amygdala in bipolar disorder


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(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) Garrett AS, Reiss AL, Howe ME, Kelley RG, Singh MK, Adleman NE, Karchemskiy A, Chang KD
Abnormal amygdala and prefrontal cortex activation to facial expressions in pediatric bipolar disorder.
J Am Acad Child Adolesc Psychiatry. 2012 Aug;51(8):821-31.
[PubMed Citation] [Order full text from Infotrieve]

2) Hammer C, Cichon S, Mühleisen TW, Haenisch B, Degenhardt F, Mattheisen M, Breuer R, Witt SH, Strohmaier J, Oruc L, Rivas F, Babadjanova G, Grigoroiu-Serbanescu M, Hauser J, Röth R, Rappold G, Rietschel M, Nöthen MM, Niesler B
Replication of functional serotonin receptor type 3A and B variants in bipolar affective disorder: a European multicenter study.
Transl Psychiatry. 2012 Feb 21;2:e103.
Serotonin type 3 receptors (5-HT(3)) are involved in learning, cognition and emotion, and have been implicated in various psychiatric phenotypes. However, their contribution to the pathomechanism of these disorders remains elusive. Three single nucleotide polymorphisms (SNPs) in the HTR3A and HTR3B genes (rs1062613, rs1176744 and rs3831455) have been associated with bipolar affective disorder (BPAD) in pilot studies, and all of them are of functional relevance. We performed a European multicenter study to confirm previous results and provide further evidence for the relevance of these SNPs to the etiology of neuropsychiatric disorders. This involved analysis of the distribution of the three SNPs among 1804 BPAD cases and 2407 healthy controls. A meta-analysis revealed a pooled odds ratio of 0.881 (P=0.009, 95% confidence intervals=0.802-0.968) for the non-synonymous functional SNP HTR3B p.Y129S (rs1176744), thereby confirming previous findings. In line with this, the three genome-wide association study samples BOMA (Bonn-Mannheim)-BPAD, WTCCC (Wellcome Trust Case Control Consortium)-BPAD and GAIN (Genetic Association Information Network)-BPAD, including >3500 patients and 5200 controls in total, showed an overrepresentation of the p.Y129 in patients. Remarkably, the meta-analysis revealed a P-value of 0.048 (OR=0.934, fixed effect model). We also performed expression analyses to gain further insights into the distribution of HTR3A and HTR3B mRNA in the human brain. HTR3A and HTR3B were detected in all investigated brain tissues with the exception of the cerebellum, and large differences in the A:B subunit ratio were observed. Interestingly, expression of the B subunit was most prominent in the brain stem, amygdalae and frontal cortex, regions of relevance to psychiatric disorders. In conclusion, the present study provides further evidence for the presence of impaired 5-HT(3) receptor function in BPAD. [PubMed Citation] [Order full text from Infotrieve]

3) Morris RW, Sparks A, Mitchell PB, Weickert CS, Green MJ
Lack of cortico-limbic coupling in bipolar disorder and schizophrenia during emotion regulation.
Transl Psychiatry. 2012 Feb 21;2:e90.
Bipolar disorder (BD) and schizophrenia (Sz) share dysfunction in prefrontal inhibitory brain systems, yet exhibit distinct forms of affective disturbance. We aimed to distinguish these disorders on the basis of differential activation in cortico-limbic pathways during voluntary emotion regulation. Patients with DSM-IV diagnosed Sz (12) or BD-I (13) and 15 healthy control (HC) participants performed a well-established emotion regulation task while undergoing functional magnetic resonance imaging. The task required participants to voluntarily upregulate or downregulate their subjective affect while viewing emotionally negative images or maintain their affective response as a comparison condition. In BD, abnormal overactivity (hyperactivation) occurred in the right ventrolateral prefrontal cortex (VLPFC) during up- and downregulation of negative affect, relative to HC. Among Sz, prefrontal hypoactivation of the right VLPFC occurred during downregulation (opposite to BD), whereas upregulation elicited hyperactivity in the right VLPFC similar to BD. Amygdala activity was significantly related to subjective negative affect in HC and BD, but not Sz. Furthermore, amygdala activity was inversely coupled with the activity in the left PFC during downregulation in HC (r=-0.76), while such coupling did not occur in BD or Sz. These preliminary results indicate that differential cortico-limbic activation can distinguish the clinical groups in line with affective disturbance: BD is characterized by ineffective cortical control over limbic regions during emotion regulation, while Sz is characterized by an apparent failure to engage cortical (hypofrontality) and limbic regions during downregulation. [PubMed Citation] [Order full text from Infotrieve]

4) Shi XF, Kondo DG, Sung YH, Hellem TL, Fiedler KK, Jeong EK, Huber RS, Renshaw PF
Frontal lobe bioenergetic metabolism in depressed adolescents with bipolar disorder: a phosphorus-31 magnetic resonance spectroscopy study.
Bipolar Disord. 2012 Jul 20;
Shi X-F, Kondo DG, Sung Y-H, Hellem TL, Fiedler KK, Jeong E-K, Huber RS, Renshaw PF. Frontal lobe bioenergetic metabolism in depressed adolescents with bipolar disorder: a phosphorus-31 magnetic resonance spectroscopy study. Bipolar Disord 2012: 00: 000-000. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives:? To compare the concentrations of high-energy phosphorus metabolites associated with mitochondrial function in the frontal lobe of depressed adolescents with bipolar disorder (BD) and healthy controls (HC). Methods:? We used in vivo phosphorus-31 magnetic resonance spectroscopy ((31) P-MRS) at 3 Tesla to measure phosphocreatine (PCr), beta-nucleoside triphosphate (?-NTP), inorganic phosphate (Pi), and other neurometabolites in the frontal lobe of eight unmedicated and six medicated adolescents with bipolar depression and 24 adolescent HCs. Results:? Analysis of covariance, including age as a covariate, revealed differences in PCr (p?=?0.037), Pi (p?=?0.017), and PCr/Pi (p?=?0.002) between participant groups. Percentage neurochemical differences were calculated with respect to mean metabolite concentrations in the HC group. Post-hoc Tukey-Kramer analysis showed that unmedicated BD participants had decreased Pi compared with both HC (17%; p?=?0.038) and medicated BD (24%; p?=?0.022). The unmedicated BD group had increased PCr compared with medicated BD (11%; p?=?0.032). The PCr/Pi ratio was increased in unmedicated BD compared with HC (24%; p?=?0.013) and with medicated BD (39%; p?=?0.002). No differences in ?-NTP or pH were observed. Conclusions:? Our results support the view that frontal lobe mitochondrial function is altered in adolescent BD and may have implications for the use of Pi as a biomarker. These findings join volumetric studies of the amygdala, and proton MRS studies of n-acetyl aspartate in pointing to potential differences in neurobiology between pediatric and adult BD. [PubMed Citation] [Order full text from Infotrieve]

5) Schneider MR, Adler CM, Whitsel R, Weber W, Mills NP, Bitter SM, Eliassen J, Strakowski SM, Delbello MP
The effects of ziprasidone on prefrontal and amygdalar activation in manic youth with bipolar disorder.
Isr J Psychiatry Relat Sci. 2012;49(2):112-20.
Background: Prior research has found that manic adolescents with bipolar disorder exhibit neurofunctional changes in the amygdala and prefrontal cortex following treatment with some pharmacological agents. We examined the neurofunctional effects of ziprasidone in manic adolescents. Method: Manic adolescents with bipolar disorder (n=23) participated in a placebo-controlled study of ziprasidone and underwent a functional magnetic resonance imaging scanning session while performing a task of sustained attention at baseline, prior to treatment as well as on days 7 and 28 (or early termination) of treatment. A comparison group of healthy adolescents (n=10) participated in a single scanning session. Region of interest analyses were performed to assess activation changes associated with treatment in Brodmann Areas (BA) 10, 11 and 47 and in the amygdala. Results: Compared with placebo, treatment with ziprasidone was associated with greater increases over time in right BA 11 and 47 activation. These effects were not associated with differences in symptom improvement between the treatment groups. Patients who subsequently responded to ziprasidone showed significantly greater deactivation in the right Brodmann area 47 at baseline than those who did not respond to ziprasidone. Similarly, among the bipolar adolescents who were treated with ziprasidone, baseline activation in right BA 47 was negatively correlated with improvement in Young Mania Rating Scale (YMRS) score. Limitations: The small sample size limits the ability to detect significant group differences in other regions of interest. Healthy comparison subjects were scanned only at a single timepoint, which limits the interpretation of the results. Ziprasidone is not currently approved by the United States Food and Drug Administration for the treatment of adolescents with mania, and, therefore, the clinical relevance of these results is limited. Conclusions: The increases in right BA 11 and 47 activation observed during sustained attention tasks following ziprasidone treatment and the association identified between lower baseline BA 47 activation and ziprasidone treatment response suggests that ziprasidone may correct prefrontal dysfunction in manic adolescents with bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

6) Vizueta N, Rudie JD, Townsend JD, Torrisi S, Moody TD, Bookheimer SY, Altshuler LL
Regional fMRI Hypoactivation and Altered Functional Connectivity During Emotion Processing in Nonmedicated Depressed Patients With Bipolar II Disorder.
Am J Psychiatry. 2012 Jul 6;
OBJECTIVE: Although the amygdala and ventrolateral prefrontal cortex have been implicated in the pathophysiology of bipolar I disorder, the neural mechanisms underlying bipolar II disorder remain unknown. The authors examined neural activity in response to negative emotional faces during an emotion perception task that reliably activates emotion regulatory regions. METHOD: Twenty-one nonmedicated depressed bipolar II patients and 21 healthy comparison subjects underwent functional MRI (fMRI) while performing an emotional face-matching task. Within- and between-group whole-brain fMRI activation and seed-based connectivity analyses were conducted. RESULTS: In depressed bipolar II patients, random-effects between-group fMRI analyses revealed a significant reduction in activation in several regions, including the left and right ventrolateral prefrontal cortices (Brodmann's area [BA] 47) and the right amygdala, a priori regions of interest. Additionally, bipolar patients exhibited significantly reduced negative functional connectivity between the right amygdala and the right orbitofrontal cortex (BA 10) as well as the right dorsolateral prefrontal cortex (BA 46) relative to healthy comparison subjects. CONCLUSIONS: These findings suggest that bipolar II depression is characterized by reduced regional orbitofrontal and limbic activation and altered connectivity in a fronto-temporal circuit implicated in working memory and emotional learning. While the amygdala hypoactivation observed in bipolar II depression is opposite to the direction seen in bipolar I mania and may therefore be state dependent, the observed orbitofrontal cortex hypoactivation is consistent with findings in bipolar I depression, mania, and euthymia, suggesting a physiologic trait marker of the disorder. [PubMed Citation] [Order full text from Infotrieve]

7) Whalley HC, Papmeyer M, Sprooten E, Romaniuk L, Blackwood DH, Glahn DC, Hall J, Lawrie SM, Sussmann J, McIntosh AM
The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI.
Transl Psychiatry. 2012;2:e130.
Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16?000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD. [PubMed Citation] [Order full text from Infotrieve]

8) Sequeira A, Martin MV, Rollins B, Moon EA, Bunney WE, Macciardi F, Lupoli S, Smith EN, Kelsoe J, Magnan CN, van Oven M, Baldi P, Wallace DC, Vawter MP
Mitochondrial mutations and polymorphisms in psychiatric disorders.
Front Genet. 2012;3:103.
Mitochondrial deficiencies with unknown causes have been observed in schizophrenia (SZ) and bipolar disorder (BD) in imaging and postmortem studies. Polymorphisms and somatic mutations in mitochondrial DNA (mtDNA) were investigated as potential causes with next generation sequencing of mtDNA (mtDNA-Seq) and genotyping arrays in subjects with SZ, BD, major depressive disorder (MDD), and controls. The common deletion of 4,977?bp in mtDNA was compared between SZ and controls in 11 different vulnerable brain regions and in blood samples, and in dorsolateral prefrontal cortex (DLPFC) of BD, SZ, and controls. In a separate analysis, association of mitochondria SNPs (mtSNPs) with SZ and BD in European ancestry individuals (n?=?6,040) was tested using Genetic Association Information Network (GAIN) and Wellcome Trust Case Control Consortium 2 (WTCCC2) datasets. The common deletion levels were highly variable across brain regions, with a 40-fold increase in some regions (nucleus accumbens, caudate nucleus and amygdala), increased with age, and showed little change in blood samples from the same subjects. The common deletion levels were increased in the DLPFC for BD compared to controls, but not in SZ. Full mtDNA genome resequencing of 23 subjects, showed seven novel homoplasmic mutations, five were novel synonymous coding mutations. By logistic regression analysis there were no significant mtSNPs associated with BD or SZ after genome wide correction. However, nominal association of mtSNPs (p?[PubMed Citation] [Order full text from Infotrieve]

9) Bhat S, Dao DT, Terrillion CE, Arad M, Smith RJ, Soldatov NM, Gould TD
CACNA1C (Ca(v)1.2) in the pathophysiology of psychiatric disease.
Prog Neurobiol. 2012 Jun 15;
One of the most consistent genetic findings to have emerged from bipolar disorder genome wide association studies (GWAS) is with CACNA1C, a gene that codes for the ?(1C) subunit of the Ca(v)1.2 voltage-dependent L-type calcium channel (LTCC). Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders, as well as changes in brain function and structure in control subjects who have no diagnosable psychiatric illness. These data are consistent with a continuum of shared neurobiological vulnerability between diverse-Diagnostic and Statistical Manual (DSM) defined-neuropsychiatric diseases. While involved in numerous cellular functions, Ca(v)1.2 is most frequently implicated in coupling of cell membrane depolarization to transient increase of the membrane permeability for calcium, leading to activation and, potentially, changes in intracellular signaling pathway activity, gene transcription, and synaptic plasticity. Ca(v)1.2 is involved in the proper function of numerous neurological circuits including those involving the hippocampus, amygdala, and mesolimbic reward system, which are strongly implicated in psychiatric disease pathophysiology. A number of behavioral effects of LTCC inhibitors have been described including antidepressant-like behavioral actions in rodent models. Clinical studies suggest possible treatment effects in a subset of patients with mood disorders. We review the genetic structure and variation of CACNA1C, discussing relevant human genetic and clinical findings, as well as the biological actions of Ca(v)1.2 that are most relevant to psychiatric illness. [PubMed Citation] [Order full text from Infotrieve]

10) Grotegerd D, Suslow T, Bauer J, Ohrmann P, Arolt V, Stuhrmann A, Heindel W, Kugel H, Dannlowski U
Discriminating unipolar and bipolar depression by means of fMRI and pattern classification: a pilot study.
Eur Arch Psychiatry Clin Neurosci. 2012 May 26;
Bipolar disorders rank among the most debilitating psychiatric diseases. Bipolar depression is often misdiagnosed as unipolar depression, leading to suboptimal therapy and poor outcomes. Discriminating unipolar and bipolar depression at earlier stages of illness could therefore help to facilitate efficient and specific treatment. In the present study, the neurobiological underpinnings of emotion processing were investigated in a sample of unipolar and bipolar depressed patients matched for age, gender, and depression severity by means of fMRI. A pattern-classification approach was employed to discriminate the two samples. The pattern classification yielded up to 90 % accuracy rates discriminating the two groups. According to the feature weights of the multivariate maps, medial prefrontal and orbitofrontal regions contributed to classifications specific to unipolar depression, whereas stronger feature weights in dorsolateral prefrontal areas contribute to classifications as bipolar. Strong feature weights were observed in the amygdala for the negative faces condition, which were specific to unipolar depression, whereas higher amygdala features weights during the positive faces condition were observed, specific to bipolar subjects. Standard univariate fMRI analysis supports an interpretation, where this might be related to a higher responsiveness, by yielding a significant emotion × group interaction within the bilateral amygdala. We conclude that pattern-classification techniques could be a promising tool to classify acutely depressed subjects as unipolar or bipolar. However, since the present approach deals with small sample sizes, it should be considered as a proof-of-concept study. Hence, results have to be confirmed in larger samples preferably of unmedicated subjects. [PubMed Citation] [Order full text from Infotrieve]

11) Blond BN, Fredericks CA, Blumberg HP
Functional neuroanatomy of bipolar disorder: structure, function, and connectivity in an amygdala-anterior paralimbic neural system.
Bipolar Disord. 2012 Jun;14(4):340-55.
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12) Townsend J, Altshuler LL
Emotion processing and regulation in bipolar disorder: a review.
Bipolar Disord. 2012 Jun;14(4):326-39.
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13) Strakowski SM, Adler CM, Almeida J, Altshuler LL, Blumberg HP, Chang KD, DelBello MP, Frangou S, McIntosh A, Phillips ML, Sussman JE, Townsend JD
The functional neuroanatomy of bipolar disorder: a consensus model.
Bipolar Disord. 2012 Jun;14(4):313-25.
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14) Hamazaki K, Hamazaki T, Inadera H
Fatty acid composition in the postmortem amygdala of patients with schizophrenia, bipolar disorder, and major depressive disorder.
J Psychiatr Res. 2012 Aug;46(8):1024-8.
Previous studies with postmortem brain tissues showed abnormalities in n-3 polyunsaturated fatty acids (PUFAs) in the orbitofrontal cortex of individuals with schizophrenia and mood disorders. However, in the hippocampus, we were not able to find any significant differences in PUFAs except for small differences in n-6 PUFAs. In the present study we investigated levels of PUFAs in the amygdala of postmortem brains from patients with schizophrenia, bipolar disorder, and major depressive disorder (MDD) compared with those of unaffected controls. Amygdala samples from patients with schizophrenia (n = 15), bipolar disorder (n = 15), or MDD (n = 15), and controls matched for age, sex, and five other confounding factors (n = 15) were analyzed for fatty acid composition by gas chromatography. In contrast to previous studies of the orbitofrontal cortex and hippocampus, we were unable to find any significant differences in major PUFAs. The relative compositions of docosahexaenoic acid (DHA), the major n-3 PUFA, were 10.0 ± 1.1%, 10.0 ± 1.3%, 9.3 ± 1.3%, and 9.7 ± 1.1%, respectively, in patients with schizophrenia, bipolar disorder, and MDD and unaffected controls (not significantly different). The corresponding relative compositions of arachidonic acid (AA), the major n-6 PUFA, were 9.0 ± 0.8%, 9.2 ± 0.5%, 9.4 ± 0.7%, and 9.4 ± 0.7%, respectively (not significantly different). Significant differences were found in some of the other fatty acids. In particular, we found a 6.5% increase in palmitic acid and 6.2% decrease in oleic acid in patients with MDD compared to controls. With regard to schizophrenia, there was an 8.0% decrease in docosatetraenoic acid compared to controls. In conclusion, the changes in DHA and/or AA seen in orbitofrontal cortex and hippocampus were not observed in amygdala. These changes may be specific to particular brain regions. [PubMed Citation] [Order full text from Infotrieve]

15) Fournier JC, Keener MT, Mullin BC, Hafeman DM, Labarbara EJ, Stiffler RS, Almeida J, Kronhaus DM, Frank E, Phillips ML
Heterogeneity of amygdala response in major depressive disorder: the impact of lifetime subthreshold mania.
Psychol Med. 2012 May 9;:1-10.
BACKGROUND: Patients with major depressive disorder (MDD) present with highly heterogeneous symptom profiles. We aimed to examine whether individual differences in amygdala activity to emotionally salient stimuli were related to heterogeneity in lifetime levels of depressive and subthreshold manic symptoms among adults with MDD.MethodWe compared age- and gender-matched adults with MDD (n=26) with healthy controls (HC, n=28). While undergoing functional magnetic resonance imaging, participants performed an implicit emotional faces task: they labeled a color flash superimposed upon initially neutral faces that dynamically morphed into one of four emotions (angry, fearful, sad, happy). Region of interest analyses examined group differences in amygdala activity. For conditions in which adults with MDD displayed abnormal amygdala activity versus HC, within-group analyses examined amygdala activity as a function of scores on a continuous measure of lifetime depression-related and mania-related pathology. RESULTS: Adults with MDD showed significantly greater right-sided amygdala activity to angry and happy conditions than HC (p<0.05, corrected). Multiple regression analyses revealed that greater right-amygdala activity to the happy condition in adults with MDD was associated with higher levels of subthreshold manic symptoms experienced across the lifespan (p=0.002). CONCLUSIONS: Among depressed adults with MDD, lifetime features of subthreshold mania were associated with abnormally elevated amygdala activity to emerging happy faces. These findings are a first step toward identifying biomarkers that reflect individual differences in neural mechanisms in MDD, and challenge conventional mood disorder diagnostic boundaries by suggesting that some adults with MDD are characterized by pathophysiological processes that overlap with bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

16) Mahon PB, Eldridge H, Crocker B, Notes L, Gindes H, Postell E, King S, Potash JB, Ratnanather JT, Barta PE
An MRI study of amygdala in schizophrenia and psychotic bipolar disorder.
Schizophr Res. 2012 Jul;138(2-3):188-91.
Meta-analyses report larger amygdala in subjects with bipolar disorder compared to schizophrenia. However, few studies have compared the size of amygdala in psychotic bipolar disorder with schizophrenia. Here we examine size of amygdala in a sample of 36 patients with psychotic bipolar disorder, 31 patients with schizophrenia and 27 healthy comparison subjects. Patients with schizophrenia had smaller amygdala compared with patients with psychotic bipolar disorder (p=0.014). These results suggest that change in volume of amygdala may represent a morphologic feature distinguishing psychotic bipolar disorder from schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

17) Kim P, Thomas LA, Rosen BH, Moscicki AM, Brotman MA, Zarate CA, Blair RJ, Pine DS, Leibenluft E
Differing amygdala responses to facial expressions in children and adults with bipolar disorder.
Am J Psychiatry. 2012 Jun 1;169(6):642-9.
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18) Foland-Ross LC, Brooks JO, Mintz J, Bartzokis G, Townsend J, Thompson PM, Altshuler LL
Mood-state effects on amygdala volume in bipolar disorder.
J Affect Disord. 2012 Aug;139(3):298-301.
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19) Mullin BC, Perlman SB, Versace A, de Almeida JR, Labarbara EJ, Klein C, Ladouceur CD, Phillips ML
An fMRI study of attentional control in the context of emotional distracters in euthymic adults with bipolar disorder.
Psychiatry Res. 2012 Mar 31;201(3):196-205.
Inability to modulate attention away from emotional stimuli may be a key component of dysregulated emotion in bipolar disorder (BD). Previous studies of BD indicate abnormalities in neural circuitry underlying attentional control, yet few studies examined attentional control in the context of emotional distracters. We compared activity and connectivity in neural circuitry supporting attentional control and emotion processing among 22 individuals with BD type 1, currently remitted and euthymic, and 19 healthy controls. Participants performed an emotional n-back paradigm, comprising high and low attentional demand conditions, each with either emotional (happy, fearful), neutral or no face flanker distracters. During the high attentional control demand conditions without emotional distracters, BD individuals showed reduced activity relative to controls in dorsolateral prefrontal cortex, dorsal anterior cingulate cortex (dACC), and inferior parietal cortex. During the high attentional control demand conditions with fearful-face distracters, BD individuals showed greater activity than controls in these regions and amygdala and striatum. Relative to controls, BD individuals also showed abnormal patterns of effective connectivity between dACC and amygdala during high attentional control demand with emotional face distracters. Inter-episode bipolar disorder is characterized by abnormal recruitment of attentional control neural circuitry, especially in the context of emotionally distracting information. [PubMed Citation] [Order full text from Infotrieve]

20) Bassett D
Borderline personality disorder and bipolar affective disorder. Spectra or spectre? A review.
Aust N Z J Psychiatry. 2012 Apr;46(4):327-39.
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