The Thalamus in Bipolar Disorder -- Neurotransmitter.net

(Updated 1/12/04)

Juckel G, Hegerl U, Mavrogiorgou P, Gallinat J, Mager T, Tigges P, Dresel S, Schroter A, Stotz G, Meller I, Greil W, Moller HJ.
Clinical and biological findings in a case with 48-hour bipolar ultrarapid cycling before and during valproate treatment.
J Clin Psychiatry 2000 Aug;61(8):585-93
"BACKGROUND: The rare cases of patients with 48-hour ultrarapid cycling allow close investigation of mood cycles in affective disorders, because rhythmic changes in psychopathologic state and biological parameters happen very precisely. METHOD: A 67-year-old white man who had experienced bipolar 48-hour ultrarapid cycling (DSM-IV 296.80) for several years was studied without any medication and then again studied 4 weeks later during treatment with valproate (1800 mg/day). RESULTS: Objective and self ratings revealed pronounced manic states 1 day and depressed states the following day, which were found to be accompanied by rhythmic fluctuations in behavior and electroencephalographic parameters, blood cortisol and growth hormone levels (both elevated on depressive days), and urinary metanephrine (dopamine metabolite) and norepinephrine levels (both elevated on manic days). Using single photon emission computed tomography, regional blood flow in the left thalamus was lower than in the right thalamus on the manic day, while symmetric perfusion of the thalamus was found on the depressive day. Under valproate treatment, the patient remitted completely, and significant rhythmic changes in most of the biological parameters were no longer detectable. CONCLUSION: The biological findings in this patient with bipolar 48-hour ultrarapid cycling, which correspond to those in other types of affective disorders, suggest that disturbances in the diencephalon-pituitary axis may be especially correlated to pathologic changes of mood." [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]

Bogousslavsky J, Ferrazzini M, Regli F, Assal G, Tanabe H, Delaloye-Bischof A.
Manic delirium and frontal-like syndrome with paramedian infarction of the right thalamus.
J Neurol Neurosurg Psychiatry 1988 Jan;51(1):116-9
"A disinhibition syndrome affecting speech (with logorrhoea, delirium, jokes, laughs, inappropriate comments, extraordinary confabulations), was the main manifestation of a right-sided thalamic infarct involving the dorsomedian nucleus, intralaminar nuclei and medial part of the ventral lateral nucleus. Resolution of conflicting tasks was severely impaired, suggesting frontal lobe dysfunction. These abnormalities correlated with the finding on SPECT of a marked hypoperfusion in the overlying hemisphere predominating in the frontal region. We suggest that this behavioural syndrome was produced by disconnecting the dorsomedian nucleus from the frontal lobe and limbic system." [Abstract]

Cummings JL, Mendez MF.
Secondary mania with focal cerebrovascular lesions.
Am J Psychiatry 1984 Sep;141(9):1084-7
"The authors describe two patients with secondary mania associated with right thalamic infarctions. Both patients exhibited hemisensory loss, denial of illness, and amnesia for the manic episode. One improved with lithium therapy and the other recovered without specific pharmacologic intervention. A review of reported cases reveals that most focal lesions associated with secondary mania involve the diencephalic region and that the majority of lateralized lesions are on the right side." [Abstract]

Kromkamp M, Uylings HB, Smidt MP, Hellemons AJ, Burbach JP, Kahn RS.
Decreased thalamic expression of the homeobox gene DLX1 in psychosis.
Arch Gen Psychiatry. 2003 Sep;60(9):869-74.
"CONTEXT: A shared vulnerability to develop psychosis can be related to abnormalities in thalamic circuits in schizophrenia and bipolar disorder and could be a genetic link between these disorders. Homeobox genes involved in development and differentiation of the brain could play an important role in these disorders. OBJECTIVE: To determine whether patients with schizophrenia and bipolar disorder have different thalamic expression patterns of 2 homeobox genes, DLX1 and SHOX2 (alias OG12X or SHOT) compared with psychiatric and nonpsychiatric control subjects. DESIGN: Postmortem sections containing the thalamic mediodorsal nucleus were subjected to in situ hybridization with mouse Dlx1 and human SHOX2 RNA probes. The number of both DLX1- and SHOX2-positive neurons relative to Nissl-stained neurons was estimated in systematic randomly sampled volume probes.Patients Fifteen patients with schizophrenia, 15 with bipolar disorder with or without history of psychosis, 15 with major depressive disorder, and 15 nonpsychiatric controls from the Stanley Foundation Brain Bank. MAIN OUTCOME MEASURE: Relative numbers of DLX1- and SHOX2-positive neurons in patients with schizophrenia and bipolar disorder with history of psychosis compared with psychiatric and nonpsychiatric controls. RESULTS: Patients with a history of psychosis showed significantly decreased relative numbers of DLX1-positive neurons compared with patients without history of psychosis and nonpsychiatric controls (P =.02), whereas no differences could be found in relative numbers of SHOX2-positive neurons (P>.15). Results were obtained blind to diagnosis, symptoms, or any other variable except hemisphere. CONCLUSION: Decreased thalamic expression of DLX1 in schizophrenia and bipolar disorder with psychosis suggests shared genetic deficits in expression of this homeobox gene." [Abstract]

Manuel A. Castro-Alamancos, and Maria E. Calcagnotto
High-Pass Filtering of Corticothalamic Activity by Neuromodulators Released in the Thalamus During Arousal: In Vitro and In Vivo
J Neurophysiol 85: 1489-1497, 2001.
"The thalamus is the principal relay station of sensory information to the neocortex. In return, the neocortex sends a massive feedback projection back to the thalamus. The thalamus also receives neuromodulatory inputs from the brain stem reticular formation, which is vigorously activated during arousal. We investigated the effects of two neuromodulators, acetylcholine and norepinephrine, on corticothalamic responses in vitro and in vivo. Results from rodent slices in vitro showed that acetylcholine and norepinephrine depress the efficacy of corticothalamic synapses while enhancing their frequency-dependent facilitation. This produces a stronger depression of low-frequency responses than of high-frequency responses. The effects of acetylcholine and norepinephrine were mimicked by muscarinic and alpha(2)-adrenergic receptor agonists and blocked by muscarinic and alpha-adrenergic antagonists, respectively. Stimulation of the brain stem reticular formation in vivo also strongly depressed corticothalamic responses. The suppression was very strong for low-frequency responses, which do not produce synaptic facilitation, but absent for high-frequency corticothalamic responses. As in vitro, application of muscarinic and alpha-adrenergic antagonists into the thalamus in vivo abolished the suppression of corticothalamic responses induced by stimulating the reticular formation. In conclusion, cholinergic and noradrenergic activation during arousal high-pass filters corticothalamic activity. Thus, during arousal only high-frequency inputs from the neocortex are allowed to reach the thalamus. Neuromodulators acting on corticothalamic synapses gate the flow of cortical activity to the thalamus as dictated by behavioral state." [Full Text]

Castro-Alamancos, Manuel A.
Role of Thalamocortical Sensory Suppression during Arousal: Focusing Sensory Inputs in Neocortex
J. Neurosci. 2002 22: 9651-9655
"The thalamus serves as a gate that regulates the flow of sensory inputs to the neocortex, and this gate is controlled by neuromodulators from the brainstem reticular formation that are released during arousal. We found recently that sensory-evoked responses are suppressed in the neocortex during arousal. This sensory suppression results from the activity-dependent depression of the thalamocortical connection caused by increased tonic firing of thalamocortical cells during arousal. In the present study, the functional consequences of thalamocortical suppression during arousal were investigated using the vibrissae system of rodents. The results show that thalamocortical suppression is associated with a strong reduction in the spread of sensory inputs through the cortex, thus reducing the size of sensory representations. In addition, when the responses of single cells to principal and adjacent whiskers are compared, the response to the adjacent whiskers was found to be strongly suppressed, much more so than that of principal whiskers. Consequently, the receptive fields of cortical neurons become more focused to the principal whisker. The results indicate that thalamocortical suppression during arousal serves to focus sensory inputs to their appropriate representations in neocortex, which may be computationally helpful for the spatial processing of sensory information." [Abstract]

Guillery RW.
Anatomical evidence concerning the role of the thalamus in corticocortical communication: a brief review.
J Anat 1995 Dec;187 ( Pt 3):583-92
"Two distinct types of thalamic nucleus are proposed on the basis of the afferent fibres that they receive from ascending pathways and from the cerebral cortex. 'First order nuclei' receive primary afferent fibres, definable on the basis of their origin and their intrathalamic synaptic relationships, from ascending pathways. These nuclei receive corticothalamic afferents from pyramidal cells in cortical layer 6, which also send branches to the thalamic reticular nucleus and appear to have a modulatory function. 'Higher order nuclei' receive most or all of their 'primary afferents' from pyramidal cells in cortical layer 5. These resemble the ascending primary afferents in the first order nuclei in terms of fine structure, synaptic relationships and in lacking a branch to the thalamic reticular nucleus. The higher order nuclei also receive modulatory afferents from layer 6. It is proposed that the higher-order nuclei are largely concerned with transmitting information about the output of one cortical area to another cortical area, and that they are likely to play a key role in corticocortical communication and higher cortical functions." [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]
Dasari M, Friedman L, Jesberger J, Stuve TA, Findling RL, Swales TP, Schulz SC.
A magnetic resonance imaging study of thalamic area in adolescent patients with either schizophrenia or bipolar disorder as compared to healthy controls.
Psychiatry Res 1999 Oct 11;91(3):155-62
"The purpose of this study was to compare thalamic size in adolescent patients with either schizophrenia or bipolar disorder and healthy controls. T2-weighted axial magnetic resonance images were used to manually define the area of the thalamus for 20 schizophrenia patients, 15 bipolar patients and 16 normal control subjects, all of whom were adolescents. Two orthogonal planned contrasts were tested: Contrast 1, patients with schizophrenia vs. patients with bipolar disorder; and Contrast 2, both patient groups taken as a single group compared to controls. Contrast 1 was not statistically significant for right or left thalamic area. Contrast 2 was statistically significant and indicated reductions in thalamic area in the patients as compared to controls. The same pattern of results emerged after adjustment for total brain volume. Our results indicate that thalamic abnormalities reported in adult schizophrenic and bipolar patients are also observed in adolescent patients. Our findings also add to the evidence implicating the thalamus in the pathophysiology of schizophrenia and bipolar disorder." [Abstract]
Caetano SC, Sassi R, Brambilla P, Harenski K, Nicoletti M, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC.
MRI study of thalamic volumes in bipolar and unipolar patients and healthy individuals.
Psychiatry Res 2001 Dec 30;108(3):161-8
"The thalamus is a key structure in brain anatomic circuits potentially involved in the pathophysiology of mood disorders. Available findings from studies that examined this brain region in mood disorder patients have been conflicting. To examine the hypothesis of anatomical abnormalities in the thalamus in patients with mood disorders, we conducted a magnetic resonance imaging (MRI) study in 25 bipolar patients (mean age+/-S.D.=34.4+/-9.8 years), 17 unipolar patients (mean age+/-S.D.=42.8+/-9.2 years), and 39 healthy control subjects (mean age+/-S.D.=36.6+/-9.7 years). Thalamic volumes Gray Matter were measured blindly with a semi-automated technique. Multivariate analysis of variance, with age and gender as covariates, revealed no significant differences in left or right thalamic volumes among bipolar patients, unipolar patients and healthy individuals. There were no significant effects of gender, age at illness onset, episode type, number of episodes, length of illness, or family history of mood disorders on thalamic measurements. Although functional abnormalities in the thalamus are likely to be implicated in the pathophysiology of mood disorders, no abnormalities in thalamic size appear present in bipolar or unipolar individuals." [Abstract]
Starkstein SE, Fedoroff P, Berthier ML, Robinson RG.
Manic-depressive and pure manic states after brain lesions.
Biol Psychiatry 1991 Jan 15;29(2):149-58
"Although mania is a rare complication of brain lesions, recent reports have emphasized the importance of lesion location and genetic predisposition in these patients. In the present study we compared patients who developed a bipolar affective disorder (i.e., mania and depression) after a brain lesion with patients who only developed mania. Although no significant between-group differences were found on demographic variables, the manic-depressed group showed significantly more impairments on the Mini Mental State Exam than the mania only group. All the bipolar patients had subcortical lesions (mainly right head of the caudate and right thalamus), while patients with unipolar mania had significantly higher frequency of cortical involvement (mainly right orbitofrontal and basotemporal cortices). It is suggested that subcortical and cortical right hemisphere lesions may produce different neurochemical and/or remote metabolic brain changes that may underlie the production of either a bipolar disease or a unipolar mania." [Abstract]
Zubieta JK, Huguelet P, Ohl LE, Koeppe RA, Kilbourn MR, Carr JM, Giordani BJ, Frey KA.
High vesicular monoamine transporter binding in asymptomatic bipolar I disorder: sex differences and cognitive correlates.
Am J Psychiatry 2000 Oct;157(10):1619-28
"OBJECTIVE: It has been hypothesized that anomalies in monoaminergic function underlie some of the manifestations of bipolar disorder. In this study the authors examined the possibility that trait-related abnormalities in the concentration of monoaminergic synaptic terminals may be present in patients with asymptomatic bipolar disorder type I. METHOD: The concentration of a stable presynaptic marker, the vesicular monoamine transporter protein (VMAT2), was quantified with (+)[(11)C]dihydrotetrabenazine (DTBZ) and positron emission tomography. Sixteen asymptomatic patients with bipolar I disorder who had a prior history of mania with psychosis (nine men and seven women) and individually matched healthy subjects were studied. Correlational analyses were conducted to examine the relationship between regional VMAT2 binding, cognitive function, and clinical variables. RESULTS: VMAT2 binding in the thalamus and ventral brainstem of the bipolar patients was higher than that in the comparison subjects. VMAT2 concentrations in these regions correlated with performance on measures of frontal, executive function. In addition, sex differences in VMAT2 binding were detected in the thalamus of the bipolar patients; the male patients had higher binding than the women. No sex differences in binding were observed in the healthy comparison group. CONCLUSIONS: These initial results suggest that higher than normal VMAT2 expression and, by extension, concentration of monoaminergic synaptic terminals, may represent a trait-related abnormality in patients with bipolar I disorder and that male and female patients show different patterns. Also, VMAT2 concentrations may be associated with some of the cognitive deficits encountered in euthymic bipolar disorder." [Abstract]
Deicken RF, Eliaz Y, Feiwell R, Schuff N.
Increased thalamic N-acetylaspartate in male patients with familial bipolar I disorder.
Psychiatry Res 2001 Feb 28;106(1):35-45
"N-Acetylaspartate (NAA) in the anterior and mediodorsal thalamic regions was measured using proton magnetic resonance spectroscopic imaging (1H-MRSI) in 15 euthymic male patients with familial bipolar I disorder and compared to values in 15 male control subjects to determine if there was evidence for altered neuronal/axonal integrity. MRI tissue segmentation methods were also utilized to obtain tissue-contribution estimates for each MRSI voxel. Relative to the comparison group, the patients with bipolar I disorder demonstrated significantly higher NAA and creatine in both the right and left thalamus. NAA was also significantly higher in the left thalamus compared to the right in both bipolar I patients and controls. There were no group or lateralized differences in the percentages of different tissue types within the MRSI voxels, suggesting that the thalamic NAA and creatine alterations were not an artifact of variations in tissue type percentages in the MRSI voxels. There was also no significant association between NAA or creatine and illness duration. The findings of increased thalamic NAA bilaterally may represent neuronal hypertrophy or hyperplasia, reduced glial cell density, or abnormal synaptic and dendritic pruning. Increased thalamic creatine bilaterally may represent altered cellular energy metabolism and is consistent with prior studies demonstrating changes in thalamic metabolism in mood disorders." [Abstract]
Kulisevsky J, Berthier ML, Gironell A, Pascual-Sedano B, Molet J, Pares P.
Mania following deep brain stimulation for Parkinson's disease.
Neurology. 2002 Nov 12;59(9):1421-4.
"Three patients with PD developed manic behavior after bilateral implantation of electrodes for deep-brain stimulation (DBS). Common to all three patients were manic symptoms unremitting after levodopa reduction or stimulation "off," lower electrodes positioning caudal to the subthalamic nucleus area, postoperative DBS with the lower contacts (0) of the quadripolar electrodes, and resolution of the manic episodes coinciding with stimulation through higher contacts." [Abstract]
Romito LM, Raja M, Daniele A, Contarino MF, Bentivoglio AR, Barbier A, Scerrati M, Albanese A.
Transient mania with hypersexuality after surgery for high frequency stimulation of the subthalamic nucleus in Parkinson's disease.
Mov Disord. 2002 Nov;17(6):1371-4.
"Among 30 Parkinson's disease patients who received high frequency stimulation of the subthalamic nucleus, 5 developed remarkable disorders of mood or sexual behavior after the implant. We describe 2 men who developed mania and hypersexuality a few days after the implant that lasted for some months and then gradually disappeared spontaneously." [Abstract]

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Recent Thalamus in Bipolar Disorder Research
1) Kempton MJ, Salvador Z, Munaf� MR, Geddes JR, Simmons A, Frangou S, Williams SC
Structural Neuroimaging Studies in Major Depressive Disorder: Meta-analysis and Comparison With Bipolar Disorder.
Arch Gen Psychiatry. 2011 Jul;68(7):675-90.
[PubMed Citation] [Order full text from Infotrieve]

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

3) Richieri R, Boyer L, Farisse J, Colavolpe C, Mundler O, Lancon C, Guedj E
Predictive value of brain perfusion SPECT for rTMS response in pharmacoresistant depression.
Eur J Nucl Med Mol Imaging. 2011 Jun 7;
PURPOSE: The aim of this study was to determine the predictive value of whole-brain voxel-based regional cerebral blood flow (rCBF) for repetitive transcranial magnetic stimulation (rTMS) response in patients with pharmacoresistant depression. METHODS: Thirty-three right-handed patients who met DSM-IV criteria for major depressive disorder (unipolar or bipolar depression) were included before rTMS. rTMS response was defined as at least 50% reduction in the baseline Beck Depression Inventory scores. The predictive value of (99m)Tc-ethyl cysteinate dimer (ECD) single photon emission computed tomography (SPECT) for rTMS response was studied before treatment by comparing rTMS responders to non-responders at voxel level using Statistical Parametric Mapping (SPM) (p??0.10). In comparison to responders, non-responders showed significant hypoperfusions (p?[PubMed Citation] [Order full text from Infotrieve]

4) Sui J, Pearlson G, Caprihan A, Adali T, Kiehl KA, Liu J, Yamamoto J, Calhoun VD
Discriminating schizophrenia and bipolar disorder by fusing fMRI and DTI in a multimodal CCA+ joint ICA model.
Neuroimage. 2011 Aug 1;57(3):839-55.
Diverse structural and functional brain alterations have been identified in both schizophrenia and bipolar disorder, but with variable replicability, significant overlap and often in limited number of subjects. In this paper, we aimed to clarify differences between bipolar disorder and schizophrenia by combining fMRI (collected during an auditory oddball task) and diffusion tensor imaging (DTI) data. We proposed a fusion method, "multimodal CCA+ joint ICA", which increases flexibility in statistical assumptions beyond existing approaches and can achieve higher estimation accuracy. The data collected from 164 participants (62 healthy controls, 54 schizophrenia and 48 bipolar) were extracted into "features" (contrast maps for fMRI and fractional anisotropy (FA) for DTI) and analyzed in multiple facets to investigate the group differences for each pair-wised groups and each modality. Specifically, both patient groups shared significant dysfunction in dorsolateral prefrontal cortex and thalamus, as well as reduced white matter (WM) integrity in anterior thalamic radiation and uncinate fasciculus. Schizophrenia and bipolar subjects were separated by functional differences in medial frontal and visual cortex, as well as WM tracts associated with occipital and frontal lobes. Both patients and controls showed similar spatial distributions in motor and parietal regions, but exhibited significant variations in temporal lobe. Furthermore, there were different group trends for age effects on loading parameters in motor cortex and multiple WM regions, suggesting that brain dysfunction and WM disruptions occurred in identified regions for both disorders. Most importantly, we can visualize an underlying function-structure network by evaluating the joint components with strong links between DTI and fMRI. Our findings suggest that although the two patient groups showed several distinct brain patterns from each other and healthy controls, they also shared common abnormalities in prefrontal thalamic WM integrity and in frontal brain mechanisms. [PubMed Citation] [Order full text from Infotrieve]

5) Marchand WR, Lee JN, Garn C, Thatcher J, Gale P, Kreitschitz S, Johnson S, Wood N
Striatal and cortical midline activation and connectivity associated with suicidal ideation and depression in bipolar II disorder.
J Affect Disord. 2011 May 26;
BACKGROUND: Considerable evidence implicates dysfunction of striatal and cortical midline structure (CMS) circuitry in mood disorders. Whether such aberrations exist in bipolar II depression is unknown. METHODS: Sixteen unmedicated subjects with bipolar II depression and 19 healthy controls were studied using functional MRI and a motor activation paradigm. Analyses of both activation and functional connectivity were conducted. RESULTS: A history of suicidal ideation (SI) was negatively correlated with activation of the left putamen while depression severity was positively correlated with activation of the left thalamus. The superior bilateral putamen was simultaneously correlated with depression severity and anti-correlated with SI. Striatal functional connectivity was altered with the bilateral CMS and right inferior parietal lobule. Depression severity was correlated with strength of connectivity between the bilateral striatum and the right lingual gyrus and left cerebellum. LIMITATIONS: Only males experiencing an episode of major depression were studied. CONCLUSIONS: Striatal and CMS circuit abnormalities likely contribute to the neurobiology of bipolar II depression. Altered connectivity of the striatum may directly impact depression severity. Further, dissociable components of activation associated with depression severity and suicidal ideation may exist. Finally, the motor activation paradigm used in this study appears to be a useful probe of some neural processes underlying bipolar II depression. [PubMed Citation] [Order full text from Infotrieve]

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

7) Li Q, Li H, Roughton K, Wang X, Kroemer G, Blomgren K, Zhu C
Lithium reduces apoptosis and autophagy after neonatal hypoxia-ischemia.
Cell Death Dis. 2010;1:e56.
Lithium is used in the treatment of bipolar mood disorder. Reportedly, lithium can be neuroprotective in models of adult brain ischemia. The purpose of this study was to evaluate the effects of lithium in a model of neonatal hypoxic-ischemic brain injury. Nine-day-old male rats were subjected to unilateral hypoxia-ischemia (HI) and 2?mmol/kg lithium chloride was injected i.p. immediately after the insult. Additional lithium injections, 1?mmol/kg, were administered at 24-h intervals. Pups were killed 6, 24 or 72?h after HI. Lithium reduced the infarct volume from 24.7�2.9 to 13.8�3.3?mm(3) (44.1%) and total tissue loss (degeneration + lack of growth) from 67.4�4.4 to 38.4�5.9?mm(3) (43.1%) compared with vehicle at 72?h after HI. Injury was reduced in the cortex, hippocampus, thalamus and striatum. Lithium reduced the ischemia-induced dephosphorylation of glycogen synthase kinase-3? and extracellular signal-regulated kinase, the activation of calpain and caspase-3, the mitochondrial release of cytochrome c and apoptosis-inducing factor, as well as autophagy. We conclude that lithium could mitigate the brain injury after HI by inhibiting neuronal apoptosis. The lithium doses used were in the same range as those used in bipolar patients, suggesting that lithium might be safely used for the avoidance of neonatal brain injury. [PubMed Citation] [Order full text from Infotrieve]

8) de Castro-Manglano P, Mechelli A, Soutullo C, Gimenez-Amaya J, Ortu�o F, McGuire P
Longitudinal changes in brain structure following the first episode of psychosis.
Psychiatry Res. 2011 Mar 31;191(3):166-73.
Both schizophrenia and bipolar disorder have been associated with progressive changes in grey matter (GM) volume. However, the temporal trajectories of these changes are poorly understood. The aim of this study was to assess longitudinal changes in grey matter volume subsequent to the first episode of schizophrenia and of affective psychoses. Adolescent patients with a first episode psychosis (n=26) were scanned twice using magnetic resonance imaging, at first presentation and after a 3-year follow-up period. An age-matched group of healthy volunteers (n=17) was scanned at the same time points. Within-group and between-group changes in regional grey matter volume were examined using voxel-based morphometry. There were significant group by time interactions (p(FDRcorr)<0.05) in the frontal, temporal, parietal, cerebellar cortex, and in the thalamus, mainly reflecting longitudinal reductions in the controls but not in the patients. Subdivision of the patient group revealed that there were similar longitudinal reductions in patients with affective psychoses as in the controls but no volumetric changes in patients with schizophrenia. Psychosis with onset in adolescence or early adulthood may be associated with a delay or a loss of longitudinal reductions in regional grey matter volume that normally occur at this stage of development. These changes may be specific to schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

9) Filiou MD, Turck CW, Martins-de-Souza D
Quantitative proteomics for investigating psychiatric disorders.
Proteomics Clin Appl. 2011 Feb;5(1-2):38-49.
The underlying pathophysiology of psychiatric disorders remains elusive. The use of quantitative proteomics to investigate disease-specific protein signatures holds great promise to improve the understanding of psychiatric disorders and identify relevant biomarkers. In this review, we discuss quantitative proteomic approaches for elucidating molecular mechanisms of psychiatric disorders, i.e. anxiety, schizophrenia, bipolar disorder and depression, by studying specimens from animal models and patients. We present gel-based, label-free and stable isotope-labeling methodologies and evaluate their strengths and limitations in the context of psychiatric research, with a focus on (15)N metabolic labeling of live animals due to its increased accuracy and potential for future applications. We also review biomarker candidate validation methods and present quantitative proteomic studies from the literature that aim to disentangle the molecular pathobiology of psychiatric disorders and identify candidate biomarkers. Finally, we explore the applicability of implementing proteomic methods as a routine diagnostic tool in the clinical laboratory. [PubMed Citation] [Order full text from Infotrieve]

10) Molina V, Galindo G, Cort�s B, de Herrera AG, Ledo A, Sanz J, Montes C, Hern�ndez-Tamames JA
Different gray matter patterns in chronic schizophrenia and chronic bipolar disorder patients identified using voxel-based morphometry.
Eur Arch Psychiatry Clin Neurosci. 2010 Dec 28;
Gray matter (GM) volume deficits have been described in patients with schizophrenia (Sz) and bipolar disorder (BD), but to date, few studies have directly compared GM volumes between these syndromes with methods allowing for whole-brain comparisons. We have used structural magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) to compare GM volumes between 38 Sz and 19 BD chronic patients. We also included 24 healthy controls. The results revealed a widespread cortical (dorsolateral and medial prefrontal and precentral) and cerebellar deficit as well as GM deficits in putamen and thalamus in Sz when compared to BD patients. Besides, a subcortical GM deficit was shown by Sz and BD groups when compared to the healthy controls, although a putaminal reduction was only evident in the Sz patients. In this comparison, the BD patients showed a limited cortical and subcortical GM deficit. These results support a partly different pattern of GM deficits associated to chronic Sz and chronic BD, with some degree of overlapping. [PubMed Citation] [Order full text from Infotrieve]

11) Mustak MS, Hegde ML, Dinesh A, Britton GB, Berrocal R, Subba Rao K, Shamasundar NM, Rao KS, Sathyanarayana Rao TS
Evidence of altered DNA integrity in the brain regions of suicidal victims of Bipolar Depression.
Indian J Psychiatry. 2010 Jul;52(3):220-8.
Deoxyribonucleic acid (DNA) integrity plays a significant role in cell function. There are limited studies with regard to the role of DNA damage in bipolar affective disorder (BP). In the present study, we have assessed DNA integrity, conformation, and stability in the brain region of bipolar depression (BD) patients (n=10) compared to age-matched controls (n=8). Genomic DNA was isolated from 10 postmortem BD patients' brain regions (frontal cortex, Pons, medulla, thalamus, cerebellum, hypothalamus, Parietal, temporal, occipital lobe, and hippocampus) and from the age-matched control subjects. DNA from the frontal cortex, pons, medulla, and thalamus showed significantly higher number of strand breaks in BD (P<0.01) compared to the age-matched controls. However, DNA from the hippocampus region was intact and did not show any strand breaks. The stability studies also indicated that the melting temperature and ethidium bromide binding pattern were altered in the DNA of BD patients' brain regions, except in the hippocampus. The conformation studies showed B-A or secondary B-DNA conformation (instead of the normal B-DNA) in BD patients' brain regions, with the exception of the hippocampus. The levels of redox metals such as Copper (Cu) and Iron (Fe) were significantly elevated in the brain regions of the sufferers of BD, while the Zinc (Zn) level was decreased. In the hippocampus, there was no change in the Fe or Cu levels, whereas, the Zn level was elevated. There was a clear correlation between Cu and Fe levels versus strand breaks in the brain regions of the BD. To date, as far as we are aware, this is a new comprehensive database on stability and conformations of DNA in different brain regions of patients affected with BD. The biological significance of these findings is discussed here. [PubMed Citation] [Order full text from Infotrieve]

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

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

14) Strakowski SM, Eliassen JC, Lamy M, Cerullo MA, Allendorfer JB, Madore M, Lee JH, Welge JA, DelBello MP, Fleck DE, Adler CM
Functional magnetic resonance imaging brain activation in bipolar mania: evidence for disruption of the ventrolateral prefrontal-amygdala emotional pathway.
Biol Psychiatry. 2011 Feb 15;69(4):381-8.
[PubMed Citation] [Order full text from Infotrieve]

15) Fleck DE, Eliassen JC, Durling M, Lamy M, Adler CM, Delbello MP, Shear PK, Cerullo MA, Lee JH, Strakowski SM
Functional MRI of sustained attention in bipolar mania.
Mol Psychiatry. 2010 Oct 26;
We examined sustained attention deficits in bipolar disorder and associated changes in brain activation assessed by functional magnetic resonance imaging (fMRI). We hypothesized that relative to healthy participants, those with mania or mixed mania would (1) exhibit incremental decrements in sustained attention over time, (2) overactivate brain regions required for emotional processing and (3) progressively underactivate attentional regions of prefrontal cortex. Fifty participants with manic/mixed bipolar disorder (BP group) and 34 healthy comparison subjects (HC group) received an fMRI scan while performing a 15-min continuous performance task (CPT). The data were divided into three consecutive 5-min vigilance periods to analyze sustained attention. Composite brain activation maps indicated that both groups activated dorsal and ventral regions of an anterior-limbic network, but the BP group exhibited less activation over time relative to baseline. Consistent with hypotheses 1 and 2, the BP group showed a marginally greater behavioral CPT sustained attention decrement and more bilateral amygdala activation than the HC group, respectively. Instead of differential activation in prefrontal cortex over time, as predicted in hypothesis 3, the BP group progressively decreased activation in subcortical regions of striatum and thalamus relative to the HC group. These results suggest that regional activation decrements in dorsolateral prefrontal cortex accompany sustained attention decrements in both bipolar and healthy individuals. Stable amygdala overactivation across prolonged vigils may interfere with sustained attention and exacerbate attentional deficits in bipolar disorder. Differential striatal and thalamic deactivation in bipolar disorder is interpreted as a loss of amygdala (emotional brain) modulation by the ventrolateral prefrontal-subcortical circuit, which interferes with attentional maintenance.Molecular Psychiatry advance online publication, 26 October 2010; doi:10.1038/mp.2010.108. [PubMed Citation] [Order full text from Infotrieve]

16) Pavuluri MN, Passarotti AM, Harral EM, Sweeney JA
Enhanced prefrontal function with pharmacotherapy on a response inhibition task in adolescent bipolar disorder.
J Clin Psychiatry. 2010 Nov;71(11):1526-34.
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17) Chan WY, Yang GL, Chia MY, Woon PS, Lee J, Keefe R, Sitoh YY, Nowinski WL, Sim K
Cortical and subcortical white matter abnormalities in adults with remitted first-episode mania revealed by Tract-Based Spatial Statistics.
Bipolar Disord. 2010 Jun;12(4):383-9.
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18) Rimol LM, Hartberg CB, Nesv�g R, Fennema-Notestine C, Hagler DJ, Pung CJ, Jennings RG, Haukvik UK, Lange E, Nakstad PH, Melle I, Andreassen OA, Dale AM, Agartz I
Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder.
Biol Psychiatry. 2010 Jul 1;68(1):41-50.
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19) Liu JX, Chen YS, Hsieh JC, Su TP, Yeh TC, Chen LF
Differences in white matter abnormalities between bipolar I and II disorders.
J Affect Disord. 2010 Dec;127(1-3):309-15.
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20) Winer JA, Bui LA, Hong JH, Prieto JJ, Larue DT
GABAergic organization of the auditory cortex in the mustached bat (Pteronotus p. parnellii).
Hear Res. 2011 Apr;274(1-2):105-20.
The structure and distribution of neurons and axon terminals (puncta) immunostained for gamma-aminobutyric acid (GABA) in the parietotemporal neocortex of the mustached bat (Pteronotus p. parnellii) was studied. The types of GABAergic neurons and puncta (putative terminals) were analyzed, and the immunocytochemical patterns were compared to those in cat auditory cortex (AC). The classic map of mustached bat primary auditory cortex (AI) corresponds to a belt of granular six-layered cortex on the temporal convexity. This area encompasses the Doppler-shifted constant frequency 60 kHz domain (DSCF) described in physiological investigations, as well as its flanking, low-frequency, posterior field (AIp) and the anterior high-frequency region (AIa). Many types of GABAergic neurons correspond to those in cat primary AC. However, the bat had a significantly lower proportion of such cells in five of the six layers. The classes of GABAergic neurons in most layers were small, medium-sized, and large multipolar cells, and bipolar and bitufted neurons. Types found in only one or two layers included horizontal cells (layers I and VI) or extraverted multipolar neurons (layer II). Only layer IV had comparable percentages (? 26%), suggesting that the GABAergic influence on lemniscal thalamocortical input is conserved phylogenetically. While the cellular basis for GABAergic cortical processing may reflect shared neural circuits and common modes of inhibitory processing, laminar differences could underlie adaptations specific to microchioptera. [PubMed Citation] [Order full text from Infotrieve]