Anterior Cingulate in Bipolar Disorder -- Neurotransmitter.net

(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) Fountoulakis KN, Giannakopoulos P, K�vari E, Bouras C
Assessing the role of cingulate cortex in bipolar disorder: Neuropathological, structural and functional imaging data.
Brain Res Rev. 2008 Apr 12;
Objectives: Most of the neuroanatomical models of bipolar disorder (BD) propose a key role for the anterior cingulate cortex (ACC). We provide here a review of currently available data regarding the CC neuroimaging and neuropathological alterations in BD. Materials and methods: After an exploratory search of the MEDLINE, we first identified all English-written articles that provide separate data for BD patients and report original experimental data on cingulate gyrus. Subsequently, we selected those including neuroimaging or neuropathological data. Among the 161 articles updated through June 2007, 81 articles were retained using this procedure. Results: The review of in vivo volumetric imaging data, as well as ex vivo morphometric and histological studies indicates that BD patients show volume changes of the subgenual ACC (sgACC-BA 25 and part of 24) during the early stages of the disease. Whether this phenomenon is due to neuronal and glial depletion or damage of corticocortical connections is still a matter of debate. The resting state activity in the left BA 25 appears to be state dependent showing significant increase during mania and decrease during depressive phases. The presence of a deficient GABAergic activity in ACC is also documented. Pharmacological treatment partly restores BD-related functional imaging changes. Conclusion: The present review reveals the striking discrepancies of the experimental results present both for functional and structural imaging studies but also for neuropathological analyses. Methodological and conceptual limitations are addressed with particular reference to the heterogeneity of BD clinical patterns. We also critically discuss the validity of CC changes as possible trait- or state-markers of the disease. [PubMed Citation] [Order full text from Infotrieve]

2) Gos T, G�nther K, Bielau H, Dobrowolny H, Mawrin C, Tr�bner K, Brisch R, Steiner J, Bernstein HG, Jankowski Z, Bogerts B
Suicide and depression in the quantitative analysis of glutamic acid decarboxylase-immunorective neuropil.
J Affect Disord. 2008 Jun 5;
BACKGROUND: Alterations of GABAergic neurotransmission are assumed to play a crucial role in the pathophysiology of mood disorders. Glutamic acid decarboxylase (GAD) is the key enzyme of GABA synthesis. METHODS: Immunohistochemical staining of GAD 65/67 was performed in the orbitofrontal, anterior cingulate and dorsolateral prefrontal cortex (DLC), the entorhinal cortex (EC), the hippocampal formation, and the medial dorsal and lateral dorsal thalamic nuclei, with consecutive determination of GAD-immunoreactive (-ir) neuropil relative density. The study was performed on paraffin-embedded brains from 21 depressed patients (14 of whom had committed suicide) and 18 matched controls. The data were tested using Kruskal-Wallis, Mann-Whitney (U) and Spearman statistical procedures. RESULTS: As shown by post-hoc U-tests, an increase in the relative density of GAD-ir neuropil was present in the hippocampal formation, specific for suicidal patients. The EC was the only area where non-suicidal patients also revealed an increase compared with controls. On the contrary, the DLC was the only area where a significant decrease existed, specific for non-suicidal patients. Numerous negative correlations were found between the investigated parameter and psychotropic medication. LIMITATIONS: A major limitation of this study is the relatively small case number. A further limitation is given by the lack of data on drug exposure across the whole life span. The possible impact of unipolar-bipolar dichotomy of mood disorders on the obtained results should also be considered. CONCLUSION: The study, revealing predominantly an increased relative density of GAD-ir neuropil, suggests the diathesis of GABAergic system specific for depressed suicidal patients. [PubMed Citation] [Order full text from Infotrieve]

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

4) Bora E, Vahip S, Akdeniz F
[The role and importance of cognitive symptoms in bipolar disorder]
Turk Psikiyatri Derg. 2008;19(1):81-93.
OBJECTIVE: Our aim was to review evidence of the role of cognitive deficits in bipolar disorder and their relationship to other factors, such as disorder variables, treatment, additional diagnoses, genetic risk, and brain imaging findings. METHOD: Studies that examined cognitive dysfunction in bipolar disorder and its relationship to the variables of clinical, genetic, and bipolar disorder subtypes, as well as neuro-anatomical and neuro-functional evidence have been reviewed. Findings from our own studies have also been used while conducting the review. RESULTS: In bipolar disorder, deficits in executive functions, memory, and attention persist in the euthymic state. The number of episodes and the course of the disorder seem to be related to the severity of memory dysfunction and psychomotor slowness. However, symptoms of cognitive dysfunction are present at the onset of the disorder. Moreover, cognitive dysfunction has been observed in the healthy relatives of bipolar disorder patients. Cognitive dysfunction in bipolar disorder is associated with functional and possibly structural anomalies in some parts of the brain, such as the frontal and cingulate cortex. Some recent studies reported a relationship between symptoms of cognitive dysfunction and genetic variations in bipolar disorder. CONCLUSION: Today, the presence of cognitive deficits in bipolar disorder is widely accepted; however, evidence of the neurobiological and clinical correlates of cognitive symptoms is still limited. More studies are needed to investigate the relationship between cognitive dysfunction in bipolar disorder and risk. Genetic studies are just now amending our body of knowledge. There have been many conflicting results reported by brain imaging studies. Different brain imaging approaches and genetic methods should be used with more specific cognitive and social-emotional tasks for increasing our knowledge about the nature of cognitive deficit in bipolar disorder. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

5) Hajek T, Kozeny J, Kopecek M, Alda M, H�schl C
Reduced subgenual cingulate volumes in mood disorders: a meta-analysis.
J Psychiatry Neurosci. 2008 Mar;33(2):91-9.
OBJECTIVE: Converging evidence suggests that the subgenual cingulate (SGC) is implicated in regulation of mood and in the pathophysiology of mood disorders. Our objective was to carry out the first meta-analysis of SGC volumes in patients with mood disorders. METHODS: We reviewed 10 volumetric magnetic resonance imaging studies of SGC volumes in patients with unipolar depression and bipolar disorders. For meta-analysis, we used standardized differences between means (SDMs) and random effects models. In the search for sources of heterogeneity, we subdivided the studies on the basis of diagnosis and presence of family history. RESULTS: The volumes of left and right SGC in patients with mood disorders were significantly reduced relative to healthy control subjects (SDM -0.38, 95% confidence interval [CI] -0.67 to -0.1 and SDM -0.2, 95% CI -0.4 to -0.007, respectively). There were significant SGC volume reductions in patients with unipolar (left SGC SDM -0.5, 95% CI -0.92 to -0.07; right SGC SDM -0.33, 95% CI -0.64 to -0.02,), but not bipolar, disorder. Patients with a positive family history of mood disorders showed significant left SGC volume decrease (SDM -0.52, 95% CI -0.96 to -0.07), which was not present among subjects without family history of mood disorders. There was no association between age and SGC volumes. CONCLUSION: The available evidence suggests the existence of left and less robust right SGC volumetric reductions in patients with mood disorders, predominantly in those with unipolar depression. The effect size of this difference was moderate and increased in more homogeneous subgroups of patients with a positive family history. The clustering of SGC abnormalities in patients with a family history, their presence early in the illness course and their lack of progression with age make SGC a candidate for a primary vulnerability marker, although studies in unaffected high-risk subjects are missing. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

6) Miller CL, Llenos IC, Cwik M, Walkup J, Weis S
Alterations in kynurenine precursor and product levels in schizophrenia and bipolar disorder.
Neurochem Int. 2008 May;52(6):1297-303.
Increased concentrations of kynurenine pathway metabolites have been reported by several groups for disorders involving psychosis, including schizophrenia and bipolar disorder. To identify components of the pathway that may be relevant as biomarkers or may underlie the etiology of psychosis, it is essential to characterize the extent of kynurenine pathway activation and to investigate known regulators of one of the key kynurenine-producing enzymes, tryptophan 2,3-dioxygenase (TDO2), previously shown in this laboratory to be increased commensurate with kynurenine in postmortem anterior cingulate brain tissue from individuals with schizophrenia. Using this same anterior cingulate sample set from individuals with schizophrenia, bipolar disorder, depression and controls (N=12-14 per group), we measured the precursor of kynurenine and two downstream products. The precursor, tryptophan, was significantly increased only in the schizophrenia group (1.54-fold the mean control value, p=0.02), and through substrate-induced activation, may be one cause of the increased kynurenine and kynurenine metabolites. This finding for tryptophan differs from some, but not all, previous reports and methodological reasons for the discrepancies are discussed. A product of kynurenine metabolism, 3-OH-anthranilic acid was also significantly increased only in the schizophrenia group (1.68-fold the mean control value, p=0.03). 3-OH-anthranilic acid is a reactive species with cytotoxic properties, although the threshold for such effects is not known for neurons. Analysis of major pre- and post-mortem variables showed that none were confounding for these between-group experimental comparisons. Nicotinamide, a pathway end product, did not differ between groups but was associated with cause of death (suicide) within the bipolar group (p=0.03). [PubMed Citation] [Order full text from Infotrieve]

7) Jogia J, Haldane M, Cobb A, Kumari V, Frangou S
Pilot investigation of the changes in cortical activation during facial affect recognition with lamotrigine monotherapy in bipolar disorder.
Br J Psychiatry. 2008 Mar;192(3):197-201.
BACKGROUND: Bipolar disorder is associated with dysfunction in prefrontal and limbic areas implicated in emotional processing. AIMS: To explore whether lamotrigine monotherapy may exert its action by improving the function of the neural network involved in emotional processing. METHOD: We used functional magnetic resonance imaging to examine changes in brain activation during a sad facial affect recognition task in 12 stable patients with bipolar disorder when medication-free compared with healthy controls and after 12 weeks of lamotrigine monotherapy. RESULTS: At baseline, compared with controls, patients with bipolar disorder showed overactivity in temporal regions and underactivity in the dorsal medial and right ventrolateral prefrontal cortex, and the dorsal cingulate gyrus. Following lamotrigine monotherapy, patients demonstrated reduced temporal and increased prefrontal activation. CONCLUSIONS: This preliminary evidence suggests that lamotrigine may enhance the function of the neural circuitry involved in affect recognition. [PubMed Citation] [Order full text from Infotrieve]

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

9) Bauer LO
A family history of psychopathology modifies the decrement in cognitive control among patients with HIV/AIDS.
Brain Cogn. 2008 Jun;67(1):103-14.
The present study was designed to evaluate the effect of HIV/AIDS on cognitive control and to determine if the effect is modified by familial risk for either alcohol or mood disorders. Sixty HIV-1 seropositive and 75 seronegative volunteers were assigned to four subgroups defined by the crossing of a diagnosis of alcohol dependence in the biological father with diagnoses of either major depressive disorder or bipolar disorder in the biological mother. Cognitive control was evaluated during a task in which subjects were asked, on occasion, to inhibit the impulse to respond in the same physical direction as the stimulus and instead respond in the opposite direction. Event related brain potentials and measures of task performance were recorded. The task evoked a negative shift in a late slow potential (SP) as well as an increment in reaction time when cognitive control was challenged. An important finding was an interaction between trial type, HIV/AIDS, and family history: HIV/AIDS and family history each attenuated the negative shift in the SP to such a degree that no further attenuation could be accomplished by the other. The effects of familial risk for alcohol versus mood disorders were equivalent. In conclusion, the absence of change in a late slow potential following a challenge to cognitive control may represent a marker of familial risk for both externalizing and internalizing disorders. The effects of familial risk on this slow potential are sufficiently robust as to attenuate the effects of HIV/AIDS on the probable generators of the response: the anterior cingulate and prefrontal cortex. [PubMed Citation] [Order full text from Infotrieve]

10) Fornito A, Malhi GS, Lagopoulos J, Ivanovski B, Wood SJ, Saling MM, Pantelis C, Y�cel M
Anatomical abnormalities of the anterior cingulate and paracingulate cortex in patients with bipolar I disorder.
Psychiatry Res. 2008 Feb 28;162(2):123-32.
Abnormalities of the anterior cingulate cortex (ACC) are thought to be involved in the pathophysiology of bipolar disorder, but structural Magnetic Resonance Imaging (MRI) studies have reported variable findings. Reasons for this include a failure to consider variability in regional cortical folding patterns and a reliance on relatively coarse measures (e.g., volume) to index anatomical change. We sought to overcome these limitations by combining a novel protocol for parcellating the ACC and adjacent paracingulate cortex (PaC) that accounts for inter-individual variations in sulcal and gyral morphology with a cortical surface-based approach that allowed calculation of regional grey matter volume, surface area and cortical thickness in 24 patients with bipolar I disorder and 24 matched controls. No changes in grey matter volume or surface area were identified in any region, but patients did show significant reductions in cortical thickness in the left rostral PaC and right dorsal PaC that were not attributable to group differences in cortical folding patterns. These findings suggest that bipolar disorder is associated with more pronounced changes in the PaC, and that reliance on volumetric measures alone may obscure more subtle differences. [PubMed Citation] [Order full text from Infotrieve]

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

12) Weis S, Haybaeck J, Dulay JR, Llenos IC
Expression of cellular prion protein (PrP(c)) in schizophrenia, bipolar disorder, and depression.
J Neural Transm. 2008 May;115(5):761-71.
Cellular prion protein (PrP(c)) is a copper-binding, membrane-attached GPI-anchored glycoprotein characterized by a high degree of amino acid sequence conservation among mammals. PrP(c) expression has been demonstrated in neurons, microglia, lymphocytes, and keratinocytes. Recently, the concept that PrP(c) may be involved in the defense against oxidative stress was advanced. In the present study, we used immunohistochemistry for PrP(c) to investigate 60 brains from the Stanley Neuropathology Consortium (15 controls, 15 patients with schizophrenia, 15 with bipolar disorder, and 15 with major depression). Rating scores as well as the numerical density of PrP(c)-positive and -negative neurons and glial cells were determined in the cingulate gyrus. All four groups showed a very high interindividual variation. PrP(c)-positive glial cells were significantly reduced in the white matter of patients with schizophrenia, bipolar disorder, and major depression. A similar result was obtained for the white matter in bipolar patients using rating scales. From the confounding variables, use of medication (i.e. antipsychotics, antidepressants, and mood stabilizers) had a significant effect on the expression of PrP(c) by neurons and glial cells. PrP(c)-immunoreactivities were significantly reduced for white matter glial cells in all examined groups. However, the results are not indicative for the occurrence of oxidative stress in the brains of schizophrenic and bipolar patients. Since the effect of antipsychotic and antidepressant medication as well as of mood stabilizers on the expression of PrP(c) was significant, it needs further clarification in experimental models. [PubMed Citation] [Order full text from Infotrieve]

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

14) Seeley WW, Allman JM, Carlin DA, Crawford RK, Macedo MN, Greicius MD, Dearmond SJ, Miller BL
Divergent social functioning in behavioral variant frontotemporal dementia and Alzheimer disease: reciprocal networks and neuronal evolution.
Alzheimer Dis Assoc Disord. 2007 Oct-Dec;21(4):S50-7.
Behavioral variant frontotemporal dementia (bvFTD) disrupts our most human social and emotional functions. Early in the disease, patients show focal anterior cingulate cortex (ACC) and orbital frontoinsula (FI) degeneration, accentuated in the right hemisphere. The ACC and FI, though sometimes considered ancient in phylogeny, feature a large bipolar projection neuron, the von Economo neuron (VEN), which is found only in humans, apes, and selected whales-all large-brained mammals with complex social structures. In contrast to bvFTD, Alzheimer disease (AD) often spares social functioning, and the ACC and FI, until late in its course, damaging instead a posterior hippocampal-cingulo-temporal-parietal network involved in episodic memory retrieval. These divergent patterns of functional and regional impairment remain mysterious despite extensive molecular-level characterization of bvFTD and AD. In this report, we further develop the hypothesis that VENs drive the regional vulnerability pattern seen in bvFTD, citing recent evidence from functional imaging in healthy humans, and also structural imaging and quantitative neuropathology data from bvFTD and AD. Our most recent findings suggest that bvFTD and AD target distinct, anticorrelated intrinsic connectivity networks and that bvFTD-related VEN injury occurs throughout the ACC-FI network. We suggest that the regional and neuronal vulnerability patterns seen in bvFTD and AD underlie the divergent impact of these disorders on recently evolved social-emotional functions. [PubMed Citation] [Order full text from Infotrieve]

15) Frazier JA, Breeze JL, Papadimitriou G, Kennedy DN, Hodge SM, Moore CM, Howard JD, Rohan MP, Caviness VS, Makris N
White matter abnormalities in children with and at risk for bipolar disorder.
Bipolar Disord. 2007 Dec;9(8):799-809.
OBJECTIVES: Diffusion tensor magnetic resonance imaging (DT-MRI) assesses the integrity of white matter (WM) tracts in the brain. Children with bipolar disorder (BPD) may have WM abnormalities that precede illness onset. To more fully examine this possibility, we scanned children with DSM-IV BPD and compared them to healthy peers and children at risk for BPD (AR-BPD), defined as having a first-degree relative with the disorder. METHODS: Ten children with BPD, eight healthy controls (HC), and seven AR-BPD, similar in age, had MRI scans on a 1.5 Tesla GE scanner, including a standard DT-MRI sequence (T2-EPI) with 25 axial slices. Fractional anisotropy (FA) values were compared between groups to determine regions of significant difference (p < 0.05). RESULTS: Compared to HC, children with BPD had decreased FA in right and left superior frontal tracts, including the superior longitudinal fasciculus I (SLF I) and the cingulate-paracingulate WM (CG-PAC(WM)). In addition, the BPD group had reduced FA in left orbital frontal WM and the right corpus callosum body. Compared to AR-BPD, children with BPD showed reduced FA in the right and left CG-PAC(WM). Both the BPD and AR-BPD groups showed reduced FA relative to HC in bilateral SLF I. CONCLUSIONS: The bilateral SLF I finding in both the BPD and AR-BPD groups may represent a trait-based marker or endophenotype of the disorder. The finding of decreased FA in the right and left CG-PAC(WM) in children with BPD compared to the other two groups may represent a disease-state related finding. [PubMed Citation] [Order full text from Infotrieve]

16) Hajek T, Gunde E, Bernier D, Slaney C, Propper L, Grof P, Macqueen G, Duffy A, Alda M
Subgenual cingulate volumes in affected and unaffected offspring of bipolar parents.
J Affect Disord. 2008 Jun;108(3):263-9.
BACKGROUND: Bipolar disorders (BD) have a strong genetic underpinning, yet no biological vulnerability markers for BD have been identified. Decreased volumes of subgenual cingulate (SGC) were replicated in familial bipolar patients. Presence of abnormality in unaffected subjects at genetic risk for an illness needs to be established before SGC volumes can be used as an endophenotype. This is the first study of SGC volumes in affected and unaffected subjects at familial risk for mood disorders. METHOD: High-risk participants were recruited from families multiply affected with BD. The high-risk sample included 13 affected and 13 unaffected offspring of bipolar I parents, who were matched by age and sex with 31 controls without a personal or family history of psychiatric disorders. The expanded sample consisted of 24 unaffected, 19 affected subjects all with a first or second degree relative suffering from BD I or II. The age range for all subjects was 15-30 years. Subgenual cingulate volumes were measured on 1.5 T 3D anatomical MRI images using standard methods. RESULTS: We found comparable SGC volumes among unaffected, affected offspring of BD I parents and controls. Likewise no SGC abnormalities were found in the expanded sample of subjects with BD I or II relatives. Left SGC volumes in all groups were smaller than right SGC volumes without laterality by group interaction. The exclusion of 5 medicated subjects did not change the results. LIMITATIONS: Cross sectional design, inclusion of both bipolar I and bipolar II probands. CONCLUSIONS: Subgenual cingulate volume abnormalities were absent in unaffected or affected relatives of bipolar patients and thus did not meet criteria for endophenotype. [PubMed Citation] [Order full text from Infotrieve]

17) Fornito A, Malhi GS, Lagopoulos J, Ivanovski B, Wood SJ, Velakoulis D, Saling MM, McGorry PD, Pantelis C, Y�cel M
In vivo evidence for early neurodevelopmental anomaly of the anterior cingulate cortex in bipolar disorder.
Acta Psychiatr Scand. 2007 Dec;116(6):467-72.
OBJECTIVE: Anterior cingulate cortex (ACC) abnormalities are commonly reported in studies of patients with bipolar disorder (BD), but it is unclear whether these precede or follow illness onset. We investigated the evidence for early neurodevelopmental anomalies in the ACC and adjacent paracingulate cortex (PaC) of BD patients by studying cortical folding patterns of the region. METHOD: Magnetic resonance images were acquired from 54 BD patients and 116 healthy controls. Cortical folding patterns were assessed by classifying the incidence of the paracingulate sulcus (PCS) and interruptions in the course of the cingulate sulcus (CS). RESULTS: Patients were significantly less likely to show a PCS bilaterally. There were no differences in the frequency of CS interruptions. CONCLUSION: The bilateral reduction observed in our patient sample implicates aberrant pre- or peri-natal developmental processes. To our knowledge, this is the first in vivo evidence for early neurodevelopmental anomaly of the ACC/PaC region in BD. [PubMed Citation] [Order full text from Infotrieve]

18) Culha AF, Osman O, Dogang�n Y, Filiz K, Suna K, Kalkan ON, Gulfizar V, Beyza A
Changes in regional cerebral blood flow demonstrated by (99m)Tc-HMPAO SPECT in euthymic bipolar patients.
Eur Arch Psychiatry Clin Neurosci. 2007 Nov 7;
Single photon emission computed tomography (SPECT) with (99m)Tc-HMPAO was used to compare regional cerebral blood flow (rCBF) in patients with bipolar disorder and in healthy controls. The sample of this study consisted of 16 euthymic bipolar patients who met the DSM-IV criteria and 10 healthy control subjects. The mean regional cerebral blood flow values of the bipolar euthymic patients were significantly lower than those of the controls in the bilateral medial-basal temporal, occipital; medial frontal; parietal regions and in the cingulate gyrus; the hypoperfusion in the cingulate had the highest significant P value (.001, Bonferroni correction). No significant differences in rCBF emerged between right and left-brain regions. The most important findings of the current study are the presence of regional cerebral perfusion alterations, particularly in the cingulate gyrus in the euthymic bipolar patients. Our results imply that underlying brain dysfunction may be independent from manic or depressive episodes in bipolar disorder. Because of the small number of subjects, however, this finding should be viewed as preliminary. [PubMed Citation] [Order full text from Infotrieve]

19) Yatham LN, Lyoo IK, Liddle P, Renshaw PF, Wan D, Lam RW, Hwang J
A magnetic resonance imaging study of mood stabilizer- and neuroleptic-na�ve first-episode mania.
Bipolar Disord. 2007 Nov;9(7):693-7.
OBJECTIVES: Patients with bipolar disorder have changes in brain structures but it is unclear if these are present at disease onset and thus predispose subjects to develop the disorder, or whether they develop during the course of the disorder, either due to the effects of multiple episodes or as a consequence of treatment with psychotropic agents. Studies in first-episode (FE) manic patients have the potential to provide answers to these questions. METHODS: Voxel-based morphometry (VBM) was used to assess magnetic resonance imaging scans of 15 FE manic patients and 15 matched healthy controls. RESULTS: Using a priori defined statistical criteria, no significant differences in brain structures were noted between the two groups. However, there was approximately a 6% reduction in left anterior cingulate, left precuneus and right posterior cingulate volume in FE patients and these reductions were significant (p[PubMed Citation] [Order full text from Infotrieve]

20) Dickstein DP, Rich BA, Roberson-Nay R, Berghorst L, Vinton D, Pine DS, Leibenluft E
Neural activation during encoding of emotional faces in pediatric bipolar disorder.
Bipolar Disord. 2007 Nov;9(7):679-92.
OBJECTIVE: Neurobiological understanding of bipolar disorder (BD) is limited by a paucity of functional magnetic resonance imaging (fMRI) research examining correlates of psychological processes. To begin to address these limitations, the current study tests the hypothesis that pediatric BD (PBD) subjects exhibit altered neural activation during encoding of emotional faces compared to typically developing controls. METHODS: Pediatric BD subjects (n=23; mean age=14.2+/-3.1 years) and controls (n=22; mean age=14.7+/-2.3 years) were matched on age, gender, and IQ. In this event-related fMRI study, subjects were scanned while viewing emotional faces and given a surprise recognition memory test 30 min postscan. Our main outcome measure was between-group differences in neural activation during successful versus unsuccessful face encoding. RESULTS: Pediatric BD youth exhibited reduced memory for emotional faces, relative to healthy comparisons, particularly on fearful faces. Event-related fMRI analyses controlling for this behavioral difference showed that PBD subjects, compared to controls, had increased neural activation in the striatum and anterior cingulate cortex when successfully encoding happy faces and in the orbitofrontal cortex when successfully encoding angry faces. There were no between-group differences in neural activation during fearful face encoding. CONCLUSIONS: Our results extend what is known about memory and face emotion processing impairments in PBD subjects by showing increased fronto-striatal activation during encoding of emotional faces. Further work is required to determine the impact of mood state, medication, and comorbid illnesses on these findings. [PubMed Citation] [Order full text from Infotrieve]