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) Zhang L, Li CT, Su TP, Hu XZ, Lanius RA, Webster MJ, Chung MY, Chen YS, Bai YM, Barker JL, Barrett JE, Li XX, Li H, Benedek DM, Ursano R
P11 expression and PET in bipolar disorders.
J Psychiatr Res. 2011 Jun 29;
BACKGROUND: Bipolar disorder (BD) is a common mental disorder, subdivided into BD-I and BD-II. Currently, few biomarkers differentiate BD-I from BD-II. However, it is suggested that peripheral blood mononuclear cell (PBMC) mRNA levels of p11 and positron emission tomography (PET) might be potential biomarkers for BD. METHODS: Healthy controls (HCs), BD-I, and BD-II patients in remission (n�=�20 in each group) underwent a resting PET study with the radiotracer [(18)F]-2-deoxy-2-fluoro-d-glucose ((18)F-FDG). PBMC p11 mRNA levels were determined by quantitative real-time PCR. RESULTS: Comparing BD patients to HCs, normalized glucose metabolism (NGM) was higher in the hippocampus, parahippocampus, and amygdala, but lower in the anterior cingulate cortex (aCC), medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (dlPFC), insula and thalamus. Compared to BD-II, BD-I had hypometabolism of glucose in the aCC, bilateral middle and inferior gyrus, insula and striatum, and hypermetabolism of glucose in the left parahippocampus. PBMC p11 mRNA was over-expressed in both BD-I and BD-II, although there was no significant difference in its expression levels between BD-I and B-II patients. Further, there were significant positive correlations between PBMC p11 mRNA and NGM in the mPFC, aCC, left insula, bilateral orbitofrontal cortex (OFC), and left middle, inferior and superior temporal gyri. Also, PBMC p11 mRNA was positively correlated to the number of depressive episodes in BD patients, especially in BD-I patients. DISCUSSION: This study demonstrates that PBMC p11 mRNA expression is associated with neural activation in the brain of BD patients and warrants a larger translational study to determine its clinical utility. [PubMed Citation] [Order full text from Infotrieve]

2) Thermenos HW, Makris N, Whitfield-Gabrieli S, Brown AB, Giuliano AJ, Lee EH, Faraone SV, Tsuang MT, Seidman LJ
A functional MRI study of working memory in adolescents and young adults at genetic risk for bipolar disorder: preliminary findings.
Bipolar Disord. 2011 May;13(3):272-286.
Thermenos HW, Makris N, Whitfield-Gabrieli S, Brown AB, Giuliano AJ, Lee EH, Faraone SV, Tsuang MT, Seidman LJ. A functional MRI study of working memory in adolescents and young adults at genetic risk for bipolar disorder: preliminary findings. Bipolar Disord 2011: 13: 272-286. � 2011 The Authors. Journal compilation � 2011 John Wiley & Sons A/S. Objectives:? In this report, we seek to (i) identify a potential neuroimaging endophenotype for bipolar disorder (BD) in emotion regulatory and autonomic circuitry in young first-degree relatives of persons with BD; and (ii) replicate our previous work identifying the functional neuroanatomy of working memory (WM) in an older sample of relatives of persons with BD. Methods:? Ten adolescent and young adult (age 13-24) unmedicated, non-ill, first-degree relatives of persons with BD (RELS) and 10 demographically comparable healthy controls performed a 2-back WM task and a 0-back control task during functional magnetic resonance imaging (fMRI). fMRI data were collected on a 1.5 Tesla scanner and analyzed using SPM-2. Mood was assessed on the day of scanning. Results:? The groups did not differ on any demographic, neuropsychological, or in-scanner task performance variables. In contrast to controls, RELS showed (i) weak task-dependent modulation activity in the cerebellar vermis (CV), insula, and amygdala/parahippocampal region, and (ii) exaggerated modulation of activity in the frontopolar cortex and brainstem, even after controlling for potential confounders. Many of the group differences were driven by differences in activity in the low-level (0-back) baseline task. Conclusions:? Young, unmedicated RELS exhibited altered task-dependent modulation of frontopolar, CV, and insula activity during WM, especially during the low-level (0-back) baseline task. Results are largely consistent with our initial study of older adult RELS, suggesting these alterations may represent biomarkers of genetic risk for BD. [PubMed Citation] [Order full text from Infotrieve]

3) Roussos P, Giakoumaki SG, Georgakopoulos A, Robakis NK, Bitsios P
The CACNA1C and ANK3 risk alleles impact on affective personality traits and startle reactivity but not on cognition or gating in healthy males.
Bipolar Disord. 2011 May;13(3):250-9.
Roussos P, Giakoumaki SG, Georgakopoulos A, Robakis NK, Bitsios P. The CACNA1C and ANK3 risk alleles impact on affective personality traits and startle reactivity but not on cognition or gating in healthy males. Bipolar Disord 2011: 13: 250-259. � 2011 The Authors. Journal compilation � 2011 John Wiley & Sons A/S. Objectives:? The rs10994336 ANK3 and rs1006737 CACNA1C genetic variants have recently been identified as the most consistent, genome-wide significant risk factors for bipolar disorder, while the CACNA1C variant has also been associated with schizophrenia and major depression. The aim of this study was to examine the phenotypic consequences of the risk CACNA1C and ANK3 alleles in a large homogeneous cohort of healthy young males. Methods:? We recruited 703 randomly selected, healthy army conscripts (mean age 22.1?�?3.0?years) from the first wave of the Learning on Genetics of Schizophrenia project in Heraklion, Crete. Of those recruited, 530 subjects entered and completed the study. Subjects were assessed for prepulse inhibition (PPI), startle reactivity, neuropsychology, and personality. Results:? UNPHASED analysis revealed that the rs1006737 A-allele was associated with lower extraversion and higher harm avoidance, trait anxiety, and paranoid ideation, while the rs10994336 T-allele was associated with lower novelty seeking and behavioral activation scores (p?[PubMed Citation] [Order full text from Infotrieve]

4) Boucher AA, Arnold JC, Hunt GE, Spiro A, Spencer J, Brown C, McGregor IS, Bennett MR, Kassiou M
Resilience and reduced c-Fos expression in P2X7 receptor knockout mice exposed to repeated forced swim test.
Neuroscience. 2011 Jun 12;
There is considerable evidence suggesting genetic factors play an important role in the pathophysiology of depression, possibly by increasing susceptibility to repeated environmental stressors. Recent linkage studies have associated a polymorphism of the gene coding for the P2X7 receptor (P2X7R) with both major depressive disorder and bipolar disorder. Here we assessed whether P2X7 deletion affected the behavioural and neural response to repeated stress. P2X7R knockout (P2X7(-/-)) mice were subjected to the forced swim test for three consecutive days and neuronal activation in response to the third exposure was assessed using c-Fos immunohistochemistry. In addition, anxiety was evaluated in another group of P2X7(-/-) mice using the elevated plus maze (EPM) and light dark emergence (LDE) tests. Equivalent levels of immobility were observed in P2X7(-/-) mice and wild-type (WT) mice on the first exposure to forced swim, but much greater immobility was seen in WT mice on second and third exposures. This suggests that P2X7(-/-) mice exhibit an impaired adaptive coping response to repeated stress. Reinforcing this view, c-Fos expression in the dentate gyrus of the hippocampus and in the basolateral amygdala was seen in WT mice but not P2X7(-/-) mice following repeated forced swim. In addition, decreased locomotor activity was detected in P2X7(-/-) mice without any specific effects on anxiety in the LDE test. However, P2X7(-/-) mice showed greater anxiety-like behaviour in the EPM. These data suggest that the P2X7R may be involved in the adaptive mechanisms elicited by exposure to repeated environmental stressors that leads to the development of depression-like behaviours. This suggests that P2X7R antagonists may be useful therapeutics for the treatment of major depression, possibly by increasing resilience in the face of repeated stress. [PubMed Citation] [Order full text from Infotrieve]

5) Mayanil T, Wegbreit E, Fitzgerald J, Pavuluri M
Emerging biosignature of brain function and intervention in pediatric bipolar disorder.
Minerva Pediatr. 2011 Jun;63(3):183-200.
Pediatric bipolar disorder (PBD) is a complex illness with a chronic course, requiring multiple medications over the longitudinal course of illness, with limited recovery and high relapse rate. Beyond the placebo controlled trials of monotherapy, there is an increased need to understand how each medication influences regions of affective and cognitive circuitry function by normalization or deployment of alternative circuitry regions. Functional studies are beginning to unravel the improved function in the fronto-limbic and fronto-temporal affective circuitry, and based on the paradigm administered, also in the interfacing cognitive fronto-striato-temporo-parietal regions. Treatment studies illustrated a pattern of improvement in functional activity consistently among the affective ventrolateral and medial prefrontal regions, and variably in the cognitive dorsolateral prefrontal cortex. While there is decreased activity in amygdala with treatment for mania or depression among patients with PBD, there appears to be residual increased amygdala activity regardless of response, relative to healthy controls, suggesting a trait-like abnormality. Parallel biochemical abnormalities in magnetic resonance spectroscopic studies and fronto-limbic activity in magnetic resonance imaging studies of brain function at baseline provide maiden data on predicting outcome. This preliminary cohort of studies that probed the hypothesized circuitries underlying specific symptom constructs, coupled with futuristic paradigms and analytic methods, serve as a guidepost to generate the next generation of studies and build on the emerging biosignature towards specific treatment targets for personalized medicine in PBD. [PubMed Citation] [Order full text from Infotrieve]

6) Whalley HC, Sussmann JE, Chakirova G, Mukerjee P, Peel A, McKirdy J, Hall J, Johnstone EC, Lawrie SM, McIntosh AM
The Neural Basis of Familial Risk and Temperamental Variation in Individuals at High Risk of Bipolar Disorder.
Biol Psychiatry. 2011 May 20;
BACKGROUND: Bipolar disorder is a highly heritable psychiatric disorder characterized by episodic elevation or depression of mood. Bipolar disorder is associated with structural and functional brain abnormalities but it is unclear whether these are present in relatives of affected individuals and if they are associated with subclinical symptoms or traits associated with the disorder. METHODS: Functional magnetic resonance imaging scans were conducted on 93 unrelated relatives of bipolar disorder patients and 70 healthy comparison subjects performing the Hayling sentence completion paradigm. Examination of comparison subjects versus high-risk individuals was followed by assessments of associations with depression scores and measures of cyclothymic temperament. RESULTS: Examination of comparison subjects versus high-risk subjects revealed increased activation in the high-risk group in the left amygdala. No interaction effects were observed between the groups for scores of depression or cyclothymia and activation in any region. Significant associations were found across the groups with depression ratings and activation in the ventral striatum and with cyclothymia and activation in ventral prefrontal regions, however no interaction effects were observed between the groups. CONCLUSIONS: Differences in activation in the left amygdala in those at familial risk may represent a heritable endophenotype of bipolar disorder. Activation in striatal and ventral prefrontal regions may, in contrast, represent a distinct biological basis of subclinical features of the illness regardless of the presence of familial risk. [PubMed Citation] [Order full text from Infotrieve]

7) Pavuluri MN, Passarotti AM, Lu LH, Carbray JA, Sweeney JA
Double-blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder: fMRI outcomes.
Psychiatry Res. 2011 Jul 30;193(1):28-37.
The aim of this research was to determine the relative effects of risperidone and divalproex on brain function in pediatric mania. This is a double-blind 6-week functional magnetic resonance imaging trial with 24 unmedicated manic patients randomized to risperidone or divalproex, and 14 healthy controls (HCs) matched for IQ and demographic factors (mean age: 13.1�3.3years). A pediatric affective color matching task, in which subjects matched the color of a positive, negative or neutral word with one of two colored circles, was administered. The primary clinical measure was the Young Mania Rating Scale (YMRS). The risperidone group, relative to HC, showed an increase in activation from pre- to post-treatment in right pregenual and subgenual anterior cingulate cortex and decreased activation in bilateral middle frontal gyrus during the negative condition; and decreased activation in left inferior and medial, and right middle frontal gyri, left inferior parietal lobe, and right striatum with positive condition. In the divalproex group, relative to HC, there was an increased activation in right superior temporal gyrus in the negative condition; and in left medial frontal gyrus and right precuneus with the positive condition. Greater pre-treatment right amygdala activity with negative and positive condition in the risperidone group, and left amygdala activity with positive condition in divalproex group, predicted poor response on YMRS. Risperidone and divalproex yield differential patterns of prefrontal activity during an emotion processing task in pediatric mania. Increased amygdala activity at baseline is a potential biomarker predicting poor treatment response to both the risperidone and divalproex. [PubMed Citation] [Order full text from Infotrieve]

8) Fleck DE, Kotwal R, Eliassen JC, Lamy M, Delbello MP, Adler CM, Durling M, Cerullo MA, Strakowski SM
Preliminary evidence for increased frontosubcortical activation on a motor impulsivity task in mixed episode bipolar disorder.
J Affect Disord. 2011 May 3;
BACKGROUND: Of all mood states, patients in mixed episodes of bipolar disorder are at the greatest risk for impulsive behaviors including attempted suicide. The aim of this study was to examine whether the neural correlates of motor impulsivity are distinct in patients with mixed mania. METHODS: Ten patients with bipolar disorder in a mixed episode (BP-M), 10 bipolar comparison participants in a depressed episode (BP-D), and 10 healthy comparison (HC) participants underwent functional MRI while performing a Go/No-Go task of motor impulsivity. RESULTS: Both patient groups had elevated, self-rated motor impulsiveness scores. The BP-M group also had a trend-level increase in commission errors relative to the HC group on the Go/No-Go task. While the full sample strongly activated a ventrolateral prefrontal-subcortical brain network, the BP-M group activated the amygdala and frontal cortex more strongly than the HC group, and the thalamus, cerebellum, and frontal cortex more strongly than the BP-D group. LIMITATIONS: This study is primarily limited by a relatively small sample size. CONCLUSIONS: Higher commission error rates on the Go/No-Go task suggest increased vulnerability to impulsive responding during mixed episodes of bipolar disorder. Moreover, the distinct pattern of increased brain activation during mixed mania may indicate a connection between behavioral impulsivity and a failure of neurophysiological "inhibition", especially in the amygdala. [PubMed Citation] [Order full text from Infotrieve]

9) Dzirasa K, McGarity DL, Bhattacharya A, Kumar S, Takahashi JS, Dunson D, McClung CA, Nicolelis MA
Impaired limbic gamma oscillatory synchrony during anxiety-related behavior in a genetic mouse model of bipolar mania.
J Neurosci. 2011 Apr 27;31(17):6449-56.
Alterations in anxiety-related processing are observed across many neuropsychiatric disorders, including bipolar disorder. Though polymorphisms in a number of circadian genes confer risk for this disorder, little is known about how changes in circadian gene function disrupt brain circuits critical for anxiety-related processing. Here we characterize neurophysiological activity simultaneously across five limbic brain areas (nucleus accumbens, amygdala, prelimbic cortex, ventral hippocampus, and ventral tegmental area) as wild-type (WT) mice and mice with a mutation in the circadian gene, CLOCK (Clock-?19 mice) perform an elevated zero maze task. In WT mice, basal limbic gamma oscillatory synchrony observed before task performance predicted future anxiety-related behaviors. Additionally, dynamic changes in limbic gamma oscillatory synchrony were observed based on the position of WT mice in the zero maze. Clock-?19 mice, which displayed an increased propensity to enter the open section of the elevated maze, showed profound deficits in these anxiety-related circuit processes. Thus, our findings link the anxiety-related behavioral deficits observed in Clock-?19 mice with dysfunctional gamma oscillatory tuning across limbic circuits and suggest that alterations in limbic oscillatory circuit function induced by circadian gene polymorphisms may contribute to the behavioral manifestations seen in bipolar mania. [PubMed Citation] [Order full text from Infotrieve]

10) Arent CO, Valvassori SS, Fries GR, Stertz L, Ferreira CL, Lopes-Borges J, Mariot E, Varela RB, Ornell F, Kapczinski F, Andersen ML, Quevedo J
Neuroanatomical profile of antimaniac effects of histone deacetylases inhibitors.
Mol Neurobiol. 2011 Jun;43(3):207-14.
An increasing number of studies have evaluated the potential therapeutic relevance of histone deacetylases (HDAC) inhibitors in mood disorder including bipolar disorder (BD). It has been suggested that the anterior limbic, which controls impulsivity and psychosis, is dysfunctional in BD. The present studies aims to evaluate the effects of microinjection of HDAC inhibitors in the ventricle, amygdala, striatum, prefrontal, and hippocampus on m-amphetamine-induced manic-like behavior in rats. Rats were given a single intracerebral (in the ventricle, amygdala, striatum, prefrontal, or hippocampus) injection of artificial cerebrospinal fluid, sodium butyrate (SB), or valproate (VPA) followed by an intraperitoneal injection of saline or m-AMPH 2 h before the open-field task. The activity of HDAC was evaluated in amygdala, striatum, prefrontal, and hippocampus of animals. The microinjection of SB and VPA in the ventricle, amygdala, striatum, and prefrontal, but not in hippocampus blocked the hyperactivity induced by m-AMPH. In addition, SB and VPA inhibited the HDAC activity; however, this effect varied depending on the experimental procedure and the brain structure evaluated. Our results suggest that the antimanic effects of SB and VPA, HDAC inhibitors, are related to the amygdala, striatum, and prefrontal, but not the hippocampus. More studies are needed to clarify the therapeutic effects of the HDAC inhibitor in BD and thereby develop new drugs. [PubMed Citation] [Order full text from Infotrieve]

11) Passarotti AM, Sweeney JA, Pavuluri MN
Fronto-limbic dysfunction in mania pre-treatment and persistent amygdala over-activity post-treatment in pediatric bipolar disorder.
Psychopharmacology (Berl). 2011 Aug;216(4):485-99.
[PubMed Citation] [Order full text from Infotrieve]

12) Chen CH, Suckling J, Lennox BR, Ooi C, Bullmore ET
A quantitative meta-analysis of fMRI studies in bipolar disorder.
Bipolar Disord. 2011 Feb;13(1):1-15.
[PubMed Citation] [Order full text from Infotrieve]

13) Perrier E, Pompei F, Ruberto G, Vassos E, Collier D, Frangou S
Initial evidence for the role of CACNA1C on subcortical brain morphology in patients with bipolar disorder.
Eur Psychiatry. 2011 Apr;26(3):135-7.
[PubMed Citation] [Order full text from Infotrieve]

14) Moretti M, Valvassori SS, Steckert AV, Rochi N, Benedet J, Scaini G, Kapczinski F, Streck EL, Zugno AI, Quevedo J
Tamoxifen effects on respiratory chain complexes and creatine kinase activities in an animal model of mania.
Pharmacol Biochem Behav. 2011 Apr;98(2):304-10.
The present study aimed to investigate the effects of tamoxifen (TMX) on locomotor behavior and on the activities of mitochondrial respiratory chain complexes and creatine kinase (CK) in the brain of rats subjected to an animal model of mania induced by d-amphetamine (D-AMPH)-reversion and prevention protocols. The D-AMPH administration increased locomotor activity in saline-treated rats under prevention and reversion treatment; furthermore, there was evident reduction in the locomotion in the D-amphetamine group treated with TMX. D-AMPH significantly decreased the activity of mitochondrial respiratory chain complexes in saline-treated rats in prefrontal cortex, hippocampus, striatum and amygdala in both prevention and reversion treatment. Depending on the cerebral area and evaluated complex, TMX was able to prevent and reverse this impairment. A decrease in CK activity was also verified in the brain of rats when D-AMPH was administrated in both experiments; the administration of TMX reversed but not prevented the decrease in CK activity induced by D-AMPH. The present study demonstrated that TMX reversed and prevented the alterations in behavioral and energy metabolism induced by D-AMPH (alterations were also observed in bipolar disorder), reinforcing the need for more studies about inhibitors of PKC as possible targets for new medications in the treatment of bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

15) Sharpley CF
A review of the neurobiological effects of psychotherapy for depression.
Psychotherapy (Chic). 2010 Dec;47(4):603-15.
Although randomized, controlled clinical trials have shown that different forms of psychotherapy may be efficacious for depression, psychotherapy has not been widely reported to have effects upon the neurobiological concomitants of depression in similar ways as medication. Neuroendocrinal changes that occur during depression (principally hypercortisolaemia) produce structural and functional alterations to the prefrontal cortex, hippocampus, and amygdala, plus the connectivity between these regions of the brain. This article reviews the evidence to date regarding the neurobiological effects of psychotherapy for depression and suggests a hypothetical pathway linking the nurturing effects of the therapist-patient "bond" and restoration of neuroendocrinal "balance." This pathway may provide a neurobiological causal link between psychotherapy and alleviation of depression in the same way as that which exists for pharmacological treatments, and argues for a model of depression that includes both biological and psychological effects of psychotherapy when considering treatment choice and application. [PubMed Citation] [Order full text from Infotrieve]

16) Bishop CA, Jenkinson M, Andersson J, Declerck J, Merhof D
Novel Fast Marching for Automated Segmentation of the Hippocampus (FMASH): method and validation on clinical data.
Neuroimage. 2011 Apr 1;55(3):1009-19.
With hippocampal atrophy both a clinical biomarker for early Alzheimer's Disease (AD) and implicated in many other neurological and psychiatric diseases, there is much interest in the accurate, reproducible delineation of this region of interest (ROI) in structural MR images. Here we present Fast Marching for Automated Segmentation of the Hippocampus (FMASH): a novel approach using the Sethian Fast Marching (FM) technique to grow a hippocampal ROI from an automatically-defined seed point. Segmentation performance is assessed on two separate clinical datasets, utilising expert manual labels as gold standard to quantify Dice coefficients, false positive rates (FPR) and false negative rates (FNR). The first clinical dataset (denoted CMA) contains normal controls (NC) and atrophied AD patients, whilst the second is a collection of NC and bipolar (BP) patients (denoted BPSA). An optimal and robust stopping criterion is established for the propagating FM front and the final FMASH segmentation estimates compared to two commonly-used methods: FIRST/FSL and Freesurfer (FS). Results show that FMASH outperforms both FIRST and FS on the BPSA data, with significantly higher Dice coefficients (0.80�0.01) and lower FPR. Despite some intrinsic bias for FIRST and FS on the CMA data, due to their training, FMASH performs comparably well on the CMA data, with an average bilateral Dice coefficient of 0.82�0.01. Furthermore, FMASH most accurately captures the hippocampal volume difference between NC and AD, and provides a more accurate estimation of the problematic hippocampus-amygdala border on both clinical datasets. The consistency in performance across the two datasets suggests that FMASH is applicable to a range of clinical data with differing image quality and demographics. [PubMed Citation] [Order full text from Infotrieve]

17) Post RM, Weiss SR
Tolerance to the Prophylactic Effects of Carbamazepine and Related Mood Stabilizers in the Treatment of Bipolar Disorders.
CNS Neurosci Ther. 2010 Dec 16;
Tolerance development after successful long-term treatment of bipolar disorder is under recognized, as are ways to prevent or show its occurrence or reverse it once it has occurred. We review the clinical literature which suggests that tolerance can develop to most treatment approaches in bipolar illness and present an animal model of tolerance development to anticonvulsant effects of carbamazepine or lamotrigine on amgydala-kindled seizures. In this model tolerance does not have a pharmacokinetic basis, but is contingent upon the drug being present in the brain at the time of amygdala stimulation. The occurrence of seizures in the absence of drug is sufficient to reverse tolerance and re-establish anticonvulsant efficacy. Based on the model, we hypothesize that some episode-induced compensatory adaptive changes in gene expression fail to occur in tolerant subjects and that episodes off medication re-induce these changes and renew drug effectiveness. Approaches that slow or reverse tolerance development in the animal model are reviewed so that they can be tested for their applicability in the clinic. Criteria for assessing tolerance development are offered in the hope that this will facilitate a more systemic literature about its prevalence, prevention, and reversal. Careful longitudinal monitoring of episode occurrence is essential to understanding tolerance development in the affective disorder and its treatment. [PubMed Citation] [Order full text from Infotrieve]

18) Allman JM, Tetreault NA, Hakeem AY, Park S
The von economo neurons in apes and humans.
Am J Hum Biol. 2011 Jan-Feb;23(1):5-21.
The von Economo neurons (VENs) are large bipolar neurons located in frontoinsular (FI) and anterior cingulate cortex (ACC) in great apes and humans but not other primates. We stereologically counted the VENs in FI and the limbic anterior (LA) area of ACC and found them to be more numerous in humans than in apes. In humans, VENs first appear in small numbers in the 36th week postconception are rare at birth and increase in number during the first 8 months after birth. There are significantly more VENs in the right hemisphere than the left in FI and LA in postnatal brains; this may be related to asymmetries in the autonomic nervous system. The activity of the inferior anterior insula, containing FI, is related to physiological changes in the body, decision-making, error recognition, and awareness. In a preliminary diffusion tensor imaging study of the connections of FI, we found that the VEN-containing regions connect with the frontal pole as well as with other parts of frontal and insular cortex, the septum, and the amygdala. The VENs and a related cell population, the fork cells, selectively express the bombesin peptides neuromedin B (NMB) and gastrin releasing pepide, which signal satiety. The loss of VENs and fork cells may be related to the loss of satiety signaling in patients with frontotemporal dementia who have damage to FI. These cells may be morphological specializations of an ancient population of neurons involved in the control of appetite present in the insular cortex in all mammals. [PubMed Citation] [Order full text from Infotrieve]

19) Yu K, Cheung C, Leung M, Li Q, Chua S, McAlonan G
Are Bipolar Disorder and Schizophrenia Neuroanatomically Distinct? An Anatomical Likelihood Meta-analysis.
Front Hum Neurosci. 2010;4:189.
Objective: There is renewed debate on whether modern diagnostic classification should adopt a dichotomous or dimensional approach to schizophrenia and bipolar disorder. This study synthesizes data from voxel-based studies of schizophrenia and bipolar disorder to estimate the extent to which these conditions have a common neuroanatomical phenotype. Methods: A post-hoc meta-analytic estimation of the extent to which bipolar disorder, schizophrenia, or both conditions contribute to brain gray matter differences compared to controls was achieved using a novel application of the conventional anatomical likelihood estimation (ALE) method. 19 schizophrenia studies (651 patients and 693 controls) were matched as closely as possible to 19 bipolar studies (540 patients and 745 controls). Result: Substantial overlaps in the regions affected by schizophrenia and bipolar disorder included regions in prefrontal cortex, thalamus, left caudate, left medial temporal lobe, and right insula. Bipolar disorder and schizophrenia jointly contributed to clusters in the right hemisphere, but schizophrenia was almost exclusively associated with additional gray matter deficits (left insula and amygdala) in the left hemisphere. Limitation: The current meta-analytic method has a number of constraints. Importantly, only studies identifying differences between controls and patient groups could be included in this analysis. Conclusion: Bipolar disorder shares many of the same brain regions as schizophrenia. However, relative to neurotypical controls, lower gray matter volume in schizophrenia is more extensive and includes the amygdala. This fresh application of ALE accommodates multiple studies in a relatively unbiased comparison. Common biological mechanisms may explain the neuroanatomical overlap between these major disorders, but explaining why brain differences are more extensive in schizophrenia remains challenging. [PubMed Citation] [Order full text from Infotrieve]

20) Yeh PH, Zhu H, Nicoletti MA, Hatch JP, Brambilla P, Soares JC
Structural equation modeling and principal component analysis of gray matter volumes in major depressive and bipolar disorders: differences in latent volumetric structure.
Psychiatry Res. 2010 Dec 30;184(3):177-85.
Abnormalities of the cortico-striatal-thalamic-cortical (CSTC) and the limbic-cortico-striatal-thalamic-cortical (LCSTC) circuits have been hypothesized in mood disorders. We performed principal component analysis (PCA) to identify latent volumetric systems on regional brain volumes and correlated these patterns with clinical characteristics; further, we performed exploratory structural equation modeling (SEM) to test a priori hypotheses about the organization among the structures comprising the CSTC and LCSTC circuits, and to investigate differences among subjects with bipolar disorder (BD), major depressive disorder (MDD), and healthy controls (HC). Participants included 45 BD and 31 MDD patients, and 72 HC. Regional MR brain volumes were used to calculate patterns of volumetric covariance. The identified latent volumetric systems were related to the depression severity and the duration of illness. BD differed from HC on the estimated parameters describing the paths of cortico-striatal, thalamo-striatal and intrastriatal loops of the CSTC circuit, and the paths between anterior and posterior cingulate cortex (PCC), and hippocampus to amygdala of the LCSTC circuit. MDD differed from HC on the paths between putamen and thalamus, and PCC to hippocampus. This study provides evidence to suggest different organizational patterns among structures within the CSTC and LCSTC circuits for BD, MDD, and HC, which may point to structural abnormalities underlying mood disorders. [PubMed Citation] [Order full text from Infotrieve]