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Walk the Road of Bipolar II-

Enlargement of the amygdala in patients with a first episode of major depression.
BACKGROUND: The amygdala plays a crucial role in the mediation of affective behavior in humans and is implemented in the limbic-thalamic-cortical network that is supposed to modulate human mood. The aim of the present study was to measure the amygdala volumes in patients with a first episode of major depression. METHODS: Thirty inpatients with a first episode of depression were compared with 30 healthy volunteers matched for age, gender, handedness, and education by performing structural magnetic resonance imaging (MRI) measures of the amygdala. RESULTS: Patients showed increased amygdala volumes in both hemispheres as compared to healthy control subjects. No significant correlations were found between amygdala volumes and age, age of onset, illness duration, or severity of depression in the patient group. CONCLUSIONS: Enlarged amygdala volumes in patients with a first episode of major depression might be due to enhanced blood flow in the amygdala rather than to a neurodevelopmental structural predisposition to major depression.
Amygdala priming results in conditioned place avoidance.
Priming involves daily stimulation of the basolateral nucleus of the amygdala (BLA) for 5 days using a dose of the GABA(A) receptor antagonist, bicuculline methiodide (BMI), that is subthreshold to generate anxiogenic-like responses. The coordinated physiological and behavioral response of the primed rat is similar to the symptoms of human panic disorder and has been used as a model to study panic attacks. If the priming procedure is indeed similar to human panic disorder, then the context in which priming occurs should become associated with aversive conditioning and avoidance as seen in secondary agoraphobia following panic attacks in humans.""" These results suggest that priming may result in phobic-like responses, similar to the avoidance behavior exhibited by panic disorder patients."
Activation of GABA(A) receptors in the amygdala blocks the acquisition
Submissive behavior during testing was significantly reduced in animals receiving infusions of muscimol immediately prior to initial defeat training. Animals that received infusions of muscimol immediately prior to being tested with a non-aggressive intruder also displayed significantly less submissive behavior than did animals receiving vehicle control. These data indicate that infusion of muscimol into the amygdala can block the acquisition and expression of conditioned defeat, a finding that indicates that GABAergic neurotransmission within the amygdala is involved in the acquisition and expression of fear or stress-induced behavioral changes. This is the first evidence indicating that the neural circuits involved in Pavlovian fear conditioning are also involved in more ethologically-relevant models examining stress-related behavioral plasticity.
Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex
The dynorphin system has been associated with the regulation of mood
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.
Glucose metabolism in the amygdala in depression: relationship to diagnostic subtype and plasma cortisol levels
Drevets WC, Price JL, Bardgett ME, Reich T, Todd RD, Raichle ME. Section on Neuroimaging of Mood and Anxiety Disorders, Molecular Imaging Branch, NIH/National Institute of Mental Health, Building 1, Room B3-10, 1 Center Drive, MSC-0135, Bethesda, MD 20892-0135, USA. drevetsw@intra.nimh.nih.gov 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;.1The 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.

Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex.
Hurd YL. Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-171 76
Stockholm, Sweden. Yasmin.hurd@ks.se
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.

Bipolar I possibly different from Bipolar II

"Brain Imaging Section, Neuroimaging Research Branch

Volume of Lateral Ventricle in Bipolar I Patients is Nearly Twice as Large as the Volume in Patients with Bipolar II Disorder

A quantitative magnetic resonance imaging comparison of bipolar I and bipolar II patients was undertaken because no previous quantitative assessments of bipolar II patients have been documented and the number of quantitative studies of bipolar I patients is small. Magnetic resonance imaging was used to estimate volume of the temporal lobe, hippocampus, and the lateral ventricle in 25 bipolar I disorder, 22 bipolar II disorder, and 19 control subjects. There were no significant differences in volume estimates for the temporal lobe and hippocampus between groups. In contrast, the lateral ventricle area and the lateral ventricle to cerebrum area ratio were approximately twice as large in the bipolar I patients as the other groups in the left hemisphere only. The results suggest that subjects diagnosed with bipolar I disorder, particularly in males, may show neurobiological alterations different from patients with bipolar II disorder or control subjects.
Hauser, P., Matochik, J.A., Altshuler, L.L., Denicoff, K.D., Conrad, A., Li, X., and Post, R.M. Journal of Affective Disorders, 60, pp. 25-32, 2000."

AMYGDALA LARGER
amygdala Enlargement in Bipolar Disorder
The bipolar and control groups did not differ significantly (t40=1.72; P=.09). The bipolar group had significantly larger amygdalae than the schizophrenia group
I am borrowing this definition from Dr.Driesen's site for amygdala amygdala
"AMYGDALA is the nuclear complex in the temporal lobe that forms part of the limbic system. The amygdala is a complex structure, consisting of about ten distinct nuclei. The amygdala mediates both inborn and acquired emotional responses. It seems to be involved in mediating both conscious and unconscious emotional feeling. Many of the autonomic expressions of emotional states are mediated by this structure through its connections to the hypothalamus (via the stria terminalis) and the autonomic nervous system. The influence of the amygdala on conscious feeling is mediated by its projections (via the ventral amygdalofugal pathway) to the cingulate gyrus and the prefrontal cortex (orbitofrontal cortex). (See image - 1 and image - 2.)"
Amygdala enlargement in dysthymia - a volumetric study of patients with temporal lobe epilepsy by Tebartz van Elst L, Woermann FG, Lemieux L, Trimble MR Institute of Neurology, University College, London, UK. Biol Psychiatry 1999 Dec 15; 46(12):1614-23
ABSTRACT
BACKGROUND: Previous studies indicated an important role of the amygdala for emotional information processing. We investigated a possible relationship between amygdala volumes, aggressive behavior, and dysthymia, in patients with temporal lobe epilepsy (TLE). METHODS: Patients with TLE with and without aggression or dysthymia and healthy volunteers were assessed using quantitative MRI. Amygdala volumes were measured in a blinded fashion and corrected for total brain volumes. RESULTS: There was a highly significant enlargement of left and right amygdala volumes in patients with dysthymia (right side, p < .000; left side, p = .001). We found a significant positive correlation between left amygdala volumes (p = .02) and a trend towards positive correlation between right amygdala volumes and depression (p = .06), as measured with the Beck Depression Inventory. Amygdala volumes of females were significantly larger than those of males (left side: p = .005; right side: p = .06). CONCLUSIONS: This is the second report of a relationship between amygdala volumes and depressed mood, confirming an earlier finding in patients with bipolar disease, and the first study reporting a correlation between amygdala volumes and depression. Increased processing of emotional information might increase amygdala blood flow and subsequently, result in amygdala enlargement.


Biol Psychiatry 2001 Nov 1;50(9):651-
Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study.
Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder
AZ, Mintun MA.
Department of Psychiatry, Washington University, St. Louis, Missouri 63110, USA.
BACKGROUND: The amygdala has a central role in processing emotions, particularly fear. During functional magnetic resonance imaging (fMRI) amygdala activation has been demonstrated outside of conscious awareness using masked emotional faces.
METHODS: We applied the masked faces paradigm to patients with major depression (n = 11) and matched control subjects (n = 11) during fMRI to compare amygdala activation in response to masked emotional faces before and after antidepressant treatment. Data were analyzed using left and right amygdala a priori regions of interest, in an analysis of variance block analysis and random effects model. RESULTS: Depressed patients had exaggerated left amygdala activation to all faces, greater for fearful faces. Right amygdala did not differ from control subjects. Following treatment, patients had bilateral reduced amygdala activation to masked fearful faces and bilateral reduced amygdala activation to all faces. Control subjects had no differences between the two scanning sessions. CONCLUSIONS: Depressed patients have left amygdala hyperarousal, even when processing stimuli outside conscious awareness. Increased amygdala activation normalizes with antidepressant treatment.
Biol Psychiatry 2002 May 1;51(9):693-707
Can't shake that feeling: event-related fMRI assessment of sustained amygdala activity in response to emotional information in depressed individuals.
Siegle GJ, Steinhauer SR, Thase ME, Stenger VA, Carter CS.
University of Pittsburgh Medical School (GJS, SRS, MET, VAS, CSC), Pittsburgh, Pennsylvania, USA
Background: Previous research suggests that depressed individuals engage in prolonged elaborative processing of emotional information. A computational neural network model of emotional information processing suggests this process involves sustained amygdala activity in response to processing negative features of information. This study examined whether brain activity in response to emotional stimuli was sustained in depressed individuals, even following subsequent distracting stimuli.Methods: Seven depressed and 10 never-depressed individuals were studied using event-related functional magnetic resonance imaging during alternating 15-sec emotional processing (valence identification) and nonemotional processing (Sternberg memory) trials. Amygdala regions were traced on high-resolution structural scans and co-registered to the functional data. The time course of activity in these areas during emotional and nonemotional processing trials was examined.Results: During emotional processing trials, never-depressed individuals displayed amygdalar responses to all stimuli, which decayed within 10 sec. In contrast, depressed individuals displayed sustained amygdala responses to negative words that lasted throughout the following nonemotional processing trials (25 sec later). The difference in sustained amygdala activity to negative and positive words was moderately related to self-reported rumination.Conclusions: Results suggest that depression is associated with sustained activity in brain areas responsible for coding emotional features.

Br J Psychiatry Suppl 2001 Jun;41:s142-7 Neuroanatomical studies on bipolar disorder.

Baumann B, Bogerts B.
Department of Psychiatry, University of Magdeburg, Germany. baumann@medizin.uni-magdeburg.de
BACKGROUND: Neuroimaging data showing structural and functional brain abnormalities in mood disorders suggest that brain alterations at the neurohistological level may underlie the macropathology seen by imaging in vivo. AIMS: To summarise recent postmortem studies on affective disorders, with a focus on bipolar disorder. METHOD: Literature review and discussion of results from volumetric, cyto-architectural and immunohistochemical analyses. RESULTS: Basal ganglia are smaller in patients with depression irrespective of diagnostic polarity. In addition, higher neuron numbers have been reported in the locus caeruleus of patients with bipolar disorder compared with those with unipolar depression. Patients with bipolar as well as unipolar illness show subtle structural deficits in the dorsal raphe. Histological data are consistent with a regional reduction in the synthesis of noradrenalin and serotonin, which appears to be compensated by antidepressants. CONCLUSION: Preliminary results suggest that, aside from functional dysregulation, subtle structural abnormalities in the brain may contribute to the pathogenesis of mood disorders.


Psychol Med 2002 Jan;32(1):93-103

Circumscribed numerical deficit of dorsal raphe neurons in mood disorders.

Baumann B, Bielau H, Krell D, Agelink MW, Diekmann S, Wurthmann C, Trubner K, Bernstein HG, Danos P, Bogerts B.

Department of Psychiatry, University, of Magdeburg, Germany.

BACKGROUND: Neurocircuits comprising limbic, striato-pallidal and thalamo cortical brain areas are assumed to be involved in the pathophysiology of mood disorders. All these brain regions receive serotonergic afferents arising from the rostral raphe, mainly the dorsal raphe. Although serotonergic systems appear to be involved in the pathology of mood disorders, there is uncertainty as to whether structural alterations in raphe nuclei exist alongside a functional dysregulation of the serotonergic system. METHODS: In the brains of 12 patients with mood disorders (major depressive disorder N= 6, bipolar disorder N = 6) and 12 normal subjects we performed a morphometric post-mortem study on neuronal morphology in all subnuclei of the dorsal raphe nucleus using Nissl stained 20 microm axial serial sections of the brainstem.


RESULTS: The number of neurones of the ventrolateral subnucleus of the dorsal raphe was reduced by 31 % in patients with mood disorders compared with non-psychiatric control subjects. Ventrally located subnuclei of the rostral dorsal raphe (ventrolateral, ventral, interfascicular) taken together also showed a smaller number of neurones. Neurone numbers of the dorsal and the caudal subnucleus and volumes of all single subnuclei appeared to be unchanged. Analysis of morphological neuronal types revealed a smaller number of triangular neurones in the ventrolateral subnucleus. Numbers of ovoid and round neurones in the ventrolateral subnucleus also showed a trend to reduction. No correlation was found between neurone numbers in any subnucleus of the dorsal raphe and duration of illness. Neurone numbers did not differ in any subnucleus between patients with unipolar and those with bipolar affective disorder. CONCLUSIONS: Results indicate that patients with primary mood disorders have a circumscribed numerical neuronal deficiency in the dorsal raphe. This structural deviation may contribute to impaired serotonergic innervation of brain regions which are involved in the pathology of mood disorders.
Reduced volume of limbic system-affiliated basal ganglia in mood disorders: preliminary data from a postmortem study.
Baumann B, Danos P, Krell D, Diekmann S, Leschinger A, Stauch R, Wurthmann C, Bernstein HG, Bogerts B.
Department of Psychiatry, University of Magdeburg, Germany.
Volumes of basal ganglia in postmortem brains of 8 patients with mood disorders and 8 control subjects without neuropsychiatric disorder were determined. Morphometry of serial whole-brain sections under the control of postmortem artifacts revealed reduced volumes of the left nucleus accumbens (-32%, P = 0.01), the right and left external pallidum (-20%, P = 0.04), and the right putamen (-15%, P = 0.04) in the patient group compared with the control group. These results suggest that, in particular, the limbic loop of the basal ganglia involving the nucleus accumbens and the pallidum is affected in mood disorders. :
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