anterior cingulate in bipolar disorder


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(Updated 8/25/04)

Blumberg HP, Stern E, Martinez D, Ricketts S, de Asis J, White T, Epstein J, McBride PA, Eidelberg D, Kocsis JH, Silbersweig DA.
Increased anterior cingulate and caudate activity in bipolar mania.
Biol Psychiatry 2000 Dec 1;48(11):1045-52
"BACKGROUND: Executive control of cognition, emotion, and behavior are disrupted in the manic state of bipolar disorder. Whereas frontal systems are implicated in such dysfunction, the localization of functional brain abnormalities in the manic state is not well understood. METHODS: We utilized a high-sensitivity H(2)(15)0 positron emission tomography technique to investigate regions of increased brain activity in mania, compared to euthymia, in bipolar disorder. RESULTS: The principal findings were manic state-related increased activity in left dorsal anterior cingulate, and left head of caudate. CONCLUSIONS: The findings suggest that the manic state of bipolar disorder may be associated with heightened activity in a frontal cortical-subcortical neural system that includes the anterior cingulate and caudate." [Abstract]

Dunn RT, Kimbrell TA, Ketter TA, Frye MA, Willis MW, Luckenbaugh DA, Post RM.
Principal components of the Beck Depression Inventory and regional cerebral metabolism in unipolar and bipolar depression.
Biol Psychiatry 2002 Mar 1;51(5):387-99
"BACKGROUND: We determined clustering of depressive symptoms in a combined group of unipolar and patients with bipolar disorder using Principle Components Analysis of the Beck Depression Inventory. Then, comparing unipolars and bipolars, these symptom clusters were examined for interrelationships, and for relationships to regional cerebral metabolism for glucose measured by positron emission tomography. METHODS: [18F]-fluoro-deoxyglucose positron emission tomography scans and Beck Depression Inventory administered to 31 unipolars and 27 bipolars, all medication-free, mildly-to-severely depressed. BDI component and total scores were correlated with global cerebral metabolism for glucose, and voxel-by-voxel with cerebral metabolism for glucose corrected for multiple comparisons. RESULTS: In both unipolars and bipolars, the psychomotor-anhedonia symptom cluster correlated with lower absolute metabolism in right insula, claustrum, anteroventral caudate/putamen, and temporal cortex, and with higher normalized metabolism in anterior cingulate. In unipolars, the negative cognitions cluster correlated with lower absolute metabolism bilaterally in frontal poles, and in right dorsolateral frontal cortex and supracallosal cingulate. CONCLUSIONS: Psychomotor-anhedonia symptoms in unipolar and bipolar depression appear to have common, largely right-sided neural substrates, and these may be fundamental to the depressive syndrome in bipolars. In unipolars, but not bipolars, negative cognitions are associated with decreased frontal metabolism. Thus, different depressive symptom clusters may have different neural substrates in unipolars, but clusters and their substrates are convergent in bipolars." [Abstract]

Moore CM, Breeze JL, Gruber SA, Babb SM, Frederick BB, Villafuerte RA, Stoll AL, Hennen J, Yurgelun-Todd DA, Cohen BM, Renshaw PF.
Choline, myo-inositol and mood in bipolar disorder: a proton magnetic resonance spectroscopic imaging study of the anterior cingulate cortex.
Bipolar Disord 2000 Sep;2(3 Pt 2):207-16
"OBJECTIVES: Alterations in choline and myo-inositol metabolism have been noted in bipolar disorder, and the therapeutic efficacy of lithium in mania may be related to these effects. We wished to determine the relationship between anterior cingulate cortex choline and myo-inositol levels, assessed using proton magnetic resonance spectroscopic imaging (MRSI), and mood state in subjects with bipolar disorder. METHODS: Serial assessments of anterior cingulate cortex choline and myo-inositol metabolism were performed in nine subjects with bipolar disorder, taking either lithium or valproate, and 14 controls. Each bipolar subject was examined between one and four times (3.1 +/- 1.3). On the occasion of each examination, standardized ratings of both depression and mania were recorded. RESULTS: In the left cingulate cortex, the bipolar subjects' depression ratings correlated positively with MRSI measures of Cho/Cr-PCr. In the right cingulate cortex, the Cho/Cr-PCr ratio was significantly higher in subjects with bipolar disorder compared with control subjects. In addition, bipolar subjects not taking antidepressants had a significantly higher right cingulate cortex Cho/Cr-PCr ratio compared with patients taking antidepressants or controls. No clinical or drug-related changes were observed for the Ino/Cr-PCr ratio. CONCLUSIONS: The results of this study suggest that bipolar disorder is associated with alterations in the metabolism of cytosolic, choline-containing compounds in the anterior cingulate cortex. As this resonance arises primarily from phosphocholine and glycerophosphocholine, both of which are metabolites of phosphatidylcholine, these results are consistent with impaired intraneuronal signaling mechanisms." [Abstract]

Davanzo P, Yue K, Thomas MA, Belin T, Mintz J, Venkatraman TN, Santoro E, Barnett S, McCracken J.
Proton magnetic resonance spectroscopy of bipolar disorder versus intermittent explosive disorder in children and adolescents.
Am J Psychiatry. 2003 Aug;160(8):1442-52.
OBJECTIVE: The diagnosis of bipolar disorder in juveniles is controversial. This study was designed to compare proton magnetic resonance spectroscopy ((1)H MRS) in patients with bipolar disorder or intermittent explosive disorder, two groups with symptomatic overlap but categorical distinction. Children with intermittent explosive disorder designate patients whose illness clinically resembles pediatric bipolar disorder but does not satisfy DSM-IV criteria for mania. Based on the authors' previous report of higher levels of (1)H MRS cingulate myo-inositol/creatine in youngsters with bipolar disorder than in normal comparison subjects, they hypothesized that patients with bipolar disorder would have higher cingulate myo-inositol/creatine-phosphocreatine measurements than patients with intermittent explosive disorder and normal comparison subjects. METHOD: Myo-inositol levels were measured with a 2x2x2 cm(3) voxel placed in the anterior cingulate for acquisition of (1)H MRS in 10 patients with bipolar disorder, 10 patients with intermittent explosive disorder, and 13 normal comparison subjects. N-Acetylaspartate, choline moieties, creatine-phosphocreatine, and glutamate-glutamine metabolite levels were also measured. RESULTS: The patients with bipolar disorder showed significantly higher anterior cingulate myo-inositol/creatine-phosphocreatine and myo-inositol (mmol/liter) levels than the patients with intermittent explosive disorder and the normal comparison subjects. No significant differences were found across groups for myo-inositol or other metabolites in the occipital cortex. CONCLUSIONS: These data provide evidence that differences in the concentration of myo-inositol (mmol/liter) in the anterior cingulate cortex in (1)H MRS may differentiate these two populations. Follow-up studies involving larger samples may conclusively estimate the biological specificity between pediatric bipolar disorder and other disorders, which overlap clinically. [Abstract]

Davanzo P, Thomas MA, Yue K, Oshiro T, Belin T, Strober M, McCracken J.
Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder.
Neuropsychopharmacology. 2001 Apr;24(4):359-69.
"This project was designed to compare differences in brain proton spectra between children and adolescents with bipolar disorder (BPD) and gender and age-matched normal controls, and to measure changes in myo-inositol levels following lithium therapy, utilizing in vivo proton magnetic resonance spectroscopy (1H MRS). A single voxel (2x2x2 cm3) was placed in brain anterior cingulate cortex for acquisition of the 1H spectra at baseline and after acute (7 days) lithium administration in 11 children (mean age 11.4 years) diagnosed with BPD, and in 11 normal controls. Acute lithium treatment was associated with a significant reduction in the myo-inositol/creatine ratio. This decrement was also significant in lithium-responders when analyzed separate from non-responders. Compared to normal controls, BPD subjects showed a trend towards a higher myo-inositol/creatine during the manic phase. These preliminary data provide evidence that a significant reduction in anterior cingulate myo-inositol magnetic resonance may occur after lithium treatment, especially among responders. Follow-up studies involving a larger sample may allow us to confirm whether changes in myo-inositol associated with acute lithium therapy persist in long-term clinical response of patients with and without lithium compliance." [Abstract]

Thomas AJ, Davis S, Ferrier IN, Kalaria RN, O'Brien JT
Elevation of cell adhesion molecule immunoreactivity in the anterior cingulate cortex in bipolar disorder.
Biol Psychiatry. 2004 Mar 15;55(6):652-5.
BACKGROUND: Neuroimaging reports of increases in signal hyperintensities in white and deep gray matter and other work indicate that there might be an inflammatory response in affective disorders. METHODS: The microvascular immunoreactivity of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 was measured with image analysis in postmortem tissue from the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) from 15 unipolar and 15 bipolar subjects and compared with each other and with 15 subjects with schizophrenia and 15 control subjects. RESULTS: Intercellular adhesion molecule-1 immunoreactivity in gray and white matter of the ACC in bipolar subjects was increased compared with control subjects (gray: p =.001; white: p <.001) and schizophrenic subjects (gray: p =.016; white: p =.025) and modestly increased in white matter compared with unipolar subjects (p =.049). No such differences were found in the DLPFC. CONCLUSIONS: These findings are consistent with the presence of an inflammatory response in the ACC in bipolar disorder. [Abstract]

Woo TU, Walsh JP, Benes FM
Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder.
Arch Gen Psychiatry. 2004 Jul;61(7):649-57.
BACKGROUND: Disturbances of gamma-aminobutyric acid interneurons in the cerebral cortex contribute to the pathophysiology of schizophrenia and bipolar disorder. The activity of these neurons is, in turn, modulated by glutamatergic inputs furnished by pyramidal neurons. OBJECTIVE: To test the hypothesis that glutamatergic inputs onto gamma-aminobutyric acid interneurons via the N-methyl-d-aspartate (NMDA) receptor are altered in the anterior cingulate cortex in schizophrenia and bipolar disorder. DESIGN: A double in situ hybridization technique was used to simultaneously label the messenger RNA (mRNA) for the NMDA NR(2A) subunit with (35)sulfur and the mRNA for the 67-kDa isoform of the gamma-aminobutyric acid synthesizing enzyme glutamic acid decarboxylase (GAD(67)) with digoxigenin. SETTING: Postmortem human brain studies. PARTICIPANTS: We studied 17 subjects with schizophrenia, 17 subjects with bipolar disorder, and 17 normal control subjects. RESULTS: The density of all GAD(67) mRNA-containing neurons was decreased by 53% and 28%, in layers 2 and 5, respectively, in subjects with schizophrenia, whereas in subjects with bipolar disorder there was a 35% reduction in layer 2 only. For GAD(67) mRNA-containing neurons that co-expressed NR(2A)mRNA, their numerical density was decreased by 73% and 52%, in layers 2 and 5, respectively, in subjects with schizophrenia and by 60% in layer 2 in those with bipolar disorder. In the schizophrenia group, the density of the GAD(67)mRNA-containing neurons that did not co-express NR(2A)mRNA was also decreased by 42% in layer 2. In both disease groups, the expression level of NR(2A)mRNA in GAD(67) mRNA-containing cells was unaltered. CONCLUSIONS: The density of gamma-aminobutyric acid interneurons that express the NMDA NR(2A)subunit appears to be decreased in schizophrenia and bipolar disorder. Future studies will address whether subpopulations of these neurons may be differentially affected in the 2 conditions. [Abstract]

Eastwood SL, Harrison PJ.
Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins.
Brain Res Bull 2001 Jul 15;55(5):569-78
"There are several reports of ultrastructural and protein changes affecting synapses in the anterior cingulate cortex in schizophrenia. Altered cytoarchitecture has also been described in this region in schizophrenia as well as in mood disorders. In this paper we review the literature and present a new study investigating synaptic abnormalities in the anterior cingulate cortex (area 24) in the Stanley Foundation brain series. We used Western blotting to assess four synaptic proteins: synaptophysin, growth-associated protein-43 (GAP-43), complexin I and complexin II, which inform about somewhat different aspects of the synaptic circuitry. Synaptophysin, complexin II and GAP-43 were reduced in bipolar disorder. The decreases correlated with the duration of illness and tended to be greater in subjects without a family history. Complexin II was also reduced in major depression. Complexin I and the housekeeping protein beta-actin did not differ between groups. None of the proteins changed significantly in schizophrenia. The results indicate the presence of a synaptic pathology in the anterior cingulate cortex in mood disorders, especially bipolar disorder. The abnormalities may contribute to the dysfunction of cingulate neural circuits. The loss of synaptophysin is suggestive of decreased synaptic density whilst the decrease in GAP-43 may denote impaired synaptic plasticity and the reduction of complexin II but not complexin I implies that the alterations particularly affect excitatory connections. The reductions may be progressive." [Abstract]

Katerina Z, Andrew K, Filomena M, Xu-Feng H.
Investigation of m1/m4 muscarinic receptors in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression disorder.
Neuropsychopharmacology. 2004 Mar;29(3):619-25.
Abnormal cholinergic neurotransmission has been suggested to occur in psychiatric illness. Therefore, this study investigated cholinergic muscarinic receptors in the anterior cingulate cortex (ACC) of schizophrenia, bipolar disorder and major depression disorder (n=15 per group). We used quantitative autoradiography to measure [(3)H]pirenzepine binding to M1 and M4 receptors. Brain tissue was obtained from the Stanley Foundation Neuropathology Consortium. [(3)H]pirenzepine binding was higher in superficial laminae (I-II) than in deep laminae (III-VI) of the ACC. There was a significant 24% reduction in the density of [(3)H]pirenzepine in the deep laminae and a significant 19% reduction in the upper laminae of the ACC in the schizophrenia group compared to the control group. There were no differences in [(3)H]pirenzepine binding in any laminae of the ACC in the bipolar or major depression groups compared with the control group, except for a trend towards decreased [(3)H]pirenzepine binding in subjects with major depression relative to control subjects. We also detected a significant effect of suicide on [(3)H]pirenzepine binding in the ACC in subjects who died as a result of suicide relative to those who did not, which was more evident in patients with schizophrenia. A significant effect of the onset of the disease was also observed that was more evident in patients with bipolar disorder. The study provides evidence of decreased muscarinic receptor density in the ACC in schizophrenia but no evidence for significant changes in these receptors in the bipolar and major depression groups. The changes observed in schizophrenia may contribute to dysfunctional ACC neural circuits. [Abstract]

Monkul ES, Yildiz A, C Soares J
[Magnetic Resonance Spectroscopy (MRS) Applications in Bipolar Disorder]
Turk Psikiyatri Derg. 2004 Summer;15(2):138-47.
OBJECTIVE: Magnetic resonance spectroscopy (MRS) is a noninvasive in vivo imaging technique that can directly assess the living biochemistry in localized brain regions without involving ionizing radiation. This review provides a brief description of spectroscopy, followed by a literature review of the key spectroscopy findings in bipolar disorder. METHOD: We conducted a Medline literature review for the period 1966-2003, and included all the controlled studies using MRS in bipolar disorder, as well as other relevant papers with important findings. RESULTS: Studies showed an increase in choline (Cho) levels in basal ganglia and cingulate, and a decrease in dorsolateral prefrontal cortical (DLPFC) and hippocampal N-acetyl aspartate (NAA) levels. Frontal lobe phosphomonoester (PME) levels were decreased in the euthymic state and were higher in the manic and depressive states. Myoinositol (mI) was reduced by lithium treatment and this decrease was positively correlated with treatment response. CONCLUSION: The findings from MRS studies of bipolar disorder demonstrate alterations in the neurochemistry of key brain regions participating in the fronto-limbic-subcortical circuits implicated in the pathophysiology of the disorder. These findings suggest abnormalities of the membrane phospholipid metabolism, cellular energy metabolism and myelin formation /maintenance in the DLPFC, cingulate, hippocampus and basal ganglia in bipolar disorder. Further studies are needed to distinguish between the changes that are due to the pathophysiology of bipolar disorder and those due to the effects of medications. [Abstract]

Rubinsztein JS, Fletcher PC, Rogers RD, Ho LW, Aigbirhio FI, Paykel ES, Robbins TW, Sahakian BJ.
Decision-making in mania: a PET study.
Brain 2001 Dec;124(Pt 12):2550-63or decision-making is often observed clinically in the manic syndrome. In normal volunteers, decision-making has been associated with activation in the ventral prefrontal cortex and the anterior cingulate gyrus. The aim of this study was to evaluate task-related activation in bipolar manic patients in these regions of the prefrontal cortex using PET. Six subjects with mania, 10 controls and six subjects with unipolar depression (an affective patient control group) were scanned using the bolus H(2)(15)O method while they were performing a decision-making task. Activations associated with the decision-making task were observed at two levels of difficulty. Task-related activation was increased in the manic patients compared with the control patients in the left dorsal anterior cingulate [Brodmann area (BA) 32] but decreased in the right frontal polar region (BA 10). In addition, controls showed greater task-related activation in the inferior frontal gyrus (BA 47) than manic patients. A positive correlation (r(s) = 0.88) between task-related activation in the anterior cingulate and increasing severity of manic symptoms was found. Depressed patients did not show significant task-related differences in activation compared with control subjects in the regions of interest. In conclusion, these patterns of activation point to abnormal task-related responses in specific frontal regions in manic patients." [Abstract]

Kruger S, Seminowicz D, Goldapple K, Kennedy SH, Mayberg HS.
State and trait influences on mood regulation in bipolar disorder: blood flow differences with an acute mood challenge.
Biol Psychiatry. 2003 Dec 1;54(11):1274-83.
BACKGROUND: Even in remission, patients with bipolar disorder (BD) remain sensitive to external stressors that can trigger new episodes. Imitating such stressors by the controlled transient exposure to an emotional stimulus may help to identify brain regions modulating this sensitivity. METHODS: Transient sadness was induced in 9 euthymic and in 11 depressed subjects with BD. Regional blood flow (rCBF) changes were measured using (15)O-water positron emission tomography. RESULTS: Common changes in both groups were increased rCBF in anterior insula and cerebellum and decreased rCBF in dorsal-ventral-medial frontal cortex, posterior cingulate, inferior parietal, and temporal cortices. Decreases in dorsal ventral medial frontal cortices occurred in both groups, but subjects in remission showed a greater magnitude of change. Unique to remitted subjects with BD were rCBF increases in dorsal anterior cingulate and in premotor cortex. Lateral prefrontal rCBF decreases were unique to depressed subjects with BD. At baseline, remitted subjects showed a unique increase in dorsal anterior cingulate and orbitofrontal cortex. CONCLUSIONS: Common rCBF changes in remitted and depressed subjects identifies potential sites of disease vulnerability. Unique cingulate and orbitofrontal changes both at baseline and with induced sadness seen in the absence of prefrontal rCBF decreases may identify regional interactions important to the euthymic state in this population. [Abstract]

Bench CJ, Frackowiak RS, Dolan RJ.
Changes in regional cerebral blood flow on recovery from depression.
Psychol Med 1995 Mar;25(2):247-61
"We have previously described focal abnormalities of regional cerebral blood flow (rCBF) in the left dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex and angular gyrus in 40 patients with major depression. We now report on the patterns of change in rCBF in a subgroup of 25 of the same patients who were rescanned following clinical remission of depression. Fifteen patients were scanned when optimally matched for drug treatment (4) or drug free on both occasions (11). The other 10 patients were fully recovered but could not be matched for drug status for clinical and ethical reasons. In a paired comparison of the same patients when ill and following recovery it was evident that remission was associated with a significant increase in rCBF in the left DLPFC and medial prefrontal cortex including anterior cingulate. Increases in rCBF in the angular gyrus were not seen when the comparison of depressed and recovered scans was matched for medication. The previously described relationship between clinical symptoms and brain perfusion in the depressed state was no longer present in the recovered state; this supports the hypothesis of state relatedness. Thus, recovery from depression is associated with increases in rCBF in the same areas in which focal decreases in rCBF are described in the depressed state in comparison with normal controls." [Abstract] [This study was not bipolar disorder specific, but it included "bipolar disorder" as a search term.]

Osuch EA, Ketter TA, Kimbrell TA, George MS, Benson BE, Willis MW, Herscovitch P, Post RM.
Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients.
Biol Psychiatry 2000 Nov 15;48(10):1020-3
"BACKGROUND: We studied the relationship between regional cerebral metabolism and the severity of anxiety in mood disorder patients, controlling for depression severity. METHODS: Fifty-two medication-free patients with unipolar or bipolar illness underwent positron emission tomography with [(18)F]-fluorodeoxyglucose. Hamilton Depression Rating Scale and Spielberger Anxiety-State Scale scores were obtained for the week of the scan. Analyses were performed on globally normalized images and were corrected for multiple comparisons. RESULTS: After covarying for depression scores, age, and gender, Spielberger Anxiety-State Scale scores correlated directly with regional cerebral metabolism in the right parahippocampal and left anterior cingulate regions, and inversely with metabolism in the cerebellum, left fusiform, left superior temporal, left angular gyrus, and left insula. In contrast, covarying for anxiety scores, age, and gender, Hamilton Depression Rating Scale scores correlated directly with regional cerebral metabolism in the bilateral medial frontal, right anterior cingulate, and right dorsolateral prefrontal cortices. CONCLUSIONS: Comorbid anxiety symptoms are associated with specific cerebral metabolic correlates that partially overlap with those in the primary anxiety disorders and differ from those associated with depression severity." [Abstract]

Chang K, Adleman NE, Dienes K, Simeonova DI, Menon V, Reiss A
Anomalous prefrontal-subcortical activation in familial pediatric bipolar disorder: a functional magnetic resonance imaging investigation.
Arch Gen Psychiatry. 2004 Aug;61(8):781-92.
BACKGROUND: The neurobiological features of pediatric bipolar disorder (BD) are largely unknown. Children and adolescents with BD may be important to study with functional neuroimaging techniques because of their unique status of early-onset BD and high familial loading for the disorder. Neuroimaging studies of adults with BD have implicated the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in the development of this disorder. OBJECTIVES: To study children and adolescents with BD via functional magnetic resonance imaging using cognitive and affective tasks and to examine possible abnormalities in the DLPFC and ACC, as well as selected subcortical areas, in pediatric familial BD. DESIGN: We evaluated 12 male subjects aged 9 to 18 years with BD who had at least 1 parent with BD as well as 10 age- and IQ-matched healthy male controls. Stimulants were discontinued for at least 24 hours; other medications were continued. Subjects underwent functional magnetic resonance imaging at 3 T while performing a 2-back visuospatial working memory task and an affective task involving the visualization of positively, neutrally, or negatively valenced pictures. SETTING: An academic referral setting, drawing from the Bay Area of San Francisco, Calif. RESULTS: Compared with controls, for the visuospatial working memory task, subjects with BD had greater activation in several areas including the bilateral ACC, left putamen, left thalamus, left DLPFC, and right inferior frontal gyrus. Controls had greater activation in the cerebellar vermis. In viewing negatively valenced pictures, subjects with BD had greater activation in the bilateral DLPFC, inferior frontal gyrus, and right insula. Controls had greater activation in the right posterior cingulate gyrus. For positively valenced pictures, subjects with BD had greater activation in the bilateral caudate and thalamus, left middle/superior frontal gyrus, and left ACC, whereas controls had no areas of greater activation. CONCLUSIONS: Children and adolescents with BD may have underlying abnormalities in the regulation of prefrontal-subcortical circuits. Further functional magnetic resonance imaging studies of attention and mood with greater sample sizes are needed. [Abstract]

Chana G, Landau S, Beasley C, Everall IP, Cotter D.
Two-dimensional assessment of cytoarchitecture in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size and increased neuronal density.
Biol Psychiatry. 2003 Jun 15;53(12):1086-98.
"BACKGROUND: Abnormalities of cortical neuronal organization and reductions in neuronal somal size have been reported in schizophrenia. The purpose of this investigation was to assess patterns of neuronal and glial distribution in the anterior cingulate cortex (ACC) in major depressive disorder (MDD), schizophrenia, bipolar disorder (BPD), and normal control subjects (15 subjects per group). METHODS: Estimates for neuronal somal and glial nuclear size and density were obtained. We employed two-dimensional morphometric analysis to examine the location of neurons and glia in a 1000-microm-wide strip of cortex. RESULTS: A decreased clustering of neurons was seen in BPD (p =.001). No other group differences were observed in the clustering of neurons, glia, or of neurons about glia. Neuronal somal size was reduced in layer 5 in schizophrenia (18%, p =.001), BPD (16%, p <.001), and MDD (9%, p =.01). Neuronal density was increased in layer 6 in BPD (63%, p =.004) and schizophrenia (61%, p =.006) and in layer 5 in MDD (24%, p =.018) and schizophrenia (33%, p =.003). CONCLUSIONS: The results of this study indicate that reduced neuronal somal size and increased neuronal density in cortical layers 5 and 6 of the ACC may be key features of schizophrenia, MDD, and BPD." [Abstract]

Cotter D, Mackay D, Landau S, Kerwin R, Everall I.
Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder.
Arch Gen Psychiatry 2001 Jun;58(6):545-53
"BACKGROUND: Glial cells are more numerous than neurons in the cortex and are crucial to neuronal function. There is evidence for reduced neuronal size in schizophrenia, with suggestive evidence for reduced glial cell density in mood disorders. In this investigation, we have simultaneously assessed glial cell density and neuronal density and size in the anterior cingulate cortex in schizophrenia, major depressive disorder, and bipolar disorder. METHODS: We examined tissue from area 24b of the supracallosal anterior cingulate cortex in 60 postmortem brain specimens from 4 groups of 15 subjects, as follows: major depressive disorder, schizophrenia, bipolar disorder, and normal controls. Glial cell density and neuronal size and density were examined in all subjects using the nucleator and the optical disector. RESULTS: Glial cell density (22%) (P =.004) and neuronal size (23%) (P =.01) were reduced in layer 6 in major depressive disorder compared with controls. There was some evidence for reduced glial density in layer 6 (20%) (P =.02) in schizophrenia compared with controls, before adjusting for multiple layerwise comparisons, but there were no significant changes in neuronal size. There was no evidence for differences in glial density or neuronal size in bipolar disorder compared with controls. Neuronal density was similar in all groups to that found in controls. CONCLUSION: These findings suggest that there is reduced frontal cortical glial cell density and neuronal size in major depressive disorder." [Abstract]

Benes FM, Vincent SL, Todtenkopf M.
The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects.
Biol Psychiatry 2001 Sep 15;50(6):395-406
"BACKGROUND: A recent study reported a decreased density of nonpyramidal neurons (NPs) in layer II of the anterior cingulate (ACCx) and prefrontal (PFCx) cortices of schizophrenic brain that was most pronounced in schizoaffective subjects. Our study assessed whether a decrease of NPs in ACCx may show a stronger covariation with affective disorder. A cohort consisting of 12 normal control (CONs), 11 schizophrenic, and 10 bipolar subjects matched for age and postmortem interval (PMI) has been analyzed. METHODS: A two-dimensional technique was employed for counting cells in a large x,y sampling column that extended across layers I through VI of ACCx. RESULTS: There was a 27% reduction in the density of NPs in layer II of the bipolar group, whereas in the schizophrenic group, this density was 16.2% lower. There were no differences in NPs in layers III through VI of either the schizophrenic or bipolar group. Both groups also showed modest decreases of PNs in the deeper laminae; however, these differences were only significant in layer IV of the schizophrenic subjects. The density of glial cells was similar across the control, schizophrenic, and bipolar groups. An Abercrombie correction for cell size did not alter the nature of the results. Subjects both with and without neuroleptic exposure showed a lower density of NPs in layer II of bipolar subjects or PNS in deeper laminae of schizophrenic subjects. CONCLUSIONS: Overall, the findings reported here suggest that local circuit cells in layer II of ACCx may be decreased in bipolar disorder, whereas projection neurons in deeper laminae are decreased in schizophrenia." [Abstract]

Lochhead RA, Parsey RV, Oquendo MA, Mann JJ
Regional brain gray matter volume differences in patients with bipolar disorder as assessed by optimized voxel-based morphometry.
Biol Psychiatry. 2004 Jun 15;55(12):1154-62.
BACKGROUND: Structural magnetic resonance imaging (MRI) studies of regions of interest in brain have been inconsistent in demonstrating volumetric differences in subjects with bipolar disorder (BD). Voxel-based morphometry (VBM) provides an unbiased survey of the brain, can identify novel brain areas, and validates previously hypothesized regions. We conducted both optimized VBM, comparing MRI gray matter volume, and traditional VBM, comparing MRI gray matter density, in 11 BD subjects and 31 healthy volunteers. To our knowledge, these are the first VBM analyses of BD. METHODS: Segmented MRI gray matter images were normalized into standardized stereotactic space, modulated to allow volumetric analysis (optimized only), smoothed, and compared at the voxel level with statistical parametric mapping. RESULTS: Optimized VBM showed that BD subjects had smaller volume in left ventromedial temporal cortex and bilateral cingulate cortex and larger volume in left insular/frontoparietal operculum cortex and left ventral occipitotemporal cortex. Traditional VBM showed that BD subjects had less gray matter density in left ventromedial temporal cortex and greater gray matter density in left insular/frontoparietal operculum cortex and bilateral thalamic cortex. Exploratory analyses suggest that these abnormalities might differ according to gender. CONCLUSIONS: Bipolar disorder is associated with volumetric and gray matter density changes that involve brain regions hypothesized to influence mood. [Abstract]

Lyoo IK, Kim MJ, Stoll AL, Demopulos CM, Parow AM, Dager SR, Friedman SD, Dunner DL, Renshaw PF
Frontal lobe gray matter density decreases in bipolar I disorder.
Biol Psychiatry. 2004 Mar 15;55(6):648-51.
BACKGROUND: This study was conducted to explore differences in gray and white matter density between bipolar and healthy comparison groups using voxel-based morphometry (VBM). METHODS: Brain magnetic resonance imaging was performed for 39 subjects with bipolar I disorder and 43 comparison subjects. Images were registered into a proportional stereotaxic space and segmented into gray matter, white mater, and cerebrospinal fluid. Statistical parametric mapping was used to calculate differences in gray and white matter density between groups. RESULTS: Bipolar subjects had decreased gray matter density in left anterior cingulate gyrus (Brodmann's area [BA] 32, 7.3% decrease), an adjacent left medial frontal gyrus (BA 10, 6.9% decrease), right inferior frontal gyrus (BA 47, 9.2% decrease), and right precentral gyrus (BA 44, 6.2% decrease), relative to comparison subjects. CONCLUSIONS: The observation of a gray matter density decrease in the left anterior cingulate, which processes emotions, in bipolar subjects is consistent with prior reports that used region-of-interest analytic methods. Decreased gray matter density in the right inferior frontal gyrus, which processes nonverbal and intrinsic functions, supports nondominant hemisphere dysfunction as a component of bipolar disorder. [Abstract]

Wilke M, Kowatch RA, DelBello MP, Mills NP, Holland SK
Voxel-based morphometry in adolescents with bipolar disorder: first results.
Psychiatry Res. 2004 May 30;131(1):57-69.
Bipolar disorder is an increasingly recognized cause of significant morbidity in the pediatric age group. However, there is still a large degree of uncertainty regarding the underlying neurobiological deficits. In this preliminary study, we performed automated volumetric studies and whole-brain voxel-based morphometry (VBM) on gray matter. Imaging data from 10 adolescents with bipolar disorder were compared with data from 52 age- and gender-matched healthy controls. Previously defined brain parcellations and optimized VBM protocols were used, based on custom-made pediatric reference data. An additional, exploratory whole-brain comparison was also implemented. The volumetric region-of-interest study revealed significantly greater gray matter volume in central gray matter structures bilaterally (including the basal ganglia and the thalamus) and the left temporal lobe in the bipolar group. VBM confirmed bilaterally larger basal ganglia. Localized gray matter deficits in bipolar subjects were found in the medial temporal lobe, orbito-frontal cortex, and the anterior cingulate, confirming and extending earlier studies. [Abstract]

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Recent Anterior Cingulate in Bipolar Disorder Research

1) Chang WC, Lee CM, Shyu BC
Temporal and spatial dynamics of thalamus-evoked activity in the anterior cingulate cortex.
Neuroscience. 2012 Jul 16;
In the present study, multielectrode array (MEA) recording was used to illustrate the spatial-temporal progression of anterior cingulate cortex (ACC) activity following stimulation of the thalamus in a thalamocingulate pathway-preserved slice. The MEA was placed under the slice that contained the ACC, and 60 channels of extracellular local field potentials evoked by bipolar electrical stimulation within the thalamus were analyzed. Several distinct thalamic-evoked responses were identified. The early negative component (N1; amplitude, -35.7 5.9 ?V) emerged in layer VI near the cingulum 8.4 0.5 ms after stimulation. N1 progressed upward to layers V and II/III in a lateral-to-medial direction. Subsequently, a positive component (P; amplitude, 27.0 3.2 ?V) appeared 12.0 0.6 ms after stimulation in layer VI. At 26.8 1.1 ms, a second negative component (N2; amplitude, -20.9 2.7 ?V) became apparent in layers II/III and V, followed by a more ventrolateral component (N3; amplitude, -18.9 2.9 ?V) at 42.8 2.6 ms. These two late components spread downward to layer VI in a medial-to-lateral direction. The trajectory paths of the evoked components were consistently represented with varied medial thalamic stimulation intensities and sites. Both AMPA/kainate and N-methyl-D-aspartate-type glutamate receptors involved in monosynaptic and polysynaptic transmission participated in this thalamocortical pathway. Morphine mainly diminished the two negative synaptic components, and this suppressive effect was reversed by naloxone. The present study confirmed that functional thalamocingulate activity was preserved in the brain-slice preparation. The thalamus-evoked responses were activated and progressed along a deep surface-deep trajectory loop across the ACC layers. Glutamatergic neurotransmitters were crucially involved in information processing. Opioid interneurons may play a modulatory role in regulating the signal flows in the cingulate cortex. [PubMed Citation] [Order full text from Infotrieve]

2) Wegbreit E, Pavuluri M
Mechanistic Comparisons of Functional Domains across Pediatric and Adult Bipolar Disorder Highlight Similarities, As Well As Differences, Influenced by the Developing Brain.
Isr J Psychiatry Relat Sci. 2012;49(2):75-83.
Recent neuroimaging studies have uncovered much about the specific neural deficits in adult bipolar disorder (ABD), but despite promising results, neuroimaging research for pediatric bipolar disorder (PBD) is still developing. The neuroimaging literature is highly heterogeneous, varying in the paradigms used and in participants' mood states and medication status. Despite this variability, several dominant patterns emerge. In response to emotional stimuli, both ABD and PBD show limbic hyperactivity coupled with hypoactivity in ventral prefrontal emotion regulation systems. This pattern occurred most robustly in response to negative incidental stimuli and was especially apparent in manic PBD. ABD showed more variability in ventral prefrontal activity, possibly due to maturational and medication factors. On numerous cognitive paradigms, PBD showed dorsal prefrontal hypoactivity linked to ventral dysfunction, whereas ABD showed compensatory frontal, parietal, and temporal activity with paradigm-specific variations. In emotion-cognition interaction paradigms, patients show dysregulation in regions interfacing between cognitive and emotional brain systems (e.g., ventral prefrontal and cingulate cortices), which expend extra effort to process emotional stimuli effectively and recruit additional posterior attention systems to cope with affective instability. In addition, novel functional connectivity techniques have uncovered connectivity deficits between frontal and limbic regions in ABD and PBD at rest and during active emotional and cognitive tasks. Finally, the neuroimaging literature currently lacks cross-sectional studies comparing PBD with ABD and longitudinal studies following children and adolescents with BD into adulthood. Such studies would provide important insights into patients' prognosis and would determine targets for early interventions in the evolving illness diathesis. [PubMed Citation] [Order full text from Infotrieve]

3) 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]

4) Williams MR, Hampton T, Pearce RK, Hirsch SR, Ansorge O, Thom M, Maier M
Astrocyte decrease in the subgenual cingulate and callosal genu in schizophrenia.
Eur Arch Psychiatry Clin Neurosci. 2012 Jun 4;
Decreases in glial cell density and in GFAP mRNA in the anterior cingulate cortex have been reported in schizophrenia, bipolar disorder and major depressive disorder. Our study examines astrocyte and oligodendrocyte density in the white and grey matter of the subgenual cingulate cortex, and at the midline of the genu of the corpus callosum, in schizophrenia, bipolar disorder, depression and normal control cases. Serial coronal sections were stained with H and E for anatomical guidance, cresyl haematoxylin for oligodendrocyte identification and GFAP immunohistochemistry for astrocyte identification. Oligodendrocyte and astrocyte density was measured using systematic anatomical distinctions and randomised counting methods. A significant decrease in astrocyte density was observed in schizophrenia compared with normal controls in the cingulate grey matter, cingulate white matter and the midline of the corpus callosum (p=0.025). Bipolar disorder and depression cases showed no significant changes in astrocyte density. Oligodendrocytes did not show any changes between diagnostic groups. In subgenual cingulate cortex, the ratio of oligodendrocytes to astrocytes was decreased between the controls and the three disease groups, suggesting a specific glial cell type specific change in schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

5) Strawn JR, Patel NC, Chu WJ, Lee JH, Adler CM, Kim MJ, Bryan HS, Alfieri DC, Welge JA, Blom TJ, Nandagopal JJ, Strakowski SM, DelBello MP
Glutamatergic effects of divalproex in adolescents with mania: a proton magnetic resonance spectroscopy study.
J Am Acad Child Adolesc Psychiatry. 2012 Jun;51(6):642-51.
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6) Ibanez A, Cetkovich M, Petroni A, Urquina H, Baez S, Gonzalez-Gadea ML, Kamienkowski JE, Torralva T, Torrente F, Strejilevich S, Teitelbaum J, Hurtado E, Guex R, Melloni M, Lischinsky A, Sigman M, Manes F
The neural basis of decision-making and reward processing in adults with euthymic bipolar disorder or attention-deficit/hyperactivity disorder (ADHD).
PLoS One. 2012;7(5):e37306.
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7) Williams MR, Chaudhry R, Perera S, Pearce RK, Hirsch SR, Ansorge O, Thom M, Maier M
Changes in cortical thickness in the frontal lobes in schizophrenia are a result of thinning of pyramidal cell layers.
Eur Arch Psychiatry Clin Neurosci. 2012 May 19;
Decreased cortical thickness and reduced activity as measured by fMRI in the grey matter of the subgenual cingulate cortex have been reported in schizophrenia and bipolar disorder, and cortical grey matter loss has been reliably reported in the frontal and temporal lobes in schizophrenia. The aim of this study was to examine the thickness of each of the six cortical layers in the subgenual cingulate cortex, five frontal lobe and four temporal lobe gyri. We examined two separate cohorts. Cohort 1 examines the subgenual cingulate cortex (SCC) in schizophrenia (n=10), bipolar disorder (n=15) and major depressive disorder (n=20) against control subjects (n=19). Cohort two examines frontal and temporal gyri in schizophrenia (n=16), major depressive disorder (n=6) against matched controls (n=32). The cohorts were selected with identical clinical criteria, but underwent different tissue processing to contrast the effect of chemical treatment on tissue shrinkage. Measurements of layer I-VI thickness were taken from cresyl-violet- and haematoxylin-stained sections in cohort one and from cresyl-violet- and H&E-stained sections in cohort two. SCC cortical thickness decreased in male subjects with bipolar disorder (p=0.048), and male schizophrenia cases showed a specific decrease in the absolute thickness of layer V (p=0.003). Compared to controls, the relative thickness of layer V in the crown of the SCC decreased in schizophrenia (p<0.001). A significant decrease in total cortical thickness was observed across the frontal lobe in schizophrenia (p<0.0001), with specific pyramidal layer thinning in layers III (p=0.0001) and V (p=0.005). There was no effect of lateralization. No changes were noted in temporal lobe cortical thickness. This study demonstrates diminished pyramidal layer thickness resulting in decreased frontal lobe thickness in schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

8) Weathers JD, Stringaris A, Deveney CM, Brotman MA, Zarate CA, Connolly ME, Fromm SJ, Lebourdais SB, Pine DS, Leibenluft E
A developmental study of the neural circuitry mediating motor inhibition in bipolar disorder.
Am J Psychiatry. 2012 Jun 1;169(6):633-41.
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9) Gos T, Steiner J, Bielau H, Dobrowolny H, Gnther K, Mawrin C, Krzyżanowski M, Hauser R, Brisch R, Bernstein HG, Jankowski Z, Braun K, Bogerts B
Differences between unipolar and bipolar I depression in the quantitative analysis of glutamic acid decarboxylase-immunoreactive neuropil.
Eur Arch Psychiatry Clin Neurosci. 2012 Apr 13;
Alterations in GABAergic neurotransmission are assumed to play a crucial role in the pathophysiology of mood disorders. Glutamic acid decarboxylase (GAD) is the key enzyme in GABA synthesis. This study aimed to differentiate between unipolar and bipolar I depression using quantitative evaluation of GAD-immunoreactive (GAD-ir) neuropil in several brain regions known to be involved in the pathophysiology of mood disorders. Immunohistochemical staining of GAD 65/67 was performed in the orbitofrontal, anterior cingulate and dorsolateral prefrontal cortex (DLPFC), the entorhinal cortex, the hippocampal formation and the medial dorsal and lateral dorsal (LD) thalamic nuclei, with a quantitative densitometric analysis of GAD-ir neuropil. The study was performed on paraffin-embedded brains from 9 unipolar and 12 bipolar I depressed patients (8 and 6 suicidal patients, respectively) and 18 matched controls. In unipolar patients, compared with controls, only the increased relative density of GAD-ir neuropil in the right LD was different from the previous results in depressed suicides from the same cohort (Gos et al. in J Affect Disord 113:45-55, 2009). On the other hand, the left DLPFC was the only area where a significant decrease was observed, specific for bipolar I depression. Significant differences between both diagnostic groups were found in these regions. By revealing abnormalities in the relative density of GAD-ir neuropil in brain structures, our study suggests a diathesis of the GABAergic system in mood disorders, which may differentiate the pathophysiology of unipolar from that of bipolar I depression. [PubMed Citation] [Order full text from Infotrieve]

10) Liu J, Blond BN, van Dyck LI, Spencer L, Wang F, Blumberg HP
Trait and state corticostriatal dysfunction in bipolar disorder during emotional face processing.
Bipolar Disord. 2012 Jun;14(4):432-41.
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11) 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]

12) Nikolaus S, Hautzel H, Heinzel A, Mller HW
Key players in major and bipolar depression--a retrospective analysis of in vivo imaging studies.
Behav Brain Res. 2012 Jul 1;232(2):358-90.
In the present study, we evaluated the contribution of the individual synaptic constituents of all assessed neurotransmitter systems by subjecting all available in vivo imaging studies on patients with unipolar major depressive disorder (MDD) and bipolar depression (BD) to a retrospective analysis. In acute MDD, findings revealed significant increases of prefrontal and frontal DA synthesis, decreases of thalamic and midbrain SERT, increases of insular SERT, decreases of midbrain 5-HT(1A) receptors and decreases of prefrontal, frontal, occipital and cingulate 5-HT(2A) receptors, whereas, in remission, decreases of striatal D? receptors, midbrain SERT, frontal, parietal, temporal, occipital and cingulate 5-HT(1A) receptors and parietal 5-HT(2A) receptors were observed. In BD, findings indicated a trend towards increased striatal D? receptors in depression and mania, decreased striatal DA synthesis in remission and decreased frontal D? receptors in all three conditions. Additionally, there is some evidence that ventrostriatal and hippocampal SERT may be decreased in depression, whereas in remission and mania elevations of thalamic and midbrain SERT, respectively, were observed. Moreover, in depression, limbic 5-HT(1A) receptors were elevated, whereas in mania a decrease of both cortical and limbic 5-HT(2A) receptor binding was observed. Furthermore, in depression, prefrontal, frontal, occipital and cingulate M2 receptor binding was found to be reduced. From this, a complex pattern of dysregulations within and between neurotransmitter systems may be derived, which is likely to be causally linked not only with the subtype and duration of disease but also with the predominance of individual symptoms and with the kind and duration of pharmacological treatment(s). [PubMed Citation] [Order full text from Infotrieve]

13) Pauli A, Prata DP, Mechelli A, Picchioni M, Fu CH, Chaddock CA, Kane F, Kalidindi S, McDonald C, Kravariti E, Toulopoulou T, Bramon E, Walshe M, Ehlert N, Georgiades A, Murray R, Collier DA, McGuire P
Interaction between effects of genes coding for dopamine and glutamate transmission on striatal and parahippocampal function.
Hum Brain Mapp. 2012 Mar 22;
The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation. Hum Brain Mapp, 2012. 2012 Wiley Periodicals, Inc. [PubMed Citation] [Order full text from Infotrieve]

14) Howells FM, Ives-Deliperi VL, Horn NR, Stein DJ
Mindfulness based cognitive therapy improves frontal control in bipolar disorder: a pilot EEG study.
BMC Psychiatry. 2012;12:15.
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15) Frangou S
Brain structural and functional correlates of resilience to Bipolar Disorder.
Front Hum Neurosci. 2011 Dec 6;5:184.
Background: Resilient adaptation can be construed in different ways, but as used here it refers to adaptive brain responses associated with avoidance of psychopathology despite expressed genetic predisposition to Bipolar Disorder (BD). Although family history of BD is associated with elevated risk of affective morbidity a significant proportion of first-degree relatives remain free of psychopathology. Examination of brain structure and function in these individuals may inform on adaptive responses that pre-empt disease expression. Methods: Data presented here are derived from the Vulnerability to Bipolar Disorders Study (VIBES) which includes BD patients, asymptomatic relatives and controls. Participants underwent extensive investigations including brain structural (sMRI) and functional magnetic resonance imaging (fMRI). We present results from sMRI voxel-based-morphometry and from conventional and connectivity analyses of fMRI data obtained during the Stroop Colour Word Test (SCWT), a task of cognitive control during conflict resolution. All analyses were implemented using Statistical Parametric Mapping software version 5 (SPM5). Resilience in relatives was operationalized as the lifetime absence of clinical-range symptoms. Results: Resilient relatives of BD patients expressed structural, functional, and connectivity changes reflecting the effect of genetic risk on the brain. These included increased insular volume, decreased activation within the posterior and inferior parietal regions involved in selective attention during the SCWT, and reduced fronto-insular and fronto-cingulate connectivity. Resilience was associated with increased cerebellar vermal volume and enhanced functional coupling between the dorsal and the ventral prefrontal cortex during the SCWT. Conclusions: Our findings suggests the presence of biological mechanisms associated with resilient adaptation of brain networks and pave the way for the identification of outcome-specific trajectories given a bipolar genotype. [PubMed Citation] [Order full text from Infotrieve]

16) Sinka L, Kovari E, Santos M, Herrmann FR, Gold G, Hof PR, Bouras C, Giannakopoulos P
Microvascular changes in late-life schizophrenia and mood disorders: stereological assessment of capillary diameters in anterior cingulate cortex.
Neuropathol Appl Neurobiol. 2012 Feb 23;
Aims:? Previous neuroimaging reports described morphological and functional abnormalities in anterior cingulate cortex (ACC) in schizophrenia and mood disorders. In earlier neuropathological studies, microvascular changes that could affect brain perfusion in these disorders have rarely been studied. Here, we analyzed morphological parameters of capillaries in this area in elderly cases affected by these psychiatric disorders. Methods:? We analyzed microvessel diameters in the dorsal and subgenual parts of the anterior cingulate cortex in 8 patients with schizophrenia, 10 patients with sporadic bipolar disorder, 8 patients with sporadic major depression, and 7 age- and gender-matched control cases on sections stained with modified Gallyas silver impregnation using a stereological counting approach. All individuals were drug-nave or had received psychotropic medication for less than 6 months, and had no history of substance abuse. Statistical analysis included Kruskal- Wallis group comparisons with Bonferroni correction as well as multivariate regression models. Results:? Mean capillary diameter was significantly decreased in the dorsal and subgenual parts of areas 24 in bipolar and unipolar depression cases, both in layers III and V, whereas schizophrenia patients were comparable to controls. These differences persisted when controlling for age, local neuronal densities, and cortical thickness. In addition, cortical thickness was significantly smaller in both layers in schizophrenia patients. Conclusions:? Our findings indicate that capillary diameters in bipolar and unipolar depression but not in schizophrenia are reduced in ACC. The significance of these findings are discussed in the light of the cytoarchitecture, brain metabolism and perfusion changes observed in ACC in mood disorders. 2012 The Authors. Neuropathology and Applied Neurobiology 2012 British Neuropathological Society. [PubMed Citation] [Order full text from Infotrieve]

17) Zhao J, Bao AM, Qi XR, Kamphuis W, Luchetti S, Lou JS, Swaab DF
Gene expression of GABA and glutamate pathway markers in the prefrontal cortex of non-suicidal elderly depressed patients.
J Affect Disord. 2012 May;138(3):494-502.
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18) Kumar N, Chadda RK
Augmentation effect of repetitive transcranial magnetic stimulation over the supplementary motor cortex in treatment refractory patients with obsessive compulsive disorder.
Indian J Psychiatry. 2011 Oct;53(4):340-2.
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19) Cauda F, Torta DM, Sacco K, D'Agata F, Geda E, Duca S, Geminiani G, Vercelli A
Functional anatomy of cortical areas characterized by Von Economo neurons.
Brain Struct Funct. 2012 Jan 29;
Von Economo's neurons (VENs) are large, bipolar or corkscrew-shaped neurons located in layers III and V of the frontoinsular and the anterior cingulate cortices. VENs are reported to be altered in pathologies such as frontotemporal dementia and autism, in which the individual's self control is seriously compromised. To investigate the role of VENs in the active human brain, we have explored the functional connectivity of brain areas containing VENs by analyzing resting state functional connectivity (rsFC) in 20 healthy volunteers. Our results show that cortical areas containing VENs form a network of frontoparietal functional connectivity. With the use of fuzzy clustering techniques, we find that this network comprises four sub-networks: the first network cluster resembles a "saliency detection" attentional network, which includes superior frontal cortex (Brodmann's Area, BA 10), inferior parietal lobe, anterior insula, and dorsal anterior cingulate cortex; the second cluster, part of a "sensory-motor network", comprises the superior temporal, precentral and postcentral areas; the third cluster consists of frontal ventromedial and ventrodorsal areas constituted by parts of the "anterior default mode network"; and the fourth cluster encompasses dorsal anterior cingulate cortex, dorsomedial prefrontal, and superior frontal (BA 10) areas, resembling the anterior part of the "dorsal attentional network". Thus, the network that emerges from analyzing functional connectivity among areas that are known to contain VENs is primarily involved in functions of saliency detection and self-regulation. In addition, parts of this network constitute sub-networks that partially overlap with the default mode, the sensory-motor and the dorsal attentional networks. [PubMed Citation] [Order full text from Infotrieve]

20) Linke J, King AV, Rietschel M, Strohmaier J, Hennerici M, Gass A, Meyer-Lindenberg A, Wessa M
Increased medial orbitofrontal and amygdala activation: evidence for a systems-level endophenotype of bipolar I disorder.
Am J Psychiatry. 2012 Mar;169(3):316-25.
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