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) Singh MK, Delbello MP, Adler CM, Stanford KE, Strakowski SM
Neuroanatomical characterization of child offspring of bipolar parents.
J Am Acad Child Adolesc Psychiatry. 2008 May;47(5):526-31.
OBJECTIVE: To examine structural differences in selected anterior limbic brain regions between at-risk children of parents with bipolar I disorder and children with healthy parents. We hypothesized that at-risk (AR) children would exhibit abnormalities in brain regions that are involved in mood regulation. METHOD: Children (8-12 years old) of parents with bipolar I disorder (AR children, n = 21) and of parents without any DSM-IV Axis I disorder (healthy controls, n = 24) were evaluated using diagnostic assessments and brain magnetic resonance imaging. Morphometric analyses were used to examine group differences in the prefrontal cortical, thalamic, striatal, and amygdalar volumes. RESULTS: Nine (43%) of the AR children met DSM-IV-TR criteria for a nonbipolar mood disorder at the time of assessment. AR and healthy control children did not demonstrate statistically significant differences across regions of interest (Wilks lambda =.86, F4,39 = 1.64, p = .18; effect size, f = 0.19). Post hoc analyses of covariance showed the largest relative effect size was contributed by the prefrontal cortex (f = 0.26). CONCLUSIONS: Eight- to 12-year-old children with a familial risk for mania do not exhibit any statistically significant volumetric differences in the prefrontal cortex, thalamus, striatum, or amygdala as compared with age-matched children of parents without any psychopathology. Longitudinal studies examining whether structural changes over time may be associated with vulnerability for developing subsequent bipolar disorder are needed to clarify the underlying pathophysiology of this disorder. [PubMed Citation] [Order full text from Infotrieve]

2) Scherk H, Backens M, Schneider-Axmann T, Kemmer C, Usher J, Reith W, Falkai P, Gruber O
Neurochemical pathology in hippocampus in euthymic patients with bipolar I disorder.
Acta Psychiatr Scand. 2008 Apr;117(4):283-8.
OBJECTIVE: Subcortical regions such as hippocampus, thalamus and ventral putamen are assumed to be involved in the pathophysiology of mood regulation. Disturbed hippocampal neuronal function indicated by reduced N-acetyl-aspartate (NAA) levels in bipolar patients was shown by several studies. Results in thalamus and putamen are inconsistent. METHOD: N-acetyl-aspartate, choline (Cho), creatine (Cr) and myo-inositol (Ins) were measured in left hippocampus, left thalamus and left putamen using proton magnetic resonance spectroscopy in 13 euthymic patients with bipolar I disorder and 13 pairwise matched healthy control subjects. Metabolic ratios NAA/Cr, NAA/Cho, Cho/Cr and Ins/Cr were calculated. RESULTS: Patients with bipolar I disorder demonstrated significantly reduced NAA/Cr in the left hippocampus compared with healthy control subjects. No alterations were found in thalamus or putamen. CONCLUSION: We hypothesize that this NAA/Cr reduction might reflect neuronal dysfunction in the left hippocampus in patients with bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

3) Akimoto J, Namatame H, Haraoka J, Kudo M
Epithelioid glioblastoma: a case report.
Brain Tumor Pathol. 2005;22(1):21-7.
A 43-year-old woman who had undergone breast cancer surgery 1 year previously complained of headache and nausea. Her brain computed tomography (CT) scan and magnetic resonance imaging (MRI) showed a well-circumscribed, heterogeneously enhanced tumor in the right thalamus. She underwent gross total resection of the tumor followed by radiochemotherapy, and her clinical course was uneventful after surgery. Histological examination revealed a moderate number of tumor cells with fine bipolar processes in a mucoid matrix, which suggested pilocytic astrocytoma. The tumor was associated with microvascular proliferation but did not show significant mitosis or necrosis. In some areas, it had an epithelioid appearance, with ribbon-like, cribriform, and pseudoglandular patterns involving cuboid-shaped cells showing nuclear atypia and mitotic figures. Immunohistochemically, the tumor cells were positive for glial fibrillary acidic protein (GFAP) and vimentin in the area resembling pilocytic astrocytoma, but in the epithelioid area they were negative for GFAP and vimentin as well as for breast cancer markers, including AE1/AE3. The proliferating potential, represented by the MIB-1 labeling index, was high (82.5%) in the area of epithelioid appearance, compared to only 3% in the area of pilocytic astrocytoma-like appearance. As a rare histoarchitectural variant of glioblastoma, the epithelioid pattern may represent a very primitive tumor cell phenotype. Typically, this pattern is characterized by well-circumscribed masses, although its clinical significance is unknown. [PubMed Citation] [Order full text from Infotrieve]

4) Field GD, Sher A, Gauthier JL, Greschner M, Shlens J, Litke AM, Chichilnisky EJ
Spatial properties and functional organization of small bistratified ganglion cells in primate retina.
J Neurosci. 2007 Nov 28;27(48):13261-72.
The primate visual system consists of parallel pathways initiated by distinct cell types in the retina that encode different features of the visual scene. Small bistratified cells (SBCs), which form a major projection to the thalamus, exhibit blue-ON/yellow-OFF [S-ON/(L+M)-OFF] light responses thought to be important for high-acuity color vision. However, the spatial processing properties of individual SBCs and their spatial arrangement across the visual field are poorly understood. The present study of peripheral primate retina reveals that contrary to previous suggestions, SBCs exhibit center-surround spatial structure, with the (L+M)-OFF component of the receptive field approximately 50% larger in diameter than the S-ON component. Analysis of response kinetics shows that the (L+M)-OFF response in SBCs is slower than the S-ON response and significantly less transient than that of simultaneously recorded OFF-parasol cells. The (L+M)-OFF response in SBCs was eliminated by bath application of the metabotropic glutamate receptor agonist L-APB. These observations indicate that the (L+M)-OFF response of SBCs is not formed by OFF-bipolar cell input as has been suspected and suggest that it arises from horizontal cell feedback. Finally, the receptive fields of SBCs form orderly mosaics, with overlap and regularity similar to those of ON-parasol cells. Thus, despite their distinctive morphology and chromatic properties, SBCs exhibit two features of other retinal ganglion cell types: center-surround antagonism and regular mosaic sampling of visual space. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

5) Frazier JA, Hodge SM, Breeze JL, Giuliano AJ, Terry JE, Moore CM, Kennedy DN, Lopez-Larson MP, Caviness VS, Seidman LJ, Zablotsky B, Makris N
Diagnostic and sex effects on limbic volumes in early-onset bipolar disorder and schizophrenia.
Schizophr Bull. 2008 Jan;34(1):37-46.
OBJECTIVE: The limbic structures in early-onset schizophrenia-spectrum illness (SZ) and bipolar disorder (BPD) were studied to discern patterns associated with diagnosis and sex. METHODS: Thirty-five youths with DSM-IV BPD without psychosis, 19 with BPD with psychosis, 20 with SZ, and 29 healthy controls (HC), similar in age (6-17 years) and sex, underwent structured and clinical interviews, neurological examination, and cognitive testing. Structural magnetic resonance images (MRIs) were acquired on a 1.5 Tesla, General Electric Signa Scanner. Differences in subcortical brain volumes, including the amygdala and hippocampus, were evaluated using two-way (diagnosis, sex) univariate analyses covarying for total cerebral volume and age. RESULTS: Youth with SZ and BPD showed no differences in amygdala and hippocampal volumes. However, boys with SZ had smallest left amygdala and girls with BPD had the smallest left hippocampal volumes. In exploratory analyses, SZ showed reduced thalamic volumes bilaterally and both BPD groups had larger right nucleus accumbens (NA) volumes relative to HC. CONCLUSION: There were no limbic volumetric differences between BPD and SZ. However, there were diagnosis-by-sex interactions in the amygdala and hippocampus, structures that are rich in sex hormone receptors. In addition, smaller thalamus was associated with SZ while larger right NA volumes were most related to BPD. This study underscores the importance of assessing diagnostic effects and sex effects on the brain in future studies and provides evidence that boys and girls with SZ and BPD may have differential patterns of neuropathology associated with disease expression. [PubMed Citation] [Order full text from Infotrieve]

6) Biederman J, Makris N, Valera EM, Monuteaux MC, Goldstein JM, Buka S, Boriel DL, Bandyopadhyay S, Kennedy DN, Caviness VS, Bush G, Aleardi M, Hammerness P, Faraone SV, Seidman LJ
Towards further understanding of the co-morbidity between attention deficit hyperactivity disorder and bipolar disorder: a MRI study of brain volumes.
Psychol Med. 2008 Jul;38(7):1045-56.
BACKGROUND: Although attention deficit hyperactivity disorder (ADHD) and bipolar disorder (BPD) co-occur frequently and represent a particularly morbid clinical form of both disorders, neuroimaging research addressing this co-morbidity is scarce. Our aim was to evaluate the morphometric magnetic resonance imaging (MRI) underpinnings of the co-morbidity of ADHD with BPD, testing the hypothesis that subjects with this co-morbidity would have neuroanatomical correlates of both disorders.MethodMorphometric MRI findings were compared between 31 adults with ADHD and BPD and with those of 18 with BPD, 26 with ADHD, and 23 healthy controls. The volumes (cm3) of our regions of interest (ROIs) were estimated as a function of ADHD status, BPD status, age, sex, and omnibus brain volume using linear regression models. RESULTS: When BPD was associated with a significantly smaller orbital prefrontal cortex and larger right thalamus, this pattern was found in co-morbid subjects with ADHD plus BPD. Likewise, when ADHD was associated with significantly less neocortical gray matter, less overall frontal lobe and superior prefrontal cortex volumes, a smaller right anterior cingulate cortex and less cerebellar gray matter, so did co-morbid ADHD plus BPD subjects. CONCLUSIONS: Our results support the hypothesis that ADHD and BPD independently contribute to volumetric alterations of selective and distinct brain structures. In the co-morbid state of ADHD plus BPD, the profile of brain volumetric abnormalities consists of structures that are altered in both disorders individually. Attention to co-morbidity is necessary to help clarify the heterogeneous neuroanatomy of both BPD and ADHD. [PubMed Citation] [Order full text from Infotrieve]

7) Debaecker T, Benosman R
Bio-inspired model of visual information encoding for localization: from the retina to the lateral geniculate nucleus.
J Integr Neurosci. 2007 Sep;6(3):477-509.
In this study, a bio-inspired approach for extracting efficient features prior to the recognition of scenes is proposed. It is highly inspired from the model of the mammals visual system. The retina contains many levels of neurons (bipolar, amacrine, horizontal and ganglion cells) accurately organized from cones and rods to the optic nerve up till the lateral geniculate nucleus (LGN) which is the main thalamic relay for inputs to the visual cortex. This structure probably eases other brain areas tasks in preprocessing the visual information. This paper is focusing on the study of these specific structures, relying on a bottom up approach to propose a comprehensive mathematical model of the low level image processing performed within the eye. The presented system takes into account the foveolar structure of the retina to produce a low-resolution representation of observed images by decomposing them into a local summation of elementary gaussian color histograms. This representation corresponds to the LGN biological organization. It has been thought that due to short timings, some very quick localization tasks involving particularly fast information processing pathways cannot be provided by the classical ones passing through higher level cortical areas. This work proposes a model of retinal coding and LGN-visual representation that we show provides reliable and sufficient early features for scenes recognition and localization. Experiments on real scenes using the developed model are presented showing the efficiency of the approach on localization. [PubMed Citation] [Order full text from Infotrieve]

8) Goldman AL, Pezawas L, Mattay VS, Fischl B, Verchinski BA, Zoltick B, Weinberger DR, Meyer-Lindenberg A
Heritability of brain morphology related to schizophrenia: a large-scale automated magnetic resonance imaging segmentation study.
Biol Psychiatry. 2008 Mar 1;63(5):475-83.
BACKGROUND: Schizophrenia is a devastating psychiatric disorder with a strong genetic component that has been related to a number of structural brain alterations. Currently available data on the heritability of these structural changes are inconsistent. METHODS: To examine heritability of morphological alterations in a large sample, we used a novel and validated fully-automated whole brain segmentation technique to study disease-related variability and heritability in anatomically defined regions of interest in 221 healthy control subjects, 169 patients with schizophrenia, and 183 unaffected siblings. RESULTS: Compared with healthy control subjects, patients showed a bilateral decrease in hippocampal and cortical gray matter volume and increases in bilateral dorsal striatum and right lateral ventricle. No significant volumetric differences were found in unaffected siblings compared with normal control subjects in any structure. Post hoc analysis of the dorsal striatum showed the volumetric increase to be widespread, including caudate, putamen, and globus pallidus. With Risch's lambda (lambda(s)), we found strong evidence for heritability of reduced cortical volume and moderate evidence for hippocampal volume, whereas abnormal striatal and ventricle volumes showed no sign of heritability. Additional exploratory analyses were performed on amygdala, thalamus, nucleus accumbens, ventral diencephalon, and cerebral and cerebellar cortex and white matter. Of these regions, patients showed increased volume in ventral diencephalon and cerebellum. CONCLUSIONS: These findings support evidence of genetic control of brain volume even in adults, particularly of hippocampal and neocortical volume and of cortical volumetric reductions being familial, but do not support measures of subcortical volumes per se as representing intermediate biologic phenotypes. [PubMed Citation] [Order full text from Infotrieve]

9) Cannon DM, Ichise M, Rollis D, Klaver JM, Gandhi SK, Charney DS, Manji HK, Drevets WC
Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder.
Biol Psychiatry. 2007 Oct 15;62(8):870-7.
BACKGROUND: Altered serotonergic function is thought to play a role in the pathophysiology of major depressive episodes based upon evidence from neuroimaging, pharmacological, postmortem and genetic studies. It remains unclear, however, whether depressed samples that differ with respect to having shown a unipolar versus a bipolar illness course also would show distinct patterns of abnormalities within the serotonergic system. The current study compared serotonin transporter (5-HTT) binding between unipolar-depressives (MDD), bipolar-depressives (BD) and healthy-controls (HC) to assess whether the abnormalities in 5-HTT binding recently found in depressed subjects with BD extend to depressed subjects with MDD. METHODS: The 5-HTT binding-potential (BP) measured using positron emission tomography (PET) and [(11)C]DASB was compared between unmedicated, depressed subjects with MDD (n = 18) or BD (n = 18) and HC (n = 34). RESULTS: Relative to the healthy group both MDD and BD groups showed significantly increased 5-HTT BP in the thalamus (24%, 14%, respectively), insula (15%) and striatum (12%). The unipolar-depressives had elevated 5-HTT BP relative to both BD and HC groups in the vicinity of the periaqueductal gray (PAG, 20%, 22%, respectively). The bipolar-depressives had reduced 5-HTT BP relative to both HC and MDD groups in the vicinity of the pontine raphe nuclei. Depression-severity correlated negatively with 5-HTT BP in the thalamus in MDD-subjects. CONCLUSIONS: The depressed phases of MDD and BD both were associated with elevated 5-HTT binding in the insula, thalamus and striatum, but showed distinct abnormalities in the brainstem. The latter findings conceivably could underlie differences in the patterns of illness symptoms and pharmacological sensitivity observed between MDD and BD. [PubMed Citation] [Order full text from Infotrieve]

10) Bielau H, Steiner J, Mawrin C, Tr�bner K, Brisch R, Meyer-Lotz G, Brodhun M, Dobrowolny H, Baumann B, Gos T, Bernstein HG, Bogerts B
Dysregulation of GABAergic neurotransmission in mood disorders: a postmortem study.
Ann N Y Acad Sci. 2007 Jan;1096:157-69.
Alterations of GABAergic neurotransmission are assumed to play a crucial role in the pathophysiology of mood disorders. Gamma-aminobutyric acid (GABA) acts via binding to A and B receptors, whereas the B receptor is G protein-coupled. Glutamic acid decarboxylase (GAD) is the key enzyme of GABA synthesis. Immunohistochemical staining of GAD 65/67-immunoreactive neurons was performed in dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, superior temporal cortex, hippocampus formation, and mediodorsal thalamus with consecutive determination of neuronal density in 20 brains of patients with mood disorders (P) and 19 controls (C). In the patients' group were 11 patients with bipolar disorder (BD) and 9 patients with major depressive disorder (MDD). The data were tested statistically using analysis of variance (ANOVA) and post hoc Tukey tests. ANOVA revealed significant differences among the groups (C, BD, MDD) in dorsolateral prefrontal cortex, orbitofrontal cortex, superior temporal cortex, and hippocampus. Post hoc tests demonstrated higher neuronal densities in unipolar patients compared with bipolar patients and controls in dorsolateral prefrontal cortex, superior temporal cortex, and hippocampus. In the orbitofrontal cortex, a higher neuronal density was found in bipolar and unipolar patients compared with controls. In mood disorder patients, dose equivalents of antidepressants given prior to death correlated positively with the neuronal density in superior temporal cortex and hippocampus. The current data on GAD 65/67 point to a dysregulation of the GABAergic system in mood disorders. Possibly, existing deficits of GABAergic neurotransmission will be compensated or overcompensated by antidepressants. Additionally, albeit speculative, an imbalance between GABA production and transport might be of relevance. [PubMed Citation] [Order full text from Infotrieve]

11) Oquendo MA, Hastings RS, Huang YY, Simpson N, Ogden RT, Hu XZ, Goldman D, Arango V, Van Heertum RL, Mann JJ, Parsey RV
Brain serotonin transporter binding in depressed patients with bipolar disorder using positron emission tomography.
Arch Gen Psychiatry. 2007 Feb;64(2):201-8.
CONTEXT: Depression in bipolar disorder is clinically indistinguishable from that observed in major depressive disorder. As in major depression, selective serotonin reuptake inhibitors targeting brain serotonin transporters are first-line treatments for bipolar depression. Associations of serotonin transporter promoter polymorphisms and bipolarity have been reported; however, research on alterations in serotonergic neurotransmission in bipolar depression remains scant. OBJECTIVES: To assess in vivo brain serotonin transporter binding potential (BP(1), proportional to serotonin transporter number) in patients with bipolar depression and controls and to examine the relationship between serotonin transporter binding and genotype. DESIGN: Case-control study. SETTING: University hospital. PARTICIPANTS: A sample of 18 medication-free patients with bipolar depression and 41 controls. MAIN OUTCOME MEASURES: In vivo brain serotonin transporter binding was measured using positron emission tomography and radiolabeled trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline ([(11)C](+)-McNeil 5652). Participants were genotyped assessing biallelic and triallelic 5-HTTLPR polymorphisms. RESULTS: Patients with bipolar disorder had 16% to 26% lower serotonin transporter BP(1) in the midbrain, amygdala, hippocampus, thalamus, putamen, and anterior cingulate cortex. Triallelic 5-HTTLPR genotypes were unrelated to serotonin transporter BP(1). CONCLUSIONS: Lower serotonin transporter BP(1) in bipolar depression overlaps with that observed in major depression and suggests that serotonergic dysfunction is common to depressive conditions. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

12) Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C, Bernstein HG, Bogerts B
Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide.
J Psychiatr Res. 2008 Jan;42(2):151-7.
OBJECTIVES: Suicide has a high prevalence in patients with schizophrenia and affective disorder. Our recent postmortem study [Steiner J, Mawrin C, Ziegeler A, Bielau H, Ullrich O, Bernstein HG, Bogerts B. Distribution of HLA-DR-positive microglia in schizophrenia reflects impaired cerebral lateralization. Acta Neuropathologica (Berl) 2006;112:305-16.] revealed increased microglial densities in two schizophrenic patients who had committed suicide. Therefore, the hypothesis of microglial activation during acute psychosis was proposed. Alternatively, "suicide" could be a diagnosis-independent factor leading to microgliosis. METHODS: To clarify this question, microglial HLA-DR expression was analyzed by immunohistochemistry in the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), mediodorsal thalamus (MD) and hippocampus of 16 schizophrenics, 14 depressed patients with affective disorder and 10 matched controls. A subgroup of six schizophrenics and seven patients with affective disorder who committed suicide was included. RESULTS: ANOVA revealed no effect of diagnosis on microglial density (DLPFC: P=0.469; ACC: P=0.349; MD: P=0.569; hippocampus: P=0.497). However, significant microgliosis was observed in the DLPFC (P=0.004), ACC (P=0.012) and MD (P=0.004) of suicide patients. A similar trend was seen in the hippocampus (P=0.057). CONCLUSION: In conclusion, immunological factors may play a hitherto underestimated role in suicide. First, microglial activation might be interpreted as a consequence of presuicidal stress. Second, one might speculate a causal link between microglial activation and suicidal behaviour, such as neuroendocrine factors, cytokines, and nitric oxide, which are released from microglial cells and are known to modulate noradrenergic or serotonergic neurotransmission and thus may trigger suicidality. [PubMed Citation] [Order full text from Infotrieve]

13) Kaladjian A, Mazzola-Pomietto P, Jeanningros R, Azorin JM
[Brain structural abnormalities of bipolar disorder]
Encephale. 2006 Jul-Aug;32(4 Pt 1):421-36.
The number of structural neuroimaging studies of bipolar disorder have increased during recent years, expanding the literature on the nature of cerebral abnormalities underlying this disorder. The purpose of this paper is to provide a selective review on the main issues concerning this literature. Consistent findings are higher rate of periventricular and deep subcortical white matter hyperintensites seen on MRI. Although there is strong evidence for links between hyper-intense lesions and age or cardio-vascular risk factors, some authors have observed the presence of these abnormalities early in the course of the illness. There are also frequent reports on ventricular enlargement, which has been described as mild and predominant in the right lateral ventricle. Total cerebral volume appears to be preserved. Whereas changes in total grey matter volume are uncertain, evidence suggests that reduced white matter volume reflects genetic factors predisposing to the disorder. Recent studies have reported volume changes in several cortical areas including the subgenual cingular, frontal and temporal cortices. Additionally, a number of reports described morphometric abnormalities in various subcortical structures, such as amygdala, basal ganglia and thalamus. Part of the variability in the morphometric abnormalities might be attributable to differences in clinical status and demographic characteristics of patient groups. Despite some inconsistencies across the studies, it emerges that abnormalities are asymmetrically distributed throughout the two cerebral hemispheres. When increase in volume is reported, it is preferentially localised in the left cerebral hemi-sphere and more specifically in prefrontal and temporal cortices and in amygdala. By contrast, when structural abnormalities concern the right cerebral hemisphere, they are identified as deficits. These latter results are in direct line with those of studies of mania following brain injuries, which report that these secondary mania result mainly from right cerebral lesions. It is also important to notice that most of the abnormalities concern both the cortical and subcortical level, ie frontal, striatal, thalamic and limbic regions. These abnormalities highlight the role in the pathophysiology of bipolar disorder of the loops involved in emotional information processing. The particular role of fronto-limbic loops in the phenomenology of bipolar disorder have been emphasised by recent data from functional neuroimaging studies. [PubMed Citation] [Order full text from Infotrieve]

14) Young KA, Holcomb LA, Bonkale WL, Hicks PB, Yazdani U, German DC
5HTTLPR polymorphism and enlargement of the pulvinar: unlocking the backdoor to the limbic system.
Biol Psychiatry. 2007 Mar 15;61(6):813-8.
BACKGROUND: The 5HTTLPR genetic variant of the serotonin transporter (SERT), which consists of a long (SERT-l) and short (SERT-s) allele, has emerged as a major factor influencing emotional behavior and brain anatomy. The pulvinar nucleus of the thalamus projects to important limbic nuclei including the amygdala and cingulate cortex, is involved in the processing of stimuli with emotional content, and contains an abundance of SERT. METHODS: Stereological methods were used to measure pulvinar neuron number in postmortem tissue from major depressive disorder (n = 11), bipolar disorder (n = 11), schizophrenia (n = 12), and control (n = 15) specimens from the Stanley Foundation Neuropathology Consortium. The effect of SERT genotype on pulvinar volume and neuron number was investigated by using analysis of covariance. RESULTS: Analysis of covariance with diagnosis, SERT genotype, age, hemisphere, postmortem interval, and time-in-formalin covariates identified a 20% increase in pulvinar neuron number and volume in SERT-ss subjects. CONCLUSIONS: The elevated number of pulvinar neurons in subjects with a SERT-ss genotype may serve to enhance subcortical input of emotionally relevant stimuli to the limbic system, providing a mechanism for the 5HTTLPR genetic variant to affect predisposition to conditions such as major depression. [PubMed Citation] [Order full text from Infotrieve]

15) Adler CM, DelBello MP, Jarvis K, Levine A, Adams J, Strakowski SM
Voxel-based study of structural changes in first-episode patients with bipolar disorder.
Biol Psychiatry. 2007 Mar 15;61(6):776-81.
BACKGROUND: Although morphometric studies of bipolar disorder (BD) suggest that neurofunctional abnormalities reflect underlying structural changes, it remains unclear whether abnormalities are present at illness onset or reflect disease progression. Previous voxel-based morphometry (VBM) findings suggest that ventrolateral prefrontal cortex (VLPFC) changes develop over time, whereas morphologic abnormalities elsewhere in the anterior limbic network (ALN) are present early in BD. In this study, we used VBM to explore structural brain changes in first-episode bipolar patients. METHODS: First-episode bipolar (n = 33) and healthy (n = 33) subjects underwent magnetic resonance imaging. Images were normalized and compared on a voxel-by-voxel basis. RESULTS: Bipolar subjects showed no change in VLPFC density or volume. We observed increased volume in left thalamus and fusiform and cerebellum bilaterally; increased gray matter density in anterior cingulate and posterior parietal structures; and increased gray matter volume and density in middle/superior temporal and posterior cingulate gyri. No areas of decreased volume or density were observed. CONCLUSIONS: These data indicate that structural changes are absent from VLPFC early in the course of BD. Morphologic abnormalities are present in other portions of the ALN and in structures previously observed to mediate neurofunctional changes in BD, suggesting that dysfunctional neuronal proliferation or pruning may occur in bipolar patients. [PubMed Citation] [Order full text from Infotrieve]

16) Cannon DM, Ichise M, Fromm SJ, Nugent AC, Rollis D, Gandhi SK, Klaver JM, Charney DS, Manji HK, Drevets WC
Serotonin transporter binding in bipolar disorder assessed using [11C]DASB and positron emission tomography.
Biol Psychiatry. 2006 Aug 1;60(3):207-17.
BACKGROUND: Evidence from neuroimaging post-mortem, and genetic studies suggests that bipolar disorder (BD) is associated with abnormalities of the serotonin-transporter (5-HTT) system. Because of various limitations of these studies, however, it has remained unclear whether 5-HTT binding is abnormal in unmedicated BD-subjects. This study used PET and [(11)C]DASB, a radioligand that afforded higher sensitivity and specificity for the 5-HTT than previously available radioligands, to compare 5-HTT binding between BD and control subjects. METHODS: The 5-HTT binding-potential (BP) was assessed in 18 currently-depressed, unmedicated BD-subjects and 37 healthy controls using PET and [(11)C]DASB. RESULTS: In BD, the mean 5-HTT BP was increased in thalamus, dorsal cingulate cortex (DCC), medial prefrontal cortex and insula and decreased in the brainstem at the level of the pontine raphe-nuclei. Anxiety ratings correlated positively with 5-HTT BP in insula and DCC, and BP in these regions was higher in subjects manifesting pathological obsessions and compulsions relative to BD-subjects lacking such symptoms. Subjects with a history of suicide attempts showed reduced 5-HTT binding in the midbrain and increased binding in anterior cingulate cortex versus controls and to BD-subjects without attempts. CONCLUSIONS: This is the first study to report abnormalities in 5-HTT binding in unmedicated BD-subjects. The direction of abnormality in the brainstem was opposite to that found in the cortex, thalamus, and striatum. Elevated 5-HTT binding in the cortex may be related to anxiety symptoms and syndromes associated with BD. [PubMed Citation] [Order full text from Infotrieve]

17) Malhi GS, Lagopoulos J, Owen AM, Ivanovski B, Shnier R, Sachdev P
Reduced activation to implicit affect induction in euthymic bipolar patients: an fMRI study.
J Affect Disord. 2007 Jan;97(1-3):109-22.
OBJECTIVE: To examine whether euthymic bipolar patients engage similar or contrasting brain regions as healthy subjects when responding to implicit affect induction. METHODS: The study examined 10 euthymic patients with bipolar I disorder, and 10 age- and gender-matched healthy subjects using event-related functional magnetic resonance imaging (fMRI) while subjects engaged in a modified word-based memory task designed to implicitly evoke negative, positive or no affective change. The activation paradigm involved nominating whether a target word was contained within a previously presented word list using specified response keys. RESULTS: The fMRI task produced significantly greater activation in healthy subjects as compared to patients in response to both negative and positive affect in the anterior and posterior cingulate, medial prefrontal cortex, middle frontal and right parahippocampal gyri. Only negative affect produced significantly greater activation in the postcentral gyrus, inferior parietal lobule, thalamus and putamen and only positive affect achieved the same in the precentral, superior temporal and lingual gyri, precuneus, cuneus, caudate, pons, midbrain and cerebellum. There were no brain regions in which responses were greater in patients as compared to healthy subjects. There were no statistically significant differences between the groups with respect to speed or accuracy. CONCLUSIONS: Diminished prefrontal, cingulate, limbic and subcortical neural activity in euthymic bipolar patients as compared to healthy subjects is suggestive of emotional compromise that is independent of cognitive and executive functioning. This finding is of clinical importance and has implications both for the diagnosis and treatment of bipolar disorder. Future studies should aim to replicate these findings and examine the development of bipolar disorder, investigating in particular the effects of medication. [PubMed Citation] [Order full text from Infotrieve]

18) Javanbakht A
Sensory gating deficits, pattern completion, and disturbed fronto-limbic balance, a model for description of hallucinations and delusions in schizophrenia.
Med Hypotheses. 2006;67(5):1173-84.
Schizophrenia, if not the most difficult, is one of the most difficult mysterious puzzles for psychiatrists, psychologists, and neuroscientists to solve. In this paper, based on the previously known pathologies of schizophrenia, a new model is proposed for explanation of the formation of positive psychotic symptoms of hallucinations and delusions. This model can be used for understanding psychotic or psychotic-like positive symptoms of bipolar mood disorder, posttraumatic stress disorder, obsessive compulsive, and amphetamine and drug-induced psychotic disorders. Based on the postulated model, a spectral view on these disorders with psychotic features is also proposed. These pathologies include auditory sensory gating deficits in hippocampus, abnormal emotional coding in amygdala, pattern completion in thalamic and cortical areas, and disturbed fronto-limbic balance. This model includes anatomical and neurotransmitter defects of hippocampus, amygdala, thalamus, cingula, and prefrontal cortex and their interconnections. A role for hippocampal sensory gating deficits in the pathogenesis of positive psychotic symptoms and interrelation between amygdala and its dopamine level with hippocampus is speculated. This model also hires the interesting function of pattern completion in thalamus and cortical areas for a better explanation of the pathogenesis of hallucinations and delusional psychotic symptoms. Furthermore, there is also explanation for the polygenic etiology of the schizophrenic and psychotic disorders and relation between schizophrenia and bipolar mood disorder in anatomy and neural systems involved. A spectral view is proposed that explains the absence of clear cut border between different psychotic or psychotic-like disorders in their form and severity based on the involved genes and brain functional systems. Including excessive prefrontal pruning, there is also explanation for the appearance of positive psychotic symptoms in early adulthood. An explanation for the high dopamine level of amygdala despite its decreased size and abnormal anatomy is also suggested as a compensatory function which might explain the decline in positive psychotic symptoms when schizophrenics age according to amygdala burn out. Based on this model, speculations are provided for: late onset of the effects of antipsychotics on positive psychotic symptoms, mechanism for the therapeutic effect of serotonin type 2A receptor blockers and GABAergic medications in psychosis, role of smoking in diminution of psychotic symptoms, and relationship between biological and psychological issues in the formation of psychotic symptoms. Finally, based on this model, a new role for nicotinic cholinergic drugs (such as galantamine) for treatment of schizophrenia and other psychotic or psychotic-like disorders is proposed. [PubMed Citation] [Order full text from Infotrieve]

19) Hendrickson A, Djajadi H, Erickson A, Possin D
Development of the human retina in the absence of ganglion cells.
Exp Eye Res. 2006 Oct;83(4):920-31.
Retinal development was studied in eyes from fetal and neonatal human anencephalic (AnC) and normal age-matched infants to determine the time of retinal ganglion cell (GC) loss and its effect on the development of other retinal neurons. At fetal week (Fwk) 14, GC loss was evident in central retina and by Fwk 19-20 almost all GC were absent, although immunocytochemical labeling for GC markers brain 3, neurofilament M and parvalbumin detected a few GC in the AnC far periphery at older ages. The inner nuclear and inner plexiform (IPL) layers showed variable amounts of thinning but all normal bipolar (BP) and horizontal cell markers were still present. The amacrine (AM) labels calbindin and calretinin were markedly reduced. Lamination for these markers in the IPL was less organized than in normal retinas, with BP and AM markers extending into the degenerated GC layer. Cone and rod photoreceptors had normal morphology and topography in AnC retina and each expressed normal phototransduction and synaptic markers. The prospective fovea was identified in AnC neonatal retina by cone packing and the absence of immunolabeled rod photoreceptors. In one AnC neonatal retina, blood vessels and astrocytes extended across the inner retina in the putative fovea and there was no evidence of a pit. In another AnC neonatal retina, blood vessels and astrocytes formed a foveal avascular zone in the inner retina and a shallow pit was present within this zone. However, both foveas showed evidence for the onset of cone elongation and packing. These findings support the model of Springer and Hendrickson [2005; Vis. Neurosci. 22, 171] in which the foveal avascular zone is critical for pit formation, but suggest that mechanisms inherent to the outer retina may be involved in early stages of foveal cone packing. [PubMed Citation] [Order full text from Infotrieve]

20) Borsotto M, Cavarec L, Bouillot M, Romey G, Macciardi F, Delaye A, Nasroune M, Bastucci M, Sambucy JL, Luan JJ, Charpagne A, Jou�t V, L�ger R, Lazdunski M, Cohen D, Chumakov I
PP2A-Bgamma subunit and KCNQ2 K+ channels in bipolar disorder.
Pharmacogenomics J. 2007 Apr;7(2):123-32.
Many bipolar affective disorder (BD) susceptibility loci have been identified but the molecular mechanisms responsible for the disease remain to be elucidated. In the locus 4p16, several candidate genes were identified but none of them was definitively shown to be associated with BD. In this region, the PPP2R2C gene encodes the Bgamma-regulatory subunit of the protein phosphatase 2A (PP2A-Bgamma). First, we identified, in two different populations, single nucleotide polymorphisms and risk haplotypes for this gene that are associated to BD. Then, we used the Bgamma subunit as bait to screen a human brain cDNA library with the yeast two-hybrid technique. This led us to two new splice variants of KCNQ2 channels and to the KCNQ2 channel itself. This unusual K+ channel has particularly interesting functional properties and belongs to a channel family that is already known to be implicated in several other monogenic diseases. In one of the BD populations, we also found a genetic association between the KCNQ2 gene and BD. We show that KCNQ2 splice variants differ from native channels by their shortened C-terminal sequences and are unique as they are active and exert a dominant-negative effect on KCNQ2 wild-type (wt) channel activity. We also show that the PP2A-Bgamma subunit significantly increases the current generated by KCNQ2wt, a channel normally inhibited by phosphorylation. The kinase glycogen synthase kinase 3 beta (GSK3beta) is considered as an interesting target of lithium, the classical drug used in BD. GSK3beta phosphorylates the KCNQ2 channel and this phosphorylation is decreased by Li+. [PubMed Citation] [Order full text from Infotrieve]