prefrontal cortex in bipolar disorder


Attention Valued Visitor: A Drug Reference Page for FDA Approved General Anesthetics is now available!
Shawn Thomas ( is working to summarize the mechanisms of action of every drug approved by the FDA for a brain- related condition. In addition, new pages with more automated content will soon replace some of the older pages on the web site. If you have suggestions about content that you would like to see, e-mail if you have anything at all to share.



(Updated 1/12/04)

Manji HK, Lenox RH.
Signaling: cellular insights into the pathophysiology of bipolar disorder.
Biol Psychiatry 2000 Sep 15;48(6):518-30
"Clinical studies over the years have provided evidence that monoamine signaling and hypothalamic-pituitary-adrenal axis disruption are integral to the pathophysiology of bipolar disorder. A full understanding of the pathophysiology from a molecular to a systems level must await the identification of the susceptibility and protective genes driving the underlying neurobiology of bipolar disorder. Furthermore, the complexity of the unique biology of this affective disorder, which includes the predisposition to episodic and often progressive mood disturbance, and the dynamic nature of compensatory processes in the brain, coupled with limitations in experimental design, have hindered our progress to date. Imaging studies in patient populations have provided evidence of a role for anterior cingulate, amygdala, and prefrontal cortex in the pathophysiology of bipolar disorder. More recent research strategies designed to uncover the molecular mechanisms underlying our pharmacologic treatments and their interaction in the regulation of signal transduction as well as more advanced brain imaging studies remain promising approaches. This experimental strategy provides data derived from the physiologic response of the system in affected individuals and addresses the critical dynamic interaction with pharmacologic agents that effectively modify the clinical expression of the pathophysiology." [Abstract]

Vawter MP, Freed WJ, Kleinman JE.
Neuropathology of bipolar disorder.
Biol Psychiatry 2000 Sep 15;48(6):486-504
"The literature on the neuropathology of bipolar disorder (BD) is reviewed. Postmortem findings in the areas of pathomorphology, signal transduction, neuropeptides, neurotransmitters, cell adhesion molecules, and synaptic proteins are considered. Decreased glial numbers and density in both BD and major depressive disorder (MDD) have been reported, whereas cortical neuron counts were not different in BD (in Brodmann's areas [BAs] 9 and 24). In contrast, MDD patients showed reductions in neuronal size and density (BA 9, BA 47). There are a number of findings of alterations in neuropeptides and monoamines in BD brains. Norepinephrine turnover was increased in several cortical regions and thalamus, whereas the serotonin metabolite, 5-hydroxyindoleacetic acid, and the serotonin transporter were reduced in the cortex. Several reports further implicated both cyclic adenosine monophosphate and phosphatidylinositol (PI) cascade abnormalities. G protein concentrations and activity increases were found in the occipital, prefrontal, and temporal cortices in BD. In the PI signal cascade, alterations in PKC activity were found in the prefrontal cortex. In the occipital cortex, PI hydrolysis was decreased. Two isoforms of the neural cell adhesion molecules were increased in the hippocampus of BD, whereas the synaptic protein marker, synaptophysin, was not changed. The findings of glial reduction, excess signal activity, neuropeptide abnormalities, and monoamine alterations suggest distinct imbalances in neurochemical regulation. Possible alterations in pathways involving ascending projections from the brain stem are considered. Larger numbers of BD brains are needed to further refine the conceptual models that have been proposed, and to develop coherent models of the pathophysiology of BD." [Abstract]

Michael N, Erfurth A, Ohrmann P, Gossling M, Arolt V, Heindel W, Pfleiderer B.
Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex.
Psychopharmacology (Berl). 2003 Apr 9 [Epub ahead of print].
"RATIONALE. The dorsolateral prefrontal cortex (DLPFC) participates in the pathophysiology of mania. In particular, left-sided structural and metabolic abnormalities have been described. OBJECTIVES. Clinical symptoms may be due to hyperactivity of cortical glutamatergic neurons, resulting in increased excitatory neurotransmitter flux and thus enhanced Glx levels. METHODS. Glutamate/glutamine (Glx) levels were assessed by proton magnetic resonance spectroscopy ((1)H-MRS) in eight acute manic patients compared with age- and gender-matched controls. RESULTS. Manic patients had significantly elevated Glx levels ( t-test; t=-3.1, P=0.008) within the left DLPFC. CONCLUSIONS. Our results indicate that the prefrontal cortical glutamatergic system is involved in the pathophysiology of acute mania. This may have implications for the treatment of mania." [Abstract]

Grisaru N, Chudakov B, Yaroslavsky Y, Belmaker RH.
Transcranial magnetic stimulation in mania: a controlled study.
Am J Psychiatry 1998 Nov;155(11):1608-10
"OBJECTIVE: Left prefrontal transcranial magnetic stimulation has been reported to have ECT-like effects in depression; therefore, the authors planned a study of transcranial magnetic stimulation in mania. METHOD: Sixteen patients completed a 14-day double-blind, controlled trial of right versus left prefrontal transcranial magnetic stimulation at 20 Hz (2-second duration per train, 20 trains/day for 10 treatment days). Mania was evaluated with the Mania Scale, the Brief Psychiatric Rating Scale, and the Clinical Global Impression. RESULTS: Significantly more improvement was observed in patients treated with right than with left prefrontal transcranial magnetic stimulation. CONCLUSIONS: The therapeutic effect of transcranial magnetic stimulation in mania may show laterality opposite to its effect in depression." [Abstract]

Baxter LR Jr, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE, Gerner RH, Sumida RM.
Reduction of prefrontal cortex glucose metabolism common to three types of depression.
Arch Gen Psychiatry 1989 Mar;46(3):243-50
"Using positron emission tomography, we studied cerebral glucose metabolism in drug-free, age- and sex-matched, right-handed patients with unipolar depression (n = 10), bipolar depression (n = 10), obsessive-compulsive disorder (OCD) with secondary depression (n = 10), OCD without major depression (n = 14), and normal controls (n = 12). Depressed patients were matched for depression on the Hamilton Depression Rating Scale, and subjects with OCD without depression and OCD with depression had similar levels of OCD without depression and OCD with depression had similar levels of OCD pathology. We also studied six non-sex-matched patients with mania. Mean (+/- SD) glucose metabolic rates for the left dorsal anterolateral prefrontal cortex, divided by the rate for the ipsilateral hemisphere as a whole (ALPFC/hem), were similar in the primary depressions (unipolar depression = 1.05 +/- 0.05; bipolar depression = 1.04 +/- 0.05), and were significantly lower than those in normal controls (1.12 +/- 0.06) or OCD without depression (1.15 +/- 0.05). Results for the right hemisphere were similar. Values in subjects with OCD with depression (1.10 +/- 0.05) were also significantly lower than in subjects with OCD without depression, and values in subjects with bipolar depression were lower than those in manic subjects (1.12 +/- 0.03) on this measure in the left hemisphere, although results were not significant in the right hemisphere. There was a significant correlation between the HAM-D score and the left ALPFC/hem. With medication for depression (n = 12), the left ALPFC/hem increased significantly and the percentage change in the Hamilton scale score correlated with the percentage change in the left ALPFC/hem." [Abstract]

Ketter TA, Kimbrell TA, George MS, Dunn RT, Speer AM, Benson BE, Willis MW, Danielson A, Frye MA, Herscovitch P, Post RM.
Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder.
Biol Psychiatry 2001 Jan 15;49(2):97-109
"BACKGROUND: Functional brain imaging studies in unipolar and secondary depression have generally found decreased prefrontal cortical activity, but in bipolar disorders findings have been more variable. METHODS: Forty-three medication-free, treatment-resistant, predominantly rapid-cycling bipolar disorder patients and 43 age- and gender-matched healthy control subjects had cerebral glucose metabolism assessed using positron emission tomography and fluorine-18-deoxyglucose. RESULTS: Depressed bipolar disorder patients compared to control subjects had decreased global, absolute prefrontal and anterior paralimbic cortical, and increased normalized subcortical (ventral striatum, thalamus, right amygdala) metabolism. Degree of depression correlated negatively with absolute prefrontal and paralimbic cortical, and positively with normalized anterior paralimbic subcortical metabolism. Increased normalized cerebello-posterior cortical metabolism was seen in all patient subgroups compared to control subjects, independent of mood state, disorder subtype, or cycle frequency. CONCLUSIONS: In bipolar depression, we observed a pattern of prefrontal hypometabolism, consistent with observations in primary unipolar and secondary depression, suggesting this is part of a common neural substrate for depression independent of etiology. In contrast, the cerebello-posterior cortical normalized hypermetabolism seen in all bipolar subgroups (including euthymic) suggests a possible congenital or acquired trait abnormality. The degree to which these findings in treatment-resistant, predominantly rapid-cycling patients pertain to community samples remains to be established." [Abstract]

Yurgelun-Todd DA, Gruber SA, Kanayama G, Killgore WD, Baird AA, Young AD.
fMRI during affect discrimination in bipolar affective disorder.
Bipolar Disord 2000 Sep;2(3 Pt 2):237-48
"OBJECTIVE: It has been hypothesized that disturbances in affect may represent distinct etiologic factors for bipolar affective disorder. The neural mechanisms mediating affective processes and their relationship to brain development and the pathophysiology of bipolar affective disorder remain to be clarified. Recent advances in neuroimaging techniques have made possible the non-invasive examination of specific brain regions during cortical challenge paradigms. This study reports findings based on fMRI data acquired during fearful and happy affect recognition paradigms in patients with bipolar affective disorder and in healthy adult subjects. METHODS: Prior to the scan, subjects were instructed to view the stimuli and to identify the type of facial expression presented. Echo planar scanning was performed on a 1.5 Tesla scanner which had been retrofitted with a whole body echo planar coil, using a head coil. RESULTS: The data indicate that in adult subjects with bipolar affective disorder, there is a reduction in dorsolateral prefrontal cortex activation and an increase in amygdalar activation in response to fearful facial affect. In a healthy comparison group, signal intensity changes were not found in these regions. In addition, although the patients with bipolar affective disorder completed the task demands, they demonstrated an impaired ability to correctly identify fearful facial affect but not the happy facial affect displayed. CONCLUSION: These findings are consistent with the hypothesis that in some patients with bipolar affective disorder, there may be a reduction of frontal cortical function which may be associated with affective as well as attentional processing deficits." [Abstract]

Cecil KM, DelBello MP, Morey R, Strakowski SM.
Frontal lobe differences in bipolar disorder as determined by proton MR spectroscopy.
Bipolar Disord. 2002 Dec;4(6):357-65.
"OBJECTIVES: Proton magnetic resonance spectroscopy (MRS) provides insight into neurochemical processes. Imaging and postmortem studies have implicated abnormalities of structure and function within the frontal lobe. Patients with bipolar disorder having a manic or mixed episode were hypothesized to demonstrate metabolic abnormalities within the frontal lobe. METHODS: Seventeen patients with bipolar disorder type I (ages 16-35 years, mean 22 +/- 7.3 years) hospitalized for a manic (n = 9) or mixed (n = 8) episode and 21 healthy subjects (ages 16-35 years, mean 21.7 +/- 5.2 years) were evaluated with proton MRS. The gray matter medially and white matter laterally within the frontal lobe were sampled. Metabolite concentrations were calculated for each voxel, corrected for cerebral spinal fluid (CSF) contributions to the voxel, and compared between study populations. RESULTS: Patients demonstrated with multivariate analyses of variance (MANOVA) a significant overall difference in gray matter metabolite concentrations compared with healthy subjects. The largest effect sizes for group differences were found with reductions of N-acetyl aspartate (NAA) and Choline (Cho) concentrations (f = 0.41 and 0.37, respectively). A significant group difference with MANOVA in white matter metabolite concentrations was also observed with the largest effect size at f = 0.44 for elevation of the composite amino acid (AA) concentration. CONCLUSIONS: A reduction of NAA within the gray matter of patients suggests neuronal dysfunction. Altered phospholipid metabolism suggestive of a trend toward decreased volume is implicated with a reduction of Cho concentrations. Within white matter, composite concentrations of AAs were elevated in patients indicating altered neurotransmission." [Abstract]

Nudmamud S, Reynolds LM, Reynolds GP.
N-acetylaspartate and N-Acetylaspartylglutamate deficits in superior temporal cortex in schizophrenia and bipolar disorder: a postmortem study.
Biol Psychiatry. 2003 Jun 15;53(12):1138-41.
"BACKGROUND: N-acetylaspartylglutamate is found in neurons and its metabolite N-acetylaspartate, which can be measured by magnetic resonance spectroscopy, is considered a marker of neuronal integrity. Several magnetic resonance spectroscopy studies have found evidence of N-acetylaspartate deficits in schizophrenia. METHODS: We employed a high-pressure liquid chromatography method to determine N-acetylaspartate and N-acetylaspartylglutamate in postmortem brain tissues taken from a well-defined series of psychiatric cases. N-acetylaspartate and N-acetylaspartylglutamate concentrations were measured in superior temporal and frontal cortices of patients with schizophrenia, bipolar disorder, and depression and control subjects. RESULTS: N-acetylaspartate was significantly decreased below controls in superior temporal cortex in schizophrenia (p <.01) and bipolar disorder (p <.01), but no deficits were found in frontal cortex. N-acetylaspartylglutamate was significantly decreased only in superior temporal cortex in schizophrenia. CONCLUSIONS: The results are consistent with evidence of superior temporal cortex abnormalities in schizophrenia. The finding in bipolar disorder suggests that temporal cortex N-acetylaspartate deficits may be a common feature of psychotic disorders." [Abstract]

Lopez-Larson MP, DelBello MP, Zimmerman ME, Schwiers ML, Strakowski SM.
Regional prefrontal gray and white matter abnormalities in bipolar disorder.
Biol Psychiatry 2002 Jul 15;52(2):93-100
"BACKGROUND: Previous magnetic resonance imaging (MRI) studies indicate that compared with healthy volunteers, patients with bipolar disorder have structural and functional abnormalities in the prefrontal cortex. The aim of this study was to investigate differences in prefrontal subregions between bipolar patients and healthy subjects. METHODS: Bipolar patients hospitalized for a manic episode (n = 17), and demographically matched healthy volunteers (n = 12) were recruited. Contiguous 1-mm coronal T1-weighted MRI slices were obtained using a Picker 1.5 Tesla scanner. The gray and white matter volumes of five prefrontal subregions of interest were measured: superior, middle, inferior, cingulate, and orbital. RESULTS: Bipolar patients had smaller left prefrontal gray matter volumes, specifically in the middle and superior subregions and smaller right prefrontal gray matter volumes, specifically in the inferior and middle subregions. White matter differences were not observed in any of the prefrontal subregions. CONCLUSIONS: The results suggest that bipolar patients have subregion-specific gray matter volume reductions in the prefrontal cortex as compared to healthy subjects. Further investigations into the role of specific prefrontal subregions in bipolar disorder are warranted." [Abstract]

Blumberg HP, Martin A, Kaufman J, Leung HC, Skudlarski P, Lacadie C, Fulbright RK, Gore JC, Charney DS, Krystal JH, Peterson BS.
Frontostriatal abnormalities in adolescents with bipolar disorder: preliminary observations from functional MRI.
Am J Psychiatry. 2003 Jul;160(7):1345-7.
"OBJECTIVE: This study investigated whether the functional abnormalities in prefrontal systems observed in adult bipolar disorder are manifested in adolescents with this illness. METHOD: Ten adolescents with bipolar disorder and 10 healthy comparison subjects participated in a color-naming Stroop task during event-related functional magnetic resonance imaging. RESULTS: Signal increases in the left putamen and thalamus were significantly greater in the bipolar disorder group than in the healthy group. Age correlated positively with signal increases in the bilateral rostroventral prefrontal cortex and the striatum in the healthy group but not in the bipolar disorder group. In the bipolar disorder subjects, depressive symptoms correlated positively with signal increases in the ventral striatum. CONCLUSIONS: These findings suggest the presence of dysfunction in the subcortical portions of the frontostriatal circuits in adolescents with bipolar disorder. The absence of the prefrontal abnormalities that were observed previously in adults and the absence of the age-related increases in prefrontal activity observed in normal comparison subjects suggest that a developmental disturbance in prefrontal function may emerge in bipolar disorder over the course of adolescence." [Abstract]

Xing G, Russell S, Hough C, O'Grady J, Zhang L, Yang S, Zhang LX, Post R.
Decreased prefrontal CaMKII alpha mRNA in bipolar illness.
Neuroreport 2002 Mar 25;13(4):501-5
"Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays critical roles in neurotransmission, synaptic plasticity, learning and memory. The aim of this study was to examine, by in situ hybridization, prefrontal cortical expression of CaMKII alpha mRNA in postmortem brains of unipolar, bipolar, schizophrenic, and control subjects. Compared to controls, bipolar patients had significantly lower levels of CaMKII alpha mRNA in laminae I-VI of Brodmann's area 9 and laminae I-III and VI of area 46. Unipolar patients also exhibited significantly lower levels of CaMKII alpha mRNA in laminae I-IV of area 9 than did controls. The significant decrease in CaMKII alpha mRNA in bipolar patients could be associated with some of the affective and cognitive alterations that have been linked to prefrontal cortical dysfunction in bipolar disorder, although this requires further direct examination." [Abstract]

Koh PO, Undie AS, Kabbani N, Levenson R, Goldman-Rakic PS, Lidow MS.
Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolar patients.
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):313-7. Epub 2002 Dec 20.
"The delineation of dopamine dysfunction in the mentally ill has been a long-standing quest of biological psychiatry. The present study focuses on a recently recognized group of dopamine receptor-interacting proteins as possible novel sites of dysfunction in schizophrenic and bipolar patients. We demonstrate that the dorsolateral prefrontal cortex in schizophrenia and bipolar cases from the Stanley Foundation Neuropathology Consortium display significantly elevated levels of the D2 dopamine receptor desensitization regulatory protein, neuronal calcium sensor-1. These levels of neuronal calcium sensor-1 were not influenced by age, gender, hemisphere, cause of death, postmortem period, alcohol consumption, or antipsychotic and mood stabilizing medications. The present study supports the hypothesis that schizophrenia and bipolar disorder may be associated with abnormalities in dopamine receptor-interacting proteins." [Abstract]

Caberlotto L, Hurd YL.
Reduced neuropeptide Y mRNA expression in the prefrontal cortex of subjects with bipolar disorder.
Neuroreport 1999 Jun 3;10(8):1747-50
"In the present study, we compared neuropeptide Y mRNA expression levels in the prefrontal cortex (Brodmann area 9 and 46) of subjects diagnosed with major depression, bipolar disorder and schizophrenia with those in normal controls without a psychiatric history. No correlation was found regarding neuropeptide Y mRNA expression and postmortem interval, age, gender, hemisphere side, suicide as cause of death, or the history of use of substances such as alcohol, marihuana and cocaine/amphetamine. The only significant alteration found was related to the clinical diagnosis; neuropeptide Y mRNA expression was reduced in the group of bipolar subjects as compared to the controls. Overall, the present results confirm an involvement of neuropeptide Y in affective disorders, and show for the first time a specific association between NPY and bipolar disorder." [Abstract]

Uranova N, Orlovskaya D, Vikhreva O, Zimina I, Kolomeets N, Vostrikov V, Rachmanova V.
Electron microscopy of oligodendroglia in severe mental illness.
Brain Res Bull 2001 Jul 15;55(5):597-610
"Qualitative electron microscopy was performed to verify whether brain pathology in schizophrenia and bipolar disorder is associated with alterations of oligodendroglial cells and myelinated fibers. Ultrastructural signs of apoptosis and necrosis of oligodendroglial cells were found in the prefrontal area 10 and the caudate nucleus in both schizophrenia and bipolar disorder." [Abstract]

Rajkowska G, Halaris A, Selemon LD.
Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder.
Biol Psychiatry 2001 May 1;49(9):741-52
"BACKGROUND: Bipolar disorder (BPD) is a mental illness in which depression and mania typically alternate, and both phases can present with psychotic features. The symptomatology of BPD, therefore, resembles major depressive disorder (MDD) and schizophrenia (SCHZ), posing diagnostic dilemmas. Distinct alterations in cellular architecture of the dorsolateral prefrontal cortex distinguish SCHZ and MDD, whereas the cellular neuropathology of BPD has not been studied. METHODS: Dorsolateral prefrontal area 9 was analyzed using a three-dimensional morphometric method in postmortem brains from 10 BPD patients and 11 matched nonpsychiatric control subjects. RESULTS: Area 9 in BPD was characterized by reduced neuronal density in layer III (16%-22%) and reduced pyramidal cell density in layers III and V (17%-30%). A 19% reduction in glial density was found in sublayer IIIc coupled with enlargement and changes in shape of glial nuclei spanning multiple layers. CONCLUSIONS: The morphologic signature of BPD, i.e., decreased neuronal and glial density in association with glial hypertrophy, is distinct from previously described elevations in neuronal density in SCHZ, instead resembling the reductions in cell density found in MDD. Thus, the neuropathologic distinctions between BPD and SCHZ are indicative of separate mental illnesses, each with a unique morphologic disturbance of specific neural circuits." [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."

Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma R, Uzunov D, Costa E, DiGiorgi Gerevini V.
Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study.
Arch Gen Psychiatry 2000 Nov;57(11):1061-9
"BACKGROUND: Reelin (RELN) is a glycoprotein secreted preferentially by cortical gamma-aminobutyric acid-ergic (GABAergic) interneurons (layers I and II) that binds to integrin receptors located on dendritic spines of pyramidal neurons or on GABAergic interneurons of layers III through V expressing the disabled-1 gene product (DAB1), a cytosolic adaptor protein that mediates RELN action. To replicate earlier findings that RELN and glutamic acid decarboxylase (GAD)(67), but not DAB1 expression, are down-regulated in schizophrenic brains, and to verify whether other psychiatric disorders express similar deficits, we analyzed, blind, an entirely new cohort of 60 postmortem brains, including equal numbers of patients matched for schizophrenia, unipolar depression, and bipolar disorder with nonpsychiatric subjects. METHODS: Reelin, GAD(65), GAD(67), DAB1, and neuron-specific-enolase messenger RNAs (mRNAs) and respective proteins were measured with quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) or Western blot analyses. Reelin-positive neurons were identified by immunohistochemistry using a monoclonal antibody. RESULTS: Prefrontal cortex and cerebellar expression of RELN mRNA, GAD(67) protein and mRNA, and prefrontal cortex RELN-positive cells was significantly decreased by 30% to 50% in patients with schizophrenia or bipolar disorder with psychosis, but not in those with unipolar depression without psychosis when compared with nonpsychiatric subjects. Group differences were absent for DAB1,GAD(65) and neuron-specific-enolase expression implying that RELN and GAD(67) down-regulations were unrelated to neuronal damage. Reelin and GAD(67) were also unrelated to postmortem intervals, dose, duration, or presence of antipsychotic medication. CONCLUSIONS: The selective down-regulation of RELN and GAD(67) in prefrontal cortex of patients with schizophrenia and bipolar disorder who have psychosis is consistent with the hypothesis that these parameters are vulnerability factors in psychosis; this plus the loss of the correlation between these 2 parameters that exists in nonpsychotic subjects support the hypothesis that these changes may be liability factors underlying psychosis." [Abstract]

Benke T, Kurzthaler I, Schmidauer Ch, Moncayo R, Donnemiller E.
Mania caused by a diencephalic lesion.
Neuropsychologia 2002;40(3):245-52
"We describe the case of a young male patient, SN, who suffered a MR-documented ischaemic lesion of both dorsomedial thalami and presented with a transient maniform syndrome. SN's neuropsychological, structural and functional imaging findings are compared with similar reported cases and are discussed in the framework of fronto-subcortical circuits and their proposed behavioural disorders. SN's mania was characterized by restlessness, mood elevation, a tendency for pleasurable activities, inflated self-esteem and loss of disease awareness. Other symptoms were sexual disinhibition, tactlessness, abnormal discourse, and reduced need for food and sleep. His neuropsychological assessment revealed an anterograde amnesia, and an impairment of frontal-executive functions. A SPECT-study showed diaschisis-related areas of hypoperfusion in both prefrontal regions which were interpreted as equivalents of SN's frontal-dysexecutive syndrome. In addition, there was a perfusion deficit in the right orbitofrontal cortex, which was taken as the imaging correlate of SN's secondary mania and personality disorder. These findings suggest that SN's mania and his other symptoms result from the twofold disruption of fronto-subcortical connections, namely of the right orbitofrontal loop which is concerned with mood regulation and socially appropriate behaviour, and of the dorsolateral prefrontal loop which mediates executive cognitive functions." [Abstract]

Pang A, Lewis SW.
Bipolar affective disorder minus left prefrontal cortex equals schizophrenia.
Br J Psychiatry 1996 May;168(5):647-50
"BACKGROUND. An investigation of the relationship between bipolar affective disorder and schizophrenia, following a severe head injury and removal of the left prefrontal cortex. METHOD. A single case report. RESULTS. An individual with past history of bipolar affective disorder suffered traumatic damages to the left prefrontal cortex with a second lesion in the left temporal lobe. The patient developed typical schizophrenia nine months later. The relevance of his brain lesions in determining the schizophrenic symptoms is discussed. CONCLUSION. We propose that the specific pattern of brain injury in this patient was sufficient to change the phenotype from bipolar affective disorder to schizophrenia." [Abstract]

Blumberg HP, Leung HC, Skudlarski P, Lacadie CM, Fredericks CA, Harris BC, Charney DS, Gore JC, Krystal JH, Peterson BS.
A functional magnetic resonance imaging study of bipolar disorder: state- and trait-related dysfunction in ventral prefrontal cortices.
Arch Gen Psychiatry. 2003 Jun;60(6):601-9.
"BACKGROUND: Abnormalities in prefrontal and anterior cingulate cortices are implicated in disturbances of attention, cognition, and impulse regulation in bipolar disorder. Acute episodes have been associated with dysfunction in these brain regions, and more enduring trait-related dysfunction has been implicated by volumetric and cellular abnormalities in these regions. The relative contributions of prefrontal regions to state and trait disturbances in bipolar disorder, however, have not been defined. We sought to characterize state- and trait-related functional impairment in frontal systems in bipolar disorder. METHODS: Thirty-six individuals with bipolar disorder I (11 with elevated, 10 with depressed, and 15 with euthymic mood states) and 20 healthy control subjects matched for handedness and sex participated in an event-related functional magnetic resonance imaging study of the color-word Stroop to determine mean percentage of regional task-related signal change. RESULTS: Signal increased during the Stroop task similarly across diagnostic groups in a distribution that included dorsal anterior cingulate and prefrontal cortices, consistent with previously reported activations in this task. Signal changes associated with specific mood states in bipolar disorder were detected in ventral prefrontal cortex, with a blunted increase in signal on the right side in the elevated mood group (P =.005) and an exaggerated increase in signal on the left side in the depressed group (P =.02) compared with the euthymic group. Patients (vs healthy controls) demonstrated blunted activation in a spatially distinct, rostral region of left ventral prefrontal cortex that was independent of mood state (P<.005). CONCLUSIONS: Bipolar disorder is associated with a trait abnormality in left ventral prefrontal cortex. Additional ventral prefrontal abnormalities may be associated with specific acute mood states. The hemispheric laterality of the abnormality and the directions of signal change may relate to the valence of the mood episode." [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):2550-63
"Poor 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. Moreover, they are consistent with neuropsychological observations in patients with lesions in the ventromedial prefrontal cortex, who show similar difficulties with decision-making and provide early evidence for context-specific neural correlates of mania." [Abstract]

Clark L, Iversen SD, Goodwin GM.
A neuropsychological investigation of prefrontal cortex involvement in acute mania.
Am J Psychiatry 2001 Oct;158(10):1605-11
"OBJECTIVE: Mania has received little attention from a contemporary neuropsychological perspective despite its clear resemblance to the disinhibition syndrome sometimes seen after frontal brain injury, particularly injury to the inferior aspect of the prefrontal cortex. The purpose of this investigation was to describe the neuropsychological profile of severe acute mania by using a range of tasks selected primarily for the detection of localized neural disruption within the prefrontal cortex. METHOD: Fifteen acutely manic inpatients were compared with 30 nonpsychiatric subjects on tasks from the Cambridge Automated Neuropsychological Test Battery (Tower of London, spatial working memory, intradimensional-extradimensional attentional shift, and rapid visual information processing tasks) and on the Iowa Gambling Task, Stroop Color and Word Test, a verbal fluency task, and the California Verbal Learning Test. RESULTS: Discriminant function analysis identified deficits in sustained attention (on the rapid visual information processing task) and verbal learning (on the California Verbal Learning Test) as the best indicators of manic performance, rather than deficits on any of the tests of executive functioning. The model correctly classified 91% of subjects overall and 87% of manic subjects. Manic patients did not resemble patients with ventromedial prefrontal cortex damage in their performance on the Iowa Gambling Task. CONCLUSIONS: Acute mania is characterized by core deficits in verbal memory and sustained attention against a background of milder impairments in functions that are traditional measures of prefrontal cortex integrity (attentional set shifting, planning, working memory). The data do not implicate ventral prefrontal cortex disruption as a locus of pathology in acute mania. Verbal memory and sustained attention deficits may relate differentially to the state and trait characteristics of bipolar disorder." [Abstract]

Blumberg HP, Stern E, Ricketts S, Martinez D, de Asis J, White T, Epstein J, Isenberg N, McBride PA, Kemperman I, Emmerich S, Dhawan V, Eidelberg D, Kocsis JH, Silbersweig DA.
Rostral and orbital prefrontal cortex dysfunction in the manic state of bipolar disorder.
Am J Psychiatry 1999 Dec;156(12):1986-8
"OBJECTIVE: This study investigated prefrontal cortex function in the manic state of bipolar disorder. METHOD: High-sensitivity [15O]H2O positron emission tomography and a word generation activation paradigm were used to study regional cerebral blood flow in five manic and six euthymic individuals with bipolar disorder and in five healthy individuals. RESULTS: Decreased right rostral and orbital prefrontal cortex activation during word generation and decreased orbitofrontal activity during rest were associated with mania. CONCLUSIONS: The data support the presence of rostral and orbital prefrontal dysfunction in primary mania. These findings, when seen in the context of the human brain lesion and the behavioral neuroanatomic literatures, may help to explain some of the neurobehavioral abnormalities characteristic of the manic state." [Abstract]

Drevets WC.
Prefrontal cortical-amygdalar metabolism in major depression.
Ann N Y Acad Sci 1999 Jun 29;877:614-37
"Functional neuroimaging studies of the anatomical correlates of familial major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of resting blood flow (BF) and glucose metabolism in depression in the amygdala and the orbital and medial prefrontal cortical (PFC) areas that are extensively connected with the amygdala. The amygdala metabolism in MDD and BD is positively correlated with both depression severity and "stressed" plasma cortisol concentrations measured during scanning. During antidepressant drug treatment, the mean amygdala metabolism decreases in treatment responders, and the persistence of elevated amygdala metabolism during remission is associated with a high risk for the development of depressive relapse. The orbital C metabolism is also abnormally elevated during depression, but is negatively correlated with both depression severity and amygdala metabolism, suggesting that this structure may be activated as a compensatory mechanism to modulate amygdala activity or amygdala-driven emotional responses. The posterior orbital C and anterior cingulate C ventral to the genu of the corpus callosum (subgenual PFC) have more recently been shown in morphometric MRI and/or post mortem histopathological studies to have reduced grey matter volume and reduced glial cell numbers (with no equivalent loss of neurons) in familial MDD and BD. These data suggest a neural model in which dysfunction of limbic PFC structures impairs the modulation of the amygdala, leading to abnormal processing of emotional stimuli. Antidepressant drugs may compensate for this dysfunction by inhibiting pathological limbic activity." [Abstract]

Blumberg HP, Charney DS, Krystal JH.
Frontotemporal neural systems in bipolar disorder.
Semin Clin Neuropsychiatry. 2002 Oct;7(4):243-54.
"Relatively less research has been performed in the delineation of the neural system abnormalities underlying bipolar disorder (BD) than in their correlates in unipolar depression. However, neuroimaging research has recently provided in vivo evidence to support the involvement of regional brain abnormalities in BD implicated by the localization of lesions associated with secondary mood symptoms. This article reviews (1) neural systems implicated in BD by brain lesions associated with secondary mood changes and impaired neuropsychologic paradigm performance; (2) structural and functional neuroimaging evidence to support the involvement of these neural systems in BD; and (3) potential functional neuroanatomic models of BD symptoms. Because depression is covered in detail elsewhere in this issue, this article focuses primarily on abnormalities associated with the manic state, as well as ones associated with euthymia, and may thus represent trait abnormalities in BD. We suggest that ventral and medial prefrontal and amygdalar abnormalities may play important roles in a subset of BD symptoms and are potential targets for treatments." [Abstract]

Curtis VA, Dixon TA, Morris RG, Bullmore ET, Brammer MJ, Williams SC, Sharma T, Murray RM, McGuire PK.
Differential frontal activation in schizophrenia and bipolar illness during verbal fluency.
J Affect Disord 2001 Oct;66(2-3):111-21
"INTRODUCTION: The precise nature of frontal lobe dysfunction in schizophrenia remains unclear. We have previously demonstrated, using fMRI, a task-specific attenuation of frontal activation in schizophrenic patients. By using an identical methodology in matched bipolar subjects, we sought to determine whether this finding is specific to schizophrenia or a correlate of psychosis in general. METHOD: Five dextral male bipolar patients and matching groups of schizophrenic subjects and controls were studied using fMRI. Echoplanar images were acquired while subjects performed two paced tasks: covert verbal fluency and a semantic decision task. Generic brain activation maps were constructed from individual images by sinusoidal regression analysis. Between-group differences in the mean power of experimental response were identified on a voxel-wise basis by an analysis of variance (ANOVA). RESULTS: The bipolar patients showed extensive prefrontal activation during verbal fluency which was significantly greater than in controls. There was no difference in the prefrontal BOLD response during the semantic decision task. CONCLUSIONS: These data indicate that bipolar patients show a strikingly different pattern of frontal responses compared to those with schizophrenia and provide further evidence that abnormal frontal activation in psychotic disorders is more apparent during verbal fluency than semantic decision." [Abstract]

Chen G, Masana MI, Manji HK.
Lithium regulates PKC-mediated intracellular cross-talk and gene expression in the CNS in vivo.
Bipolar Disord 2000 Sep;2(3 Pt 2):217-36
"It has become increasingly appreciated that the long-term treatment of complex neuropsychiatric disorders like bipolar disorder (BD) involves the strategic regulation of signaling pathways and gene expression in critical neuronal circuits. Accumulating evidence from our laboratories and others has identified the family of protein kinase C (PKC) isozymes as a shared target in the brain for the long-term action of both lithium and valproate (VPA) in the treatment of BD. In rats chronically treated with lithium at therapeutic levels, there is a reduction in the levels of frontal cortical and hippocampal membrane-associated PKC alpha and PKC epsilon. Using in vivO microdialysis, we have investigated the effects of chronic lithium on the intracellular cross-talk between PKC and the cyclic AMP (cAMP) generating system in vivo. We have found that activation of PKC produces an increase in dialysate cAMP levels in both prefrontal cortex and hippocampus, effects which are attenuated by chronic lithium administration. Lithium also regulates the activity of another major signaling pathway the c-Jun N-terminal kinase pathway--in a PKC-dependent manner. Both Li and VPA, at therapeutically relevant concentrations, increase the DNA binding of activator protein 1 (AP-1) family of transcription factors in cultured cells in vitro, and in rat brain ex vivo. Furthermore, both agents increase the expression of an AP-1 driven reporter gene, as well as the expression of several endogenous genes known to be regulated by AP-1. Together, these results suggest that the PKC signaling pathway and PKC-mediated gene expression may be important mediators of lithium's long-term therapeutic effects in a disorder as complex as BD." [Abstract]

Young LT, Li PP, Kish SJ, Siu KP, Kamble A, Hornykiewicz O, Warsh JJ.
Cerebral cortex Gs alpha protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder.
J Neurochem 1993 Sep;61(3):890-8
"Experimental animal and peripheral blood cell studies point to guanine nucleotide regulatory (G) protein disturbances in bipolar affective disorder. We have previously reported elevated prefrontal cortex Gs alpha protein in bipolar affective disorder and have now extended these preliminary observations in a larger number of subjects, assessing the brain regional specificity of these changes in greater detail, determining the functional biochemical correlates of such changes, and evaluating their diagnostic specificity. Membrane G protein (Gs alpha, Gi alpha, Go alpha, and G beta) immunoreactivities were estimated by western blotting in postmortem brain regions obtained from 10 patients with a DSMIII-R diagnosis of bipolar affective disorder and 10 nonpsychiatric controls matched on the basis of age, postmortem delay, and brain pH. To examine whether there were functional correlates to the observed elevated Gs alpha levels, basal and GTP gamma S- and forskolin-stimulated cyclic AMP production was determined in the same brain regions. Compared with controls, Gs alpha (52-kDa species) immunoreactivity was significantly (p < 0.05) elevated in prefrontal (+36%), temporal (+65%), and occipital (+96%) cortex but not in hippocampus (+28%), thalamus (-23%), or cerebellum (+21%). In contrast, no significant differences were found in the other G protein subunits (Gi alpha, Go alpha, G beta) measured in these regions. Forskolin-stimulated cyclic AMP production was significantly increased in temporal (+31%) and occipital (+96%) cortex but not in other regions. No significant differences were apparent in basal or GTP gamma S-stimulated cyclic AMP production." [Abstract]

Beasley CL, Zhang ZJ, Patten I, Reynolds GP.
Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins.
Biol Psychiatry 2002 Oct 1;52(7):708-15
"BACKGROUND: Postmortem studies have provided evidence for abnormalities of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia, including deficits of GABA-containing interneurons. The calcium-binding proteins parvalbumin, calbindin, and calretinin can be used as markers for specific subpopulations of cortical GABAergic interneurons.METHODS: Following our previous observation of a reduction in the density of parvalbumin- but not calretinin-immunoreactive cells in the prefrontal cortex (Brodmann area 10) in schizophrenia, we have quantified the laminar density of neurons immunoreactive for the calcium-binding proteins parvalbumin, calbindin, and calretinin in a further prefrontal cortical region (Brodmann area 9) in patients with schizophrenia, bipolar disorder, major depression, and in matched control subjects (each group n = 15).RESULTS: Initial statistical analysis revealed reductions in the total cortical density of parvalbumin- and calbindin- but not calretinin-immunoreactive neurons in schizophrenia relative to control subjects. Further analysis comparing individual laminar densities between groups indicated that, following correction for multiple comparisons, only a reduction in calbindin-immunoreactive neurons in cortical layer II in the schizophrenic group attained statistical significance.CONCLUSIONS: These findings suggest that deficits of specific GABAergic neurons, defined by the presence of calcium-binding proteins, are present in schizophrenia. Trends toward similar reductions are observed in bipolar disorder." [Abstract]

Elizabeth A. Thomas, Brian Dean, Geoffrey Pavey, and J. Gregor Sutcliffe
Increased CNS levels of apolipoprotein D in schizophrenic and bipolar subjects: Implications for the pathophysiology of psychiatric disorders
PNAS 98: 4066-4071, March 2001.
"Chronic administration of the atypical antipsychotic drug, clozapine, to rodents has been shown to increase the concentration of apolipoprotein D (apoD) in several area of the brain, suggesting that apoD could be involved in the therapeutic effects of antipsychotic drugs and/or the pathology of psychotic illnesses. Here, we measured a significant decrease in the concentration of apoD in serum samples from schizophrenic patients. In contrast, apoD levels were significantly increased (92-287%) in dorsolateral prefrontal cortex (Brodmann's area 9) of schizophrenic and bipolar subjects. Elevated levels of apoD expression were also observed in the caudate of schizophrenic and bipolar subjects (68-89%). No differences in apoD immunoreactivity were detected in occipital cortex (Brodmann's area 18) in either group, or in the hippocampus, substantia nigra, or cerebellum of the schizophrenic group. The low serum concentrations of apoD observed in these patients supports recent hypotheses involving systemic insufficiencies in lipid metabolism/signaling in schizophrenia. Elevation of apoD expression selectively within central nervous system regions implicated in the pathology of these neuropsychiatric disorders suggests a focal compensatory response that neuroleptic drug regimens may augment." [Full Text]

Rajkowska G.
Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells.
Biol Psychiatry 2000 Oct 15;48(8):766-77
"The influence of stress and glucocorticoids on neuronal pathology has been demonstrated in animal and clinical studies. It has been proposed that stress-induced changes in the hippocampus may be central to the development of depression in genetically vulnerable individuals. New evidence implicates the prefrontal cortex (PFC) in addition to the hippocampus as a site of neuropathology in depression. The PFC may be involved in stress-mediated neurotoxicity because stress alters PFC functions and glucocorticoid receptors, the PFC is directly interconnected with the hippocampus, and metabolic alterations are present in the PFC in depressed patients. Postmortem studies in major depression and bipolar disorder provide the first evidence for specific neuronal and glial histopathology in mood disorders. Three patterns of morphometric cellular changes are noted: cell loss (subgenual PFC), cell atrophy (dorsolateral PFC and orbitofrontal cortex), and increased numbers of cells (hypothalamus, dorsal raphe nucleus). The relevance of cellular changes in mood disorders to stress and prolonged PFC development and a role of neurotrophic/neuroprotective factors are suggested, and a link between cellular changes and the action of therapeutic drugs is discussed. The precise anatomic localization of dysfunctional neurons and glia in mood disorders may reveal cortical targets for novel antidepressants and mood stabilizers." [Abstract]

Winsberg ME, Sachs N, Tate DL, Adalsteinsson E, Spielman D, Ketter TA.
Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder.
Biol Psychiatry 2000 Mar 15;47(6):475-81
"BACKGROUND: N-acetyl aspartate (NAA) is an amino acid present in high concentrations in neurons and is thus a putative neuronal marker. In vivo proton magnetic resonance spectroscopy ((1)H MRS) studies have shown lower NAA concentrations in patients with various neurodegenerative disorders, suggesting decreased neuronal number, size, or function. Dorsolateral prefrontal (DLPF) NAA has not been extensively assessed in bipolar disorder patients, but it could be decreased in view of consistent reports of decreased DLPF cerebral blood flow and metabolism in mood disorders. We measured DLPF NAA in patients with bipolar disorder and healthy control subjects using in vivo (1)H MRS. METHODS: We obtained ratios of NAA, choline, and myoinositol (mI) to creatine-phosphocreatine (Cr-PCr) in bilateral DLPF 8-mL voxels of 20 bipolar patients (10 Bipolar I, 10 Bipolar II) and 20 age- and gender-matched healthy control subjects using (1)H MRS. RESULTS: DLPF NAA/Cr-PCr ratios were lower on the right hemisphere (p<.03) and the left hemisphere (p<.003) in bipolar disorder patients compared with healthy control subjects. CONCLUSIONS: These preliminary data suggest that bipolar disorder patients have decreased DLPF NAA/Cr-PCr. This finding could represent decreased neuronal density or neuronal dysfunction in the DLPF region." [Abstract]

Chang K, Adleman N, Dienes K, Barnea-Goraly N, Reiss A, Ketter T.
Decreased N-acetylaspartate in children with familial bipolar disorder.
Biol Psychiatry. 2003 Jun 1;53(11):1059-65.
"BACKGROUND: Relatively low levels of brain N-acetylaspartate, as measured by magnetic resonance spectroscopy, may indicate decreased neuronal density or viability. Dorsolateral prefrontal levels of N-acetylaspartate have been reported to be decreased in adults with bipolar disorder. We used proton magnetic resonance spectroscopy to investigate dorsolateral prefrontal N-acetylaspartate levels in children with familial bipolar disorder. METHODS: Subjects were 15 children and adolescents with bipolar disorder, who each had at least one parent with bipolar disorder, and 11 healthy controls. Mean age was 12.6 years for subjects and controls. Subjects were allowed to continue current medications. Proton magnetic resonance spectroscopy at 3-Tesla was used to study 8 cm(3) voxels placed in left and right dorsolateral prefrontal cortex. RESULTS: Bipolar subjects had lower N-acetylaspartate/Creatine ratios only in the right dorsolateral prefrontal cortex (p <.02). No differences in myoinositol or choline levels were found. CONCLUSIONS: Children and adolescents with bipolar disorder may have decreased dorsolateral prefrontal N-acetylaspartate, similar to adults with BD, indicating a common neuropathophysiology. Longitudinal studies of at-risk children before the onset and during the early course of bipolar disorder are needed to determine the role of prefrontal N-acetylaspartate as a possible risk marker and/or indication of early bipolar illness progression." [Abstract]

Dost Öngür, Wayne C. Drevets, and Joseph L. Price
Glial reduction in the subgenual prefrontal cortex in mood disorders
PNAS 95: 13290-13295, 1998.
"Mood disorders are among the most common neuropsychiatric illnesses, yet little is known about their neurobiology. Recent neuroimaging studies have found that the volume of the subgenual part of Brodmann's area 24 (sg24) is reduced in familial forms of major depressive disorder (MDD) and bipolar disorder (BD). In this histological study, we used unbiased stereological techniques to examine the cellular composition of area sg24 in two different sets of brains. There was no change in the number or size of neurons in area sg24 in mood disorders. In contrast, the numbers of glia were reduced markedly in both MDD and BD. The reduction in glial number was most prominent in subgroups of subjects with familial MDD (24%, P = 0.01) or BD (41%, P = 0.01). The glial reduction in subjects without a clear family history was lower in magnitude and not statistically significant. Consistent with neuroimaging findings, cortical volume was reduced in area sg24 in subjects with familial mood disorders. Schizophrenic brains studied as psychiatric controls had normal neuronal and glial numbers and cortical volume. Glial and neuronal numbers also were counted in area 3b of the somatosensory cortex in the same group of brains and were normal in all psychiatric groups. Glia affect several processes, including regulation of extracellular potassium, glucose storage and metabolism, and glutamate uptake, all of which are crucial for normal neuronal activity. We thus have identified a biological marker associated with familial mood disorders that may provide important clues regarding the pathogenesis of these common psychiatric conditions." [Full Text]

Drevets WC, Ongur D, Price JL.
Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders.
Mol Psychiatry 1998 May;3(3):220-6, 190-1
"The prefrontal cortex (PFC) ventral to the genu of the corpus callosum has been implicated in the modulation of visceral responses to stressful and emotionally provocative stimuli, based upon analysis of lesion effects involving this area in humans and experimental animals. In a recent magnetic resonance imaging (MRI) study of familial mood disorders, we demonstrated that the mean grey matter volume of this cortex is abnormally reduced in subjects with major depressive disorder (MDD) and bipolar disorder, irrespective of their treatment status or current mood state. Moreover, in preliminary histopathological assessments of subgenual PFC tissue taken post mortem from subjects with MDD and bipolar disorder we obtained results suggesting that this decrement in grey matter volume is associated with a reduction in glia without an equivalent loss of neurons. The potential functional significance of these neuroimaging and microscopic abnormalities is discussed with respect to evidence that subgenual PFC dysfunction may disturb stress-related autonomic and neuroendocrine responses and reward-related mesolimbic dopamine function. These data may thus hold important implications for the development of neural models of mood disorders that can account for the abnormal hedonic, motivational, neuroendocrine, and autonomic manifestations evident in these idiopathic conditions." [Abstract]

Brambilla P, Nicoletti MA, Harenski K, Sassi RB, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC.
Anatomical MRI study of subgenual prefrontal cortex in bipolar and unipolar subjects.
Neuropsychopharmacology. 2002 Nov;27(5):792-9.
"This study attempted to replicate previous findings of decreased gray matter content in the subgenual prefrontal cortex (SGPFC) in mood disorder patients. Eighteen DSM-IV unipolar patients, 27 DSM-IV bipolar patients, and 38 healthy controls were studied. A 1.5T GE Signa Imaging System with Signa 5.4.3 software was used. The semi-automated software MedX (Sensor Systems, Sterling, VA) was utilized for the anatomical measures of SGPFC volumes. There were no significant differences in SGPFC volumes in familial and non-familial unipolar and bipolar patients compared with healthy controls, nor between drug-free and lithium-treated bipolar patients (ANOVA, p >.05). In vivo abnormalities in the volumes of SGPFC were not identified in mildly depressed or euthymic unipolar or bipolar mood disorder outpatients, either familial or non-familial." [Abstract]

Gooding DC, Tallent KA.
The association between antisaccade task and working memory task performance in schizophrenia and bipolar disorder.
J Nerv Ment Dis 2001 Jan;189(1):8-16
"To date, the research literature has yielded conflicting reports regarding the specificity of antisaccade deficits to schizophrenia. We sought to examine antisaccade and working memory task performance in schizophrenia patients and bipolar patients, as well as to examine the relationship between the two tasks in both patient populations. Thirty-four schizophrenia patients, 20 bipolar patients, and 30 nonpatient controls were administered saccadic inhibition (antisaccade), working memory, and sensorimotor tasks. Compared with the controls, the schizophrenia patients displayed both antisaccade deficits and working memory deficits. In contrast, the bipolar patients produced significantly more errors on the antisaccade task than the controls, though the bipolar group performed similarly to the control group on the working memory task. Mediational analyses demonstrated that working memory partially mediates the relationship between patients' diagnostic group status and antisaccade task performance; working memory performance contributed uniquely to the prediction of antisaccade task performance in the two patient groups. Antisaccade deficits do not appear specific to schizophrenia. The results suggest that in schizophrenia, working memory and antisaccade tasks are tapping similar cognitive processes, whereas in bipolar patients the processes underlying antisaccade and working memory performance are disparate." [Abstract]


->Back to Home<- //->Back to Bipolar Disorder Index<-

Recent Bipolar Disorder & PFC Research

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

2) Sprooten E, McIntosh AM, Lawrie SM, Hall J, Sussmann JE, Dahmen N, Konrad A, Bastin ME, Winterer G
An investigation of a genomewide supported psychosis variant in ZNF804A and white matter integrity in the human brain.
Magn Reson Imaging. 2012 Jul 25;
ZNF804A, a genomewide supported susceptibility gene for schizophrenia and bipolar disorder, has been associated with task-independent functional connectivity between the left and right dorsolateral prefrontal cortices. Several lines of evidence have converged on the hypothesis that this effect may be mediated by structural connectivity. We tested this hypothesis using diffusion tensor magnetic resonance imaging in three samples: one German sample of 50 healthy individuals, one Scottish sample of 83 healthy individuals and one Scottish sample of 84 unaffected relatives of bipolar patients. Voxel-based analysis and tract-based spatial statistics did not detect any fractional anisotropy (FA) differences between minor allele carriers and individuals homozygous for the major allele at rs1344706. Similarly, region-of-interest analyses and quantitative tractography of the genu of the corpus callosum revealed no significant FA differences between the genotype groups. Examination of effect sizes and confidence intervals indicated that this negative finding is very unlikely to be due to a lack of statistical power. In summary, despite using various analysis techniques in three different samples, our results were strikingly and consistently negative. These data therefore suggest that it is unlikely that the effects of genetic variation at rs1344706 on functional connectivity are mediated by structural integrity differences in large, long-range white matter fiber connections. [PubMed Citation] [Order full text from Infotrieve]

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

4) Sinclair D, Webster MJ, Fullerton JM, Shannon Weickert C
Glucocorticoid receptor mRNA and protein isoform alterations in the orbitofrontal cortex in schizophrenia and bipolar disorder.
BMC Psychiatry. 2012 Jul 20;12(1):84.
ABSTRACT: BACKGROUND: The orbitofrontal cortex (OFC) may play a role in the pathogenesis of psychiatric illnesses such as bipolar disorder and schizophrenia, in which hypothalamic-pituitary-adrenal (HPA) axis abnormalities are observed and stress has been implicated. A critical component of the HPA axis which mediates cellular stress responses in the OFC, and has been implicated in psychiatric illness, is the glucocorticoid receptor (GR). METHODS: In the lateral OFC, we employed quantitative real-time PCR and western blotting to investigate GR mRNA and protein expression in 34 bipolar disorder cases, 35 schizophrenia cases and 35 controls. Genotype data for eleven GR gene (NR3C1) polymorphisms was also used to explore possible effects of NR3C1 sequence variation on GR mRNA and protein expression in the lateral OFC. RESULTS: We found no diagnostic differences in pan GR, GR-1C or GR-1F mRNA expression. However, the GR-1B mRNA transcript variant was decreased (14.3%) in bipolar disorder cases relative to controls (p<0.05), while GR-1H mRNA was decreased (22.0%) in schizophrenia cases relative to controls (p<0.005). By western blotting, there were significant increases in abundance of a truncated GRalpha isoform, putative GRalpha-D1, in bipolar disorder (56.1%, p<0.005) and schizophrenia (31.5% p<0.05). Using genotype data for eleven NR3C1 polymorphisms, we found no evidence of effects of NR3C1 genotype on GR mRNA or GRalpha protein expression in the OFC. CONCLUSIONS: These findings reveal selective abnormalities of GR mRNA expression in the lateral OFC in psychiatric illness, which are more specific and may be less influenced by NR3C1 genotype than those of the dorsolateral prefrontal cortex reported previously. Our results suggest that the GRalpha-D1 protein isoform may be up-regulated widely across the frontal cortex in psychiatric illness. [PubMed Citation] [Order full text from Infotrieve]

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

6) 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]

7) Bellani M, Bonivento C, Brambilla P
Interaction between cognition and emotion in developmental psychopathology: the role of linguistic stimuli.
Epidemiol Psychiatr Sci. 2012 May 15;:1-5.
Investigations on emotional words demonstrated that processing emotional information in child patients with anxiety disorders diagnosed for anxiety (generalized anxiety disorder and post-traumatic stress disorder) or depression is biased towards pathology-related stimuli. Also, neuroimaging studies showed a failure of prefrontal areas in inhibiting the emotional reaction in children with bipolar disorder. Finally, despite several studies investigated memory and attention using emotional words, little is known about the development of emotional lexicon in both healthy and psychopathological children. [PubMed Citation] [Order full text from Infotrieve]

8) Keilp JG, Gorlyn M, Russell M, Oquendo MA, Burke AK, Harkavy-Friedman J, Mann JJ
Neuropsychological function and suicidal behavior: attention control, memory and executive dysfunction in suicide attempt.
Psychol Med. 2012 Jul 10;:1-13.
BACKGROUND: Executive dysfunction, distinct from other cognitive deficits in depression, has been associated with suicidal behavior. However, this dysfunction is not found consistently across samples. Method Medication-free subjects with DSM-IV major depressive episode (major depressive disorder and bipolar type I disorder) and a past history of suicidal behavior (n=72) were compared to medication-free depressed subjects with no history of suicidal behavior (n=80) and healthy volunteers (n=56) on a battery of tests assessing neuropsychological functions typically affected by depression (motor and psychomotor speed, attention, memory) and executive functions reportedly impaired in suicide attempters (abstract/contingent learning, working memory, language fluency, impulse control). RESULTS: All of the depressed subjects performed worse than healthy volunteers on motor, psychomotor and language fluency tasks. Past suicide attempters, in turn, performed worse than depressed non-attempters on attention and memory/working memory tasks [a computerized Stroop task, the Buschke Selective Reminding Task (SRT), the Benton Visual Retention Test (VRT) and an N-back task] but not on other executive function measures, including a task associated with ventral prefrontal function (Object Alternation). Deficits were not accounted for by current suicidal ideation or the lethality of past attempts. A small subsample of those using a violent method in their most lethal attempt showed a pattern of poor executive performance. CONCLUSIONS: Deficits in specific components of attention control, memory and working memory were associated with suicidal behavior in a sample where non-violent attempt predominated. Broader executive dysfunction in depression may be associated with specific forms of suicidal behavior, rather than suicidal behavior per se. [PubMed Citation] [Order full text from Infotrieve]

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

10) Björkholm C, Jardemark K, Marcus MM, Malmerfelt A, Nyberg S, Schilström B, Svensson TH
Role of concomitant inhibition of the norepinephrine transporter for the antipsychotic effect of quetiapine.
Eur Neuropsychopharmacol. 2012 Jun 23;
Quetiapine alleviates both positive and negative symptoms as well as certain cognitive impairments in schizophrenia despite a low D(2) receptor occupancy and may also be used as monotherapy in bipolar and major depressive disorder. The mechanisms underlying the broad clinical utility of quetiapine remain to be clarified, but may be related to the potent inhibition of the norepinephrine transporter (NET) by norquetiapine, the major metabolite of quetiapine in humans. Since norquetiapine is not formed in rodents we here investigated in rats whether NET-inhibition may, in principle, contribute to the clinical effectiveness of quetiapine and allow for its low D(2) receptor occupancy, by combining quetiapine with the selective NET-inhibitor reboxetine. Antipsychotic-like activity was assessed using the conditioned avoidance response (CAR) test, dopamine output in the medial prefrontal cortex (mPFC) and the nucleus accumbens was measured using in vivo microdialysis, and NMDA receptor-mediated transmission was measured using intracellular electrophysiological recordings in pyramidal cells of the mPFC in vitro. Adjunct reboxetine potentiated the suppression of CAR by quetiapine. Moreover, concomitant administration of quetiapine and reboxetine resulted in a synergistic increase in cortical, but not accumbal, dopamine output. The combination of low, clinically relevant concentrations of quetiapine (60nM) and reboxetine (20nM) markedly facilitated cortical NMDA receptor-mediated transmission in contrast to either drug alone, an effect that could be inhibited by the D(1) receptor antagonist SCH23390. We conclude that concomitant NET-inhibition by norquetiapine may contribute to the overall antipsychotic effectiveness of quetiapine in spite of its relatively low level of D(2) occupancy. [PubMed Citation] [Order full text from Infotrieve]

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

12) Soeiro-de-Souza MG, Machado-Vieira R, Soares Bio D, Do Prado CM, Moreno RA
COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder.
Bipolar Disord. 2012 Aug;14(5):554-64.
Soeiro-de-Souza MG, Machado-Vieira R, Soares Bio D, Do Prado CM, Moreno RA. COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder. Bipolar Disord 2012: 14: 554-564. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective:? The dopaminergic system plays an important role in the prefrontal cortex (PFC) and is believed to mediate cognitive dysfunction (CD) in bipolar disorder (BD). The enzyme catechol-O-methyltransferase (COMT) is involved in the catabolism of dopamine in the PFC, and an association between COMT single nucleotide polymorphisms (SNPs) and BD has been reported. COMT SNPs have also been associated with executive and working memory performance in healthy subjects, patients with schizophrenia, and euthymic BD patients. The objective of this study was to investigate the association between COMT SNPs and acute CD during BD mood episodes. Methods:? Seventy-two symptomatic, medication-free subjects with bipolar I disorder (BD-I) and 76 healthy controls were evaluated using neuropsychological tests, and genotyped for COMT SNPs rs4680 and rs165599. Results:? Patients undergoing mania and mixed episodes carrying the COMT allele G had better performance on executive function, memory, verbal fluency, and intelligence tests. Moreover, an interaction was detected between the COMT allele G and the Young Mania Rating Scale in BD CD. Conclusions:? Allele G from COMT SNPs rs4680 and rs165599 may represent reliable state-dependent predictors of global CD during manic and mixed episodes in BD. Further studies in larger samples are necessary to confirm these findings. [PubMed Citation] [Order full text from Infotrieve]

13) Yucel K, Nazarov A, Taylor VH, Macdonald K, Hall GB, Macqueen GM
Cerebellar vermis volume in major depressive disorder.
Brain Struct Funct. 2012 Jun 14;
The vermis is located in the midline of the cerebellum and is involved in the regulation of affect and cognitive processes. Although changes in vermis size have been reported in several psychiatric disorders such as schizophrenia and bipolar disorder, no volumetric studies have been conducted on samples of patients with major depressive disorder (MDD). One-hundred and five adult subjects were recruited: 35 patients who were presenting for first treatment (FT; 22 females), 35 patients with known previous treatment (PT; 22 females), and 35 healthy controls (NC; 22 females), matched for age and gender. We compared the volumes of the total vermis, the anterior lobe (V1), the superior-posterior lobe (V2), and the inferior-posterior lobe (V3), among these study groups. Anterior vermis (V1) was larger in patients with MDD with a long history of antidepressant treatment compared to healthy controls. This finding was evident only in men [F(2, 36) = 9.23, p = .001]. Patients in the FT group did not differ from healthy controls in any vermian region. We found no correlations between vermian subregional volumes and clinical variables such as illness duration or age at onset of illness. We speculate that the larger anterior vermis volumes might arise from abnormalities in connectivity or as compensatory responses to the prefrontal dysfunction noted in patients with MDD but confirmation of this hypothesis awaits further studies. [PubMed Citation] [Order full text from Infotrieve]

14) Roybal DJ, Singh MK, Roybal VJ, Cosgrove DE, Howe M, Kelley R, Goraly NB, Chang KD
Biological Evidence for a Neurodevelopmental Model of Pediatric Bipolar Disorder.
Isr J Psychiatry Relat Sci. 2012;49(1):28-43.
Bipolar disorder (BD) is a chronic illness with high morbidity and mortality. Pediatric onset BD has a more severe course of illness with higher rates of relapse and psychosocial impairment. Discovering interventions early in the course of BD in youth is paramount to preventing full illness expression and improve functioning in these individuals throughout the lifespan. It is therefore important to understand the mechanisms involved in the development of BD in order to determine which youth are at most risk and provide biological targets for early intervention. To serve this cause, we propose a neurodevelopmental model of BD, based on the existing data that implicate prefrontal - subcortical network dysfunction, caused by pre-existing genetic susceptibility and triggered by pathological reactions to stress and chronic inflammatory processes. [PubMed Citation] [Order full text from Infotrieve]

15) Adleman NE, Fromm SJ, Razdan V, Kayser R, Dickstein DP, Brotman MA, Pine DS, Leibenluft E
Cross-sectional and longitudinal abnormalities in brain structure in children with severe mood dysregulation or bipolar disorder.
J Child Psychol Psychiatry. 2012 Jun 1;
Background:? There is debate as to whether chronic irritability (operationalized as severe mood dysregulation, SMD) is a developmental form of bipolar disorder (BD). Although structural brain abnormalities in BD have been demonstrated, no study compares neuroanatomy among SMD, BD, and healthy volunteers (HV) either cross-sectionally or over time. Furthermore, the developmental trajectories of structural abnormalities in BD or SMD are unknown. This study provides such data in BD, SMD, and HV. Methods:? An optimized, modulated voxel-based morphometry (VBM) analysis was conducted on structural MRI scans from 201 children (78 SMD, 55 BD, and 68 HV). In addition, 92 children (31 SMD, 34 BD, and 27 HV) were rescanned after 2?years (mean interval 1.99?±?0.94?years), to compare time-related changes among the three groups. Results:? Cross-sectionally, the groups differed in gray matter (GM) volume in presupplementary motor area (pre-SMA), dorsolateral prefrontal cortex (DLPFC), insula, and globus pallidus. The cortical differences were driven mainly by increased GM volume in HV compared with BD and SMD. In globus pallidus, there was increased GM in BD compared with HV and SMD. Longitudinally, group-by-time interactions were evident in two clusters in the superior/inferior parietal lobule (R SPL/IPL) and in the precuneus. In both clusters, the interactions were driven by an abnormal increase in volume in BD. Conclusions:? Cross-sectionally, both BD and SMD are associated with structural abnormalities in frontal cortex, insula, and basal ganglia. Although some of these deficits overlap (insula and DLPFC), others differentiate SMD and BD (pre-SMA and globus pallidus). Abnormal developmental trajectories in lateral parietal cortex and precuneus are present in, and unique to, BD. Because of the high proportion of co-occurring ADHD in the SMD subjects, we could not separate effects of ADHD from those of SMD, and future research including a nonirritable ADHD group must address this issue. [PubMed Citation] [Order full text from Infotrieve]

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

17) 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.
[PubMed Citation] [Order full text from Infotrieve]

18) Jogia J, Dima D, Frangou S
Sex differences in bipolar disorder: a review of neuroimaging findings and new evidence.
Bipolar Disord. 2012 Jun;14(4):461-71.
[PubMed Citation] [Order full text from Infotrieve]

19) Whalley HC, Papmeyer M, Sprooten E, Lawrie SM, Sussmann JE, McIntosh AM
Review of functional magnetic resonance imaging studies comparing bipolar disorder and schizophrenia.
Bipolar Disord. 2012 Jun;14(4):411-31.
[PubMed Citation] [Order full text from Infotrieve]

20) Blond BN, Fredericks CA, Blumberg HP
Functional neuroanatomy of bipolar disorder: structure, function, and connectivity in an amygdala-anterior paralimbic neural system.
Bipolar Disord. 2012 Jun;14(4):340-55.
[PubMed Citation] [Order full text from Infotrieve]