disorder and Alzheimer's disease, which also have a high prevalence of metabolic syndrome. Treatment with ketamine, a non-competitive glutamate N-methyl-d-aspartic acid (NMDA) receptor antagonist, is known to have paradoxical effects of neuroprotection and neurotoxicity. We investigated gene expression in brain tissue of adult mice treated with ketamine to characterize the expression profiles and to identify the affected metabolic pathways. Adult male mice were treated by a single intraperitoneal (i.p.) injection of either s(+)ketamine (80 mg/kg) or distilled water (as the control). Fifty genes were differentially expressed in ketamine-treated mouse brains compared with control mice using oligonucleotide microarray analysis, and the expression of Troponin T1 (Tnnt1) gene was consistently elevated (2- to 4-fold) (p<0.001). Ketamine-induced Tnnt1 expression was confirmed and characterized using RNA in situ hybridization techniques in paraffin embedded brain tissue sections. Tnnt1 expression was induced in the granule layer of the hippocampus, amygdala, hypothalamus, Purkinje cells of cerebellum (p<0.0001), and cerebral cortex. Tnnt1 gene is known to interact directly with FoxO1, which is involved in multiple peripheral metabolic pathways and central energy homeostasis. Our findings suggest that the induction of Tnnt1 gene expression in adult mouse brains by ketamine may illustrate the genes involved in the metabolic syndromes observed in neuropsychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

19) Goldman AL, Pezawas L, Mattay VS, Fischl B, Verchinski BA, Zoltick B, Weinberger DR, Meyer-Lindenberg A
Heritability of brain morphology related to schizophrenia: a large-scale automated magnetic resonance imaging segmentation study.
Biol Psychiatry. 2008 Mar 1;63(5):475-83.
BACKGROUND: Schizophrenia is a devastating psychiatric disorder with a strong genetic component that has been related to a number of structural brain alterations. Currently available data on the heritability of these structural changes are inconsistent. METHODS: To examine heritability of morphological alterations in a large sample, we used a novel and validated fully-automated whole brain segmentation technique to study disease-related variability and heritability in anatomically defined regions of interest in 221 healthy control subjects, 169 patients with schizophrenia, and 183 unaffected siblings. RESULTS: Compared with healthy control subjects, patients showed a bilateral decrease in hippocampal and cortical gray matter volume and increases in bilateral dorsal striatum and right lateral ventricle. No significant volumetric differences were found in unaffected siblings compared with normal control subjects in any structure. Post hoc analysis of the dorsal striatum showed the volumetric increase to be widespread, including caudate, putamen, and globus pallidus. With Risch's lambda (lambda(s)), we found strong evidence for heritability of reduced cortical volume and moderate evidence for hippocampal volume, whereas abnormal striatal and ventricle volumes showed no sign of heritability. Additional exploratory analyses were performed on amygdala, thalamus, nucleus accumbens, ventral diencephalon, and cerebral and cerebellar cortex and white matter. Of these regions, patients showed increased volume in ventral diencephalon and cerebellum. CONCLUSIONS: These findings support evidence of genetic control of brain volume even in adults, particularly of hippocampal and neocortical volume and of cortical volumetric reductions being familial, but do not support measures of subcortical volumes per se as representing intermediate biologic phenotypes. [PubMed Citation] [Order full text from Infotrieve]

20) Berretta S, Pantazopoulos H, Lange N
Neuron numbers and volume of the amygdala in subjects diagnosed with bipolar disorder or schizophrenia.
Biol Psychiatry. 2007 Oct 15;62(8):884-93.
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. [PubMed Citation] [Order full text from Infotrieve]