Associations of altered leukocyte DDR1 promoter methylation and childhood trauma with bipolar disorder and suicidal behavior in euthymic patients.

Altered DNA methylation (DNAm) patterns of discoidin domain receptor 1 (DDR1) have been found in the blood and brain of patients with schizophrenia (SCZ) and the brain of patients with bipolar disorder (BD). Childhood trauma (CT) is associated with changes in DNAm that in turn are related to suicidal behavior (SB) in patients with several psychiatric disorders. Here, using MassARRAY® technology, we studied 128 patients diagnosed with BD in remission and 141 healthy controls (HCs) to compare leukocyte DDR1 promoter DNAm patterns between patients and HCs and between patients with and without SB. Additionally, we investigated whether CT was associated with DDR1 DNAm and mediated SB. We found hypermethylation at DDR1 cg19215110 and cg23953820 sites and hypomethylation at cg14279856 and cg03270204 sites in patients with BD compared to HCs. Logistic regression models showed that hypermethylation of DDR1 cg23953820 but not cg19215110 and CT were risk factors for BD, while cg14279856 and cg03270204 hypomethylation were protective factors. In patients, CT was a risk factor for SB, but DDR1 DNAm, although associated with CT, did not mediate the association of CT with SB. This is the first study demonstrating altered leukocyte DDR1 promoter DNAm in euthymic patients with BD. We conclude that altered DDR1 DNAm may be related to immune and inflammatory mechanisms and could be a potential blood biomarker for the diagnosis and stratification of psychiatric patients.

Widespread intra-axonal signal fraction abnormalities in bipolar disorder from multicompartment diffusion MRI: Sensitivity to diagnosis, association with clinical features and pharmacologic treatment.

Despite diffusion tensor imaging (DTI) evidence for widespread fractional anisotropy (FA) reductions in the brain white matter of patients with bipolar disorder, questions remain regarding the specificity and sensitivity of FA abnormalities as opposed to other diffusion metrics in the disorder. We conducted a whole-brain voxel-based multicompartment diffusion MRI study on 316 participants (i.e., 158 patients and 158 matched healthy controls) employing four diffusion metrics: the mean diffusivity (MD) and FA estimated from DTI, and the intra-axonal signal fraction (IASF) and microscopic axonal parallel diffusivity (Dpar) derived from the spherical mean technique. Our findings provide novel evidence about widespread abnormalities in other diffusion metrics in BD. An extensive overlap between the FA and IASF results suggests that the lower FA in patients may be caused by a reduced intra-axonal volume fraction or a higher macromolecular content in the intra-axonal water. We also found a diffuse alteration in MD involving white and grey matter tissue and more localised changes in Dpar. A Machine Learning analysis revealed that FA, followed by IASF, were the most helpful metric for the automatic diagnosis of BD patients, reaching an accuracy of 72%. Number of mood episodes, age of onset/duration of illness, psychotic symptoms, and current treatment with lithium, antipsychotics, antidepressants, and antiepileptics were all significantly associated with microstructure abnormalities. Lithium treatment was associated with less microstructure abnormality.

Negative schizophrenic symptoms as prefrontal cortex dysfunction: Examination using a task measuring goal neglect.

BACKGROUND: The negative symptoms of schizophrenia have been proposed to reflect prefrontal cortex dysfunction. However, this proposal has not been consistently supported in functional imaging studies, which have also used executive tasks that may not capture key aspects of negative symptoms such as lack of volition. METHOD: Twenty-four DSM-5 schizophrenic patients with high negative symptoms (HNS), 25 with absent negative symptoms (ANS) and 30 healthy controls underwent fMRI during performance of the Computerized Multiple Elements Test (CMET), a task designed to measure poor organization of goal directed behaviour or 'goal neglect'. Negative symptoms were rated using the PANSS and the Clinical Assessment Interview for Negative Symptoms (CAINS). RESULTS: On whole brain analysis, the ANS patients showed no significant clusters of reduced activation compared to the healthy controls. In contrast, the HNS patients showed hypoactivation compared to the healthy controls in the left anterior frontal cortex, the right dorsolateral prefrontal cortex (DLPFC), the anterior insula bilaterally and the bilateral inferior parietal cortex. When compared to the ANS patients, the HNS patients showed reduced activation in the left anterior frontal cortex, the left DLPFC and the left inferior parietal cortex. After controlling for disorganization scores, differences remained in clusters in the left anterior frontal cortex and the bilateral inferior parietal cortex. CONCLUSIONS: This study provides evidence that reduced prefrontal activation, perhaps especially in the left anterior frontal cortex, is a brain functional correlate of negative symptoms in schizophrenia. The simultaneous finding of reduced inferior parietal cortex activation was unexpected, but could reflect this region's involvement in cognitive control, particularly the 'regulative' component of this.

Longitudinal Structural Brain Changes in Bipolar Disorder: A Multicenter Neuroimaging Study of 1232 Individuals by the ENIGMA Bipolar Disorder Working Group.

BACKGROUND: Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD. METHODS: Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables. RESULTS: Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18