Hippocampus In Bipolar Disorder Research Articles

Neurovascular correlates of retinal microvascular caliber in adolescent bipolar disorder

BackgroundThe connection between vascular and brain metrics is well-studied in older adults, but neglected in youth and in psychiatric populations at increased cardiovascular risk. We therefore examined the association of retinal vascular caliber with cerebral blood flow (CBF) in adolescents with and without bipolar disorder (BD). MethodsNinety-four adolescents (n = 48 BD, n = 46 controls) completed retinal fundus imaging, yielding estimates of arteriolar and venular diameter. Arterial spin labelling MRI was performed to measure CBF. We tested for associations between retinal vascular caliber and CBF in regions of interest; anterior cingulate cortex (ACC), middle frontal gyrus, and hippocampus in BD and controls separately. Complementary voxel-wise analyses were also performed. ResultsIn the BD group, higher arteriovenous ratio (AVR) was associated with greater ACC CBF (β = 0.34, puncorrected = 0.02), after controlling for age, sex, and BMI, however this finding did not survive correction for multiple comparisons. The control group did not show any associations (β = 0.13, puncorrected = 0.40). Voxel-wise analyses within the BD group detected a significant positive association between AVR and regional CBF in two distinct clusters: i) left hippocampus (p < 0.0001); ii) right middle temporal gyrus (p = 0.04). LimitationsLimited sample size; young, medically healthy sample limits signal detection; cross-sectional design. ConclusionThis study reveals that higher AVR is associated with higher regional CBF in adolescents with BD. Present findings advance understanding of potential neurofunctional mechanisms linking retinal vascular caliber with psychiatric diagnoses. This proof-of-concept study was designed to generate initial insights to guide future studies focusing on the vascular-brain connection in youth and in psychiatry.

Similar and Different Regional Homogeneity Changes Between Bipolar Disorder and Unipolar Depression: A Resting-State fMRI Study.

ObjectiveTo investigate the regional homogeneity (ReHo) between unipolar depression (UD) and bipolar disorder (BD), and to search for brain imaging markers for distinguishing UD and BD.MethodsA total of 58 patients who met the diagnosis criteria of UD in DSM–Ⅳ, 40 patients who met the diagnosis criteria of BD in DSM-Ⅳ and 54 healthy controls (HC) completed the resting-state functional magnetic resonance (rs-fMRI) scans. The ReHo of the three groups was compared and Pearson correlation analysis was performed between the ReHo values and the clinical symptoms.Results(1) Significant differences were found in the right hippocampus, right parahippocampal gyrus, right Inferior orbitofrontal gyrus, right superior temporal gyrus, right inferior temporal gyrus, and right middle occipital gyrus across the three groups. (2) Compared to HC, the ReHo in the right parahippocampal gyrus in UD significantly increased. (3) When compared to HC, the ReHo in the right hippocampus in BD significantly increased. The ReHo in the right middle occipital gyrus decreased. (4) Compared to UD, BD exhibited significantly decreased ReHo in the right inferior temporal gyrus. No correlations were observed between the scores of 24-item Hamilton Depression Rating Scale (HDMD-24), Hamilton Anxiety Scale (HAMA), Young Mania Rating Scale (YMRS), and the ReHo values of altered brain regions between BD and UD.ConclusionThe results suggest that there was a considerable difference in the ReHo of brain among UD, BD, and HCs. ReHo in the right inferior temporal gyrus showed significant differences between BD and UD that might serve as neuroimaging markers to identify BD and UD.

Variation in the CACNB2 gene is associated with functional connectivity of the Hippocampus in bipolar disorder

BackgroundCalcium voltage-gated channel auxiliary subunit β2 is a protein that, in humans, is encoded by the CACNB2 gene. The β2 subunit is an auxiliary protein of voltage-gated calcium channels, which is predominantly expressed in hippocampal pyramidal neurons. A single-nucleotide polymorphism at the CACNB2 gene (rs11013860) has been reported in genome-wide association studies to be associated with bipolar disorder (BD). However, the neural effects of rs11013860 expression are unknown. Thus, the current study investigated the mechanisms of how the CACNB2 gene influences hippocampal-cortical limbic circuits in patients with bipolar disorder (BD).MethodsA total of 202 subjects were studied [69 BD patients and 133 healthy controls (HC)]. Participants agreed to undergo resting-state functional magnetic resonance imaging (rs-fMRI) and have blood drawn for genetic testing. Participants were found to belong to either a CC group homozygous for the C-allele (17 BD, 41 HC), or an A-carrier group carrying the high risk A-allele (AA/CA genotypes; 52 BD, 92 HC). Brain activity was assessed using resting-state functional connectivity (rs-FC) analyses.ResultsA main effect of genotype showed that the rs-FC of the AA/CA group was elevated more than that of the CC-group between the hippocampus and the regions of right-inferior temporal, fusiform, and left-inferior occipital gyri. Additionally, a significant diagnosis × genotype interaction was noted between the hippocampus and right pars triangularis. Furthermore, in BD patients, the AA/CA group showed lower rs-FC when compared to that of the CC group. Additionally, individuals from HC within the AA/CA group showed higher rs-FC than that of the CC group. Finally, within C-allele-carrying groups, individuals with BD showed significantly increased rs-FC compared to that of HC.ConclusionsOur study demonstrates that BD patients with the CACNB2 rs11013860 AA/CA genotype may exhibit altered hippocampal-cortical connectivity.

Volume, metabolites and neuroinflammation of the hippocampus in bipolar disorder – A combined magnetic resonance imaging and positron emission tomography study

BackgroundThe hippocampus is one of the brain regions that is involved in several pathophysiological theories about bipolar disorder (BD), such as the neuroinflammation theory and the corticolimbic metabolic dysregulation theory. We compared hippocampal volume and hippocampal metabolites in bipolar I disorder (BD-I) patients versus healthy controls (HCs) with magnetic resonance imaging (MRI) and spectroscopy (MRS). We post hoc investigated whether hippocampal volume and hippocampal metabolites were associated with microglial activation and explored if potential illness modifying factors affected these hippocampal measurements and whether these were associated with experienced mood and functioning. Materials and methodsTwenty-two BD-I patients and twenty-four HCs were included in the analyses. All subjects underwent psychiatric interviews as well as an MRI scan, including a T1 scan and PRESS magnetic resonance spectroscopy (MRS). Volumetric analysis was performed with Freesurfer. MRS quantification was performed with LC Model. A subgroup of 14 patients and 11 HCs also underwent a successful [11C]-(R)-PK11195 neuroinflammation positron emission tomography scan. ResultsIn contrast to our hypothesis, hippocampal volumes were not decreased in patients compared to HC after correcting for individual whole-brain volume variations. We demonstrated decreased N-acetylaspartate (NAA)+N-acetyl-aspartyl-glutamate (NAAG) and creatine (Cr)+phosphocreatine (PCr) concentrations in the left hippocampus. In the explorative analyses in the left hippocampus we identified positive associations between microglial activation and the NAA+NAAG concentration, between alcohol use and NAA+NAAG concentration, between microglial activation and the depression score and a negative relation between Cr+PCr concentration and experienced occupational disability. Duration of illness associated positively with volume bilaterally. ConclusionCompared to HCs, the decreased NAA+NAAG concentration in the left hippocampus of BD-I patients suggests a decreased neuronal integrity in this region. In addition we found a positive relation between microglial activation and neuronal integrity in vivo, corresponding to a differentiated microglial function where some microglia induce apoptosis while others stimulate neurogenesis.

Three-dimensional mapping of hippocampal and amygdalar structure in euthymic adults with bipolar disorder not treated with lithium

Structural neuroimaging studies of the amygdala and hippocampus in bipolar disorder have been largely inconsistent. This may be due in part to differences in the proportion of subjects taking lithium or experiencing an acute mood state, as both factors have recently been shown to influence gray matter structure. To avoid these problems, we evaluated euthymic subjects not currently taking lithium. Thirty-two subjects with bipolar type I disorder and 32 healthy subjects were scanned using magnetic resonance imaging. Subcortical regions were manually traced, and converted to three-dimensional meshes to evaluate the main effect of bipolar illness on radial distance. Statistical analyses found no evidence for a main effect of bipolar illness in either region, although exploratory analyses found a significant age by diagnosis interaction in the right amygdala, as well as positive associations between radial distance of the left amygdala and both prior hospitalizations for mania and current medication status. These findings suggest that, when not treated with lithium or in an acute mood state, patients with bipolar disorder exhibit no structural abnormalities of the amygdala or hippocampus. Future studies, nevertheless, that further elucidate the impact of age, course of illness, and medication on amygdala structure in bipolar disorder are warranted.

Structure–function associations in hippocampus in bipolar disorder

Hippocampus volume decreases and verbal memory deficits have been reported in bipolar disorder (BD) as independent observations. We investigated potential associations between these deficits in subjects with BD. Hippocampus volumes were measured on magnetic resonance images of 31 subjects with BD and 32 healthy comparison (HC) subjects. The California Verbal Learning Test-Second Edition (CVLT) assessed verbal memory function in these subjects. Compared to the HC group, the BD group showed both significantly smaller hippocampus volumes and impaired performance on CVLT tests of immediate, short delay and long delay cued and free recall. Further, smaller hippocampus volume correlated with impaired performance in BD. Post hoc analyses revealed a trend towards improved memory in BD subjects taking antidepressant medications. These results support associations between morphological changes in hippocampus structure in BD and verbal memory impairment. They provide preliminary evidence pharmacotherapy may reverse hippocampus-related memory deficits.

Effects of the Brain-Derived Neurotrophic Growth Factor Val66Met Variation on Hippocampus Morphology in Bipolar Disorder

Histological and behavioral research in bipolar disorder (BD) implicates structural abnormalities in the hippocampus. Brain-derived neurotrophic growth factor (BDNF) protein is associated with hippocampal development and plasticity, and in mood disorder pathophysiology. We tested the hypotheses that both the BDNF val66met polymorphism and BD diagnosis are associated with decreased hippocampus volume, and that individuals with BD who carry the met allele have the smallest hippocampus volumes compared to individuals without BD and val/val homozygotes. We further explored localization of morphological differences within hippocampus in BD associated with the met allele. Twenty individuals with BD and 18 healthy comparison (HC) subjects participated in high-resolution magnetic resonance imaging scans from which hippocampus volumes were defined and measured. We used linear mixed model analysis to study effects of diagnosis and BDNF genotype on hippocampus volumes. We then employed three-dimensional mapping to localize areas of change within the hippocampus associated with the BDNF met allele in BD. We found that hippocampus volumes were significantly smaller in BD compared to HC subjects, and presence of the BDNF met allele was associated with smaller hippocampus volume in both diagnostic groups. The BD subgroup who carried the BDNF met allele had the smallest hippocampus volumes, and three-dimensional mapping identified these decreases as most prominent in left anterior hippocampus. These results support effects of BD diagnosis and BDNF genotype on hippocampus structure and suggest a genetic subgroup within BD who may be most vulnerable to deficits in hippocampus and may most benefit from interventions that influence BDNF-mediated signaling.

Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder

Objectives: Schizophrenia is associated with dysfunction of glutamatergic neurotransmission, and several studies have suggested glutamatergic abnormalities in bipolar disorder. Recent data suggest involvement of the NMDA receptor signaling complex, which includes NMDA receptor subunits as well as associated intracellular interacting proteins critical for NMDA receptor assembly, trafficking, and activation; the most well-characterized being PSD93, PSD95, SAP102, and NF-L. Previously, studies from our laboratories have described changes in glutamate receptor subunit transcript and binding site expression in schizophrenia and changes in NMDA receptor binding site expression in bipolar disorder in postmortem brain tissue. In the present work, we focus on the expression of these molecules in hippocampus in schizophrenia and bipolar affective disorder I. Methods: We performed in situ hybridization to assess hippocampal expression of the transcripts encoding NMDA receptor subunits NR1, 2A, 2B, 2C and 2D, and the transcripts for the NMDA receptor associated PSD proteins PSD95, PSD93, NF-L, and SAP102 in subjects with schizophrenia, bipolar affective disorder I, and a comparison group. We also measured [ 3H]CGP39653 and [ 3H]MK-801 binding site expression in the hippocampus in schizophrenia. Results: There was a significant decrease in the expression of transcripts for NR1 and NR2A subunits and SAP102 in bipolar disorder. We did not detect any changes in these transcripts or in binding site expression in the hippocampus in schizophrenia. Conclusions: We propose that the NMDA receptor signaling complex, including the intracellular machinery that is coupled to the NMDA receptor subunits, is abnormal in the hippocampus in bipolar disorder. These data suggest that bipolar disorder might be associated with abnormalities of glutamate-linked intracellular signaling and trafficking processes.

Hippocampus, III: GABA-Containing Cell Bodies and GAD mRNA

Back to table of contents Previous article Next article Images in NeuroscienceFull AccessHippocampus, III: GABA-Containing Cell Bodies and GAD mRNAStephan Heckers, M.D., and Francine Benes, M.D., Ph.D., Stephan HeckersSearch for more papers by this author, M.D., and Francine BenesSearch for more papers by this author, M.D., Ph.D., Belmont, Mass.Published Online:1 Mar 2005https://doi.org/10.1176/appi.ajp.162.3.450AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Neuronal signaling in the hippocampus is predominately mediated by excitatory, glutamatergic neurons. Their firing is modulated by a much smaller contingent of γ-aminobutyric acid (GABA)-containing interneurons. The balance between excitatory pyramidal cell firing and GABA-mediated inhibition determines hippocampal function. The rate-limiting enzyme of GABA synthesis is glutamic acid decarboxylase (GAD). Two different genes code for two isoforms of GAD protein found in the human brain, GAD65 and GAD67. The expression of GAD mRNA distinguishes the GABA-containing interneurons from the non-GABA-containing pyramidal neurons.The figure illustrates the relative density of GAD65 mRNA-positive neurons in the human hippocampus, taken from a comprehensive survey of healthy comparison subjects, patients with schizophrenia, and patients with bipolar disorder. The highest density of GAD mRNA-positive neurons is found in the cornu ammonis (CA) subfield 4. Intermediate levels are seen in CA 2/3 and CA 1, and the lowest levels are seen in the dentate gyrus (DG). The high-power photomicrograph in panel C (taken at a location indicated by the box in panel A) shows three GABA-containing neurons expressing GAD65 mRNA in CA 4 and the polymorph (p) and granule (g) layers of the dentate gyrus. In bipolar disorder patients, GAD mRNA-positive neurons are decreased in number, especially in CA 4, relative to healthy comparison subjects. These results suggest a decreased inhibition of pyramidal neuron activity in distinct regions of the hippocampus in bipolar disorder patients.Address reprint requests to Dr. Tamminga, UT Southwestern Medical Center, Department of Psychiatry, 5323 Harry Hines Blvd., #NC5.914, Dallas, TX 75390-9070; [email protected] (e-mail). figure FiguresReferencesCited byDetailsCited bySchizophrenia Research, Vol. 167, No. 1-3Neuropharmacology, Vol. 62, No. 3Neurobiology of Aging, Vol. 28, No. 11 Volume 162Issue 3 March 2005Pages 450-450 Metrics PDF download History Published online 1 March 2005 Published in print 1 March 2005

VASE-containing N-CAM isoforms are increased in the hippocampus in bipolar disorder but not schizophrenia.

The neural cell adhesion molecule (N-CAM) is a cell recognition molecule that is involved in cellular migration, synaptic plasticity, and CNS development. In schizophrenia, a 105- to 115-kDa N-CAM protein is increased in CSF and in the hippocampus and prefrontal cortex. The variable alternatively spliced exon (VASE) of N-CAM is developmentally regulated and can be spliced into any of the major 120-, 140-, and 180-kDa N-CAM isoforms. We determined that the variable alternative spliced exon of N-CAM (VASE) also is increased in bipolar disorder by quantitative Western immunoblot. VASE immunoreactive proteins (triplet bands around 140 kDa and a single band around 145 kDa) were identified in soluble and membrane brain extracts and quantified in the hippocampus. Soluble VASE 140 kDa was increased in the hippocampus of patients with bipolar disorder as compared to controls, patients with schizophrenia, and suicide cases. Membrane-extracted VASE 140 and 145 kDa were unchanged in the same groups. Multiple 145-kDa VASE-immunoreactive proteins that also reacted to an N-CAM antibody were separated by isoelectric focusing and electrophoresis followed by western immunoblotting; however, the VASE 140-kDa proteins were only weakly N-CAM immunoreactive. By immunohistochemistry, VASE colocalized with GFAP-positive astrocytes in the hippocampus. VASE immunostaining was also observed in the cytoplasm of CA4 pyramidal neurons that were positive for phosphorylated high molecular weight neurofilament and synaptophysin terminals. Thus no differences in VASE were found in patients with schizophrenia, but there was a marked increase of VASE immunoreactive proteins in bipolar disorder. It is possible that abnormal regulation of N-CAM proteins results in differing patterns of abnormal expression in neuropsychiatric disorders.