Josselin Houenou

Neuroimaging-based markers of bipolar disorder: Evidence from two meta-analyses

BACKGROUND Bipolar disorder (BD) is often misdiagnosed or tardily detected, leading to inadequate treatment and devastating consequences. The identification of objective biomarkers, such as functional and structural brain abnormalities of BD might improve diagnosis and help elucidate its pathophysiology. METHODS To identify neurobiological markers of BD, two meta-analyses, one of functional neuroimaging studies related to emotional processing and a second of structural whole-brain neuroimaging studies in BD were conducted in the present study. Conducting a literature search on studies published up to September 2009 we identified 28 studies that were eligible for the meta-analyses: 13 functional magnetic resonance imaging studies, related to emotional processing and 15 structural imaging studies using whole-brain voxel-based morphometry. Only studies comparing patients with bipolar disorder to healthy controls were considered. Data were extracted or converted to a single anatomical reference (Talairach space). The activation likelihood estimation technique was used to assess the voxel-wise correspondence of results between studies. RESULTS In patients with BD, decreased activation and diminution of gray matter were identified in a cortical-cognitive brain network that has been associated with the regulation of emotions. By contrast, patients with BD exhibited increased activation in ventral limbic brain regions that mediate the experience of emotions and generation of emotional responses. The present study provides evidence for functional and anatomical alterations in BD in brain networks associated with the experience and regulation of emotions. CONCLUSIONS These alterations support previously proposed neurobiological models of BD and might represent valid neurobiological markers of the disorder. The specificity of these results to unipolar depression remains to be explored.

Biomarkers in bipolar disorder: A positional paper from the International Society for Bipolar Disorders Biomarkers Task Force

Although the etiology of bipolar disorder remains uncertain, multiple studies examining neuroimaging, peripheral markers and genetics have provided important insights into the pathophysiologic processes underlying bipolar disorder. Neuroimaging studies have consistently demonstrated loss of gray matter, as well as altered activation of subcortical, anterior temporal and ventral prefrontal regions in response to emotional stimuli in bipolar disorder. Genetics studies have identified several potential candidate genes associated with increased risk for developing bipolar disorder that involve circadian rhythm, neuronal development and calcium metabolism. Notably, several groups have found decreased levels of neurotrophic factors and increased pro-inflammatory cytokines and oxidative stress markers. Together these findings provide the background for the identification of potential biomarkers for vulnerability, disease expression and to help understand the course of illness and treatment response. In other areas of medicine, validated biomarkers now inform clinical decision-making. Although the findings reviewed herein hold promise, further research involving large collaborative studies is needed to validate these potential biomarkers prior to employing them for clinical purposes. Therefore, in this positional paper from the ISBD-BIONET (biomarkers network from the International Society for Bipolar Disorders), we will discuss our view of biomarkers for these three areas: neuroimaging, peripheral measurements and genetics; and conclude the paper with our position for the next steps in the search for biomarkers for bipolar disorder.

A meta-analysis of whole-brain diffusion tensor imaging studies in bipolar disorder.

OBJECTIVES White matter abnormalities are one of the most consistently reported findings in neuroimaging studies of bipolar disorder (BD). We conducted an anatomical likelihood estimation meta-analysis of BD whole-brain diffusion tensor imaging (DTI) studies, with the aim of identifying statistically consistent fractional anisotropy (FA) changes reflecting microstructural modifications to white matter in BD. METHODS We performed online searches of the PUBMED and EMBASE databases in January 2011. Studies were considered for inclusion if they used diffusion tensor MRI, compared a group of subjects with BD with healthy controls and involved whole-brain white matter analysis of FA. The analyses were conducted in Talairach space, using the activation likelihood estimation technique. We carried out a meta-analysis restricted to studies reporting a lower FA in patients with BD than in healthy controls. RESULTS Ten studies were included. We identified two significant clusters of decreased FA on the right side of the brain. The first was located in the right white matter, close to the parahippocampal gyrus. Four of the ten studies included contributed to this cluster. The second cluster was located close to the right anterior and subgenual cingulate cortex. These two clusters of decreased FA in BD are crossed by several white matter tracts. CONCLUSIONS These two clusters of altered FA may underlie the abnormal emotional processing and altered functional limbic connectivity in BD. Explorations based on DTI-based tractography are required to identify the tracts involved in the pathophysiology of BD.

Relationship between Toxoplasma gondii infection and bipolar disorder in a French sample

BACKGROUND Prenatal exposure to viruses or parasites with tropism for the central nervous system is one of the risk factors for psychotic disorders. However, the relationship between past exposure to Toxoplasma gondii (T. gondii) and incidence of bipolar disorders (BD) is poorly documented across populations. METHODS We explored the potential association between T. gondii exposure and BD in France, a country of high prevalence of Toxoplasmosis, comparing the prevalence of serological markers (IgG/IgM class antibodies) for T. gondii infection in 110 BD patients and 106 healthy controls all living in France. In a subgroup of 42 patients and 42 controls we also evaluated the levels of interleukin 6 (IL-6) transcripts, an adjunct marker of inflammation. RESULTS We found that the sero-positive group for IgG antibodies to T. gondii had a 2.7 fold odds of having BD as compared to the sero-negative group (OR=2.17 CI 95%=1.09-4.36, p=0.028). Despite the fact that BD patients had significantly higher levels of IL-6 than the non-patient controls, no notable association between T. gondii status and IL-6 transcript levels was found. We did not find any clinical or demographic correlates of Toxoplasma exposure in the study population. LIMITATIONS Our results are to be interpreted with caution because of our small sample size. RESULTS We confirm the association between seropositive status to T. gondii and bipolar disorders reported in other populations and extend it to French patients. Our data strengthen the importance of early detection of T. gondii infected patients in order to propose specific and adequate treatments.

A Multicenter Tractography Study of Deep White Matter Tracts in Bipolar I Disorder: Psychotic Features and Interhemispheric Disconnectivity

IMPORTANCE Tractography studies investigating white matter (WM) abnormalities in patients with bipolar disorder have yielded heterogeneous results owing to small sample sizes. The small size limits their generalizability, a critical issue for neuroimaging studies of biomarkers of bipolar I disorder (BPI). OBJECTIVES To study WM abnormalities using whole-brain tractography in a large international multicenter sample of BPI patients and to compare these alterations between patients with or without a history of psychotic features during mood episodes. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional, multicenter, international, Q-ball imaging tractography study comparing 118 BPI patients and 86 healthy control individuals. In addition, among the patient group, we compared those with and without a history of psychotic features. University hospitals in France, Germany, and the United States contributed participants. INTERVENTIONS Participants underwent assessment using the Diagnostic Interview for Genetic Studies at the French sites or the Structured Clinical Interview for DSM-IV at the German and US sites. Diffusion-weighted magnetic resonance images were acquired using the same acquisition parameters and scanning hardware at each site. We reconstructed 22 known deep WM tracts using Q-ball imaging tractography and an automatized segmentation technique. MAIN OUTCOMES AND MEASURES Generalized fractional anisotropy values along each reconstructed WM tract. RESULTS Compared with controls, BPI patients had significant reductions in mean generalized fractional anisotropy values along the body and the splenium of the corpus callosum, the left cingulum, and the anterior part of the left arcuate fasciculus when controlling for age, sex, and acquisition site (corrected for multiple testing). Patients with a history of psychotic features had a lower mean generalized fractional anisotropy value than those without along the body of the corpus callosum (corrected for multiple testing). CONCLUSIONS AND RELEVANCE In this multicenter sample, BPI patients had reduced WM integrity in interhemispheric, limbic, and arcuate WM tracts. Interhemispheric pathways are more disrupted in patients with than in those without psychotic symptoms. Together these results highlight the existence of an anatomic disconnectivity in BPI and further underscore a role for interhemispheric disconnectivity in the pathophysiological features of psychosis in BPI.

Molecular characteristics of Human Endogenous Retrovirus type-W in schizophrenia and bipolar disorder

Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type ‘W’ family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10–4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders.

White matter alterations in bipolar disorder: potential for drug discovery and development

Brain white matter (WM) alterations have recently emerged as potentially relevant in bipolar disorder. New techniques such as diffusion tensor imaging allow precise exploration of these WM microstructural alterations in bipolar disorder. Our objective was to critically review WM alterations in bipolar disorder, using neuroimaging and neuropathological studies, in the context of neural models and the potential for drug discovery and development.

Cerebellar volume in schizophrenia and bipolar I disorder with and without psychotic features.

There is growing evidence that cerebellum plays a crucial role in cognition and emotional regulation. Cerebellum is likely to be involved in the physiopathology of both bipolar disorder and schizophrenia. The objective of our study was to compare cerebellar size between patients with bipolar disorder, patients with schizophrenia, and healthy controls in a multicenter sample. In addition, we studied the influence of psychotic features on cerebellar size in patients with bipolar disorder.

Brain changes in early-onset bipolar and unipolar depressive disorders: a systematic review in children and adolescents

Pediatric bipolar disorder (BD) and unipolar disorder (UD) share common symptomatic and functional impairments. Various brain imaging techniques have been used to investigate the integrity of brain white matter (WM) and gray matter (GM) in these disorders. Despite promising preliminary findings, it is still unclear whether these alterations may be considered as common trait markers or may be used to distinguish BD from UD. A systematic literature search of studies between 1980 and September 2013 which reported WM/GM changes in pediatric and adolescent BD/UD, as detected by diffusion tensor imaging and voxel-based analysis was conducted. Of the 34 articles judged as eligible, 17 fulfilled our inclusion criteria and were finally retained in this review. More abnormalities have been documented in the brains of children and adolescents with BD than UD. Reductions in the volume of basal ganglia and the hippocampus appeared more specific for pediatric UD, whereas reduced corpus callosum volume and increased rates of deep WM hyperintensities were more specific for pediatric BD. Seminal papers failed to address the possibility that the differences between unipolar and bipolar samples might be related to illness severity, medication status, comorbidity or diagnosis. UD and BD present both shared and distinctive impairments in the WM and GM compartments. More WM abnormalities have been reported in children and adolescents with bipolar disease than in those with unipolar disease, maybe as a result of a low number of DTI studies in pediatric UD. Future longitudinal studies should investigate whether neurodevelopmental changes are diagnosis-specific.

Polymorphism of Toll-like receptor 4 gene in bipolar disorder

BACKGROUND Bipolar disorder (BD) is considered as a multifactorial disorder involving complex interactions between genetic and environmental factors, where immune dysfunction is thought to play a key etiopathogenic role. In particular, excess of winter births associated with early-life infections raise the possibility of the implication of innate immunity. Given the pivotal role of Toll-like receptor 4 (TLR-4), a major innate immune sensor molecule, we hypothesized that genetic variations of TLR-4 may be associated to BD. METHODS Genomic DNAs from 572 BD patients and 202 healthy controls (HC) were analyzed for the distribution of six single nucleotides polymorphisms (SNPs) scattered along the TLR-4 locus (rs1927914, rs10759932, rs4986790, rs4986791, rs11536889 and rs11536891). Associations between BD and these polymorphisms were examined using the Chi-square test. RESULTS We found that rs1927914 AA and rs11536891 TT genotype are more frequent in BD patients than in controls (corrected p; pc=.02 and .02 respectively) particularly in early-onset BD patients (pc=.004 and .006) born during the summer season (pc=.02 and .002 respectively). We also found that rs4986790 AG and rs4986791 CT genotypes were significantly associated with presence of autoimmune thyroiditis (pc=.002). LIMITATIONS Our results are to be confirmed by replication in independent BD cohorts. CONCLUSIONS We report for the first time a genetic association between BD and TLR-4 a major player of innate immunity. Possible mechanisms underlying bipolar disorders linking altered TLR-4 expression and increased susceptibility to infections and/or autoimmunity are discussed.