Functional connectivity and neuronal variability of resting state activity in bipolar disorder--reduction and decoupling in anterior cortical midline structures.

INTRODUCTION: The cortical midline structures seem to be involved in the modulation of different resting state networks, such as the default mode network (DMN) and salience network (SN). Alterations in these systems, in particular in the perigenual anterior cingulate cortex (PACC), seem to play a central role in bipolar disorder (BD). However, the exact role of the PACC, and its functional connections to other midline regions (within and outside DMN) still remains unclear in BD. METHODS: We investigated functional connectivity (FC), standard deviation (SD, as a measure of neuronal variability) and their correlation in bipolar patients (n = 40) versus healthy controls (n = 40), in the PACC and in its connections in different frequency bands (standard: 0.01-0.10 Hz; Slow-5: 0.01-0.027 Hz; Slow-4: 0.027-0.073 Hz). Finally, we studied the correlations between FC alterations and clinical-neuropsychological parameters and we explored whether subgroups of patients in different phases of the illness present different patterns of FC abnormalities. RESULTS: We found in BD decreased FC (especially in Slow-5) from the PACC to other regions located predominantly in the posterior DMN (such as the posterior cingulate cortex (PCC) and inferior temporal gyrus) and in the SN (such as the supragenual anterior cingulate cortex and ventrolateral prefrontal cortex). Second, we found in BD a decoupling between PACC-based FC and variability in the various target regions (without alteration in variability itself). Finally, in our subgroups explorative analysis, we found a decrease in FC between the PACC and supragenual ACC (in depressive phase) and between the PACC and PCC (in manic phase). CONCLUSIONS: These findings suggest that in BD the communication, that is, information transfer, between the different cortical midline regions within the cingulate gyrus does not seem to work properly. This may result in dysbalance between different resting state networks like the DMN and SN. A deficit in the anterior DMN-SN connectivity could lead to an abnormal shifting toward the DMN, while a deficit in the anterior DMN-posterior DMN connectivity could lead to an abnormal shifting toward the SN, resulting in excessive focusing on internal contents and reduced transition from idea to action or in excessive focusing on external contents and increased transition from idea to action, respectively, which could represent central dimensions of depression and mania. If confirmed, they could represent diagnostic markers in BD.

The HPA axis in bipolar disorder: Systematic review and meta-analysis.

OBJECTIVES: To provide a quantitative and qualitative synthesis of the available evidence on the role of Hypothalamic-Pituitary-Adrenal (HPA) axis in the pathophysiology of Bipolar Disorder (BD). METHODS: Meta-analysis and meta-regression of case-control studies examining the levels of cortisol, ACTH, CRH levels. Systematic review of stress reactivity, genetic, molecular and neuroimaging studies related to HPA axis activity in BD. RESULTS: Forty-one studies were included in the meta-analyses. BD was associated with significantly increased levels of cortisol (basal and post-dexamethasone) and ACTH, but not of CRH. In the meta-regression, case-control differences in cortisol levels were positively associated with the manic phase (p=0.005) and participants' age (p=0.08), and negatively with antipsychotics use (p=0.001). Reviewed studies suggest that BD is associated with abnormalities of stress-related molecular pathways in several brain areas. Variants of HPA axis-related genes seem not associated with a direct risk of developing BD, but with different clinical presentations. Also, studies on unaffected relatives suggest that HPA axis dysregulation is not an endophenotype of BD, but seems related to environmental risk factors, such as childhood trauma. Progressive HPA axis dysfunction is a putative mechanism that might underlie the clinical and cognitive deterioration of patients with BD. CONCLUSIONS: BD is associated with dysfunction of HPA axis activity, with important pathophysiological implications. Targeting HPA axis dysfunctions might be a novel strategy to improve the outcomes of BD.

Effect of a CD-ROM-based educational intervention on resident knowledge and adherence to deep venous thrombosis prophylaxis guidelines.

BACKGROUND: CD-ROM-based educational methods are not new to residency training, yet little is known about how they affect resident knowledge and patient care practices. OBJECTIVE: We evaluated the effects of a CD-ROM-based educational tool on residents' knowledge of anticoagulation and their adherence to anticoagulation guidelines. DESIGN, SETTING AND PARTICIPANTS: Residents in the departments of cardiothoracic surgery, emergency medicine, otolaryngology, internal medicine, neurosurgery, dental medicine, neurology, obstetrics and gynecology, orthopedics, surgery, and urology at a university hospital participated in the study. INTERVENTION: Residents were provided with CD-ROM-based training on the proper use of anticoagulation based on the sixth ACCP guidelines for antithrombotic therapy. Multiple choice testing was carried out before and after the CD-ROM intervention to assess resident knowledge, and resident compliance with venous thromboembolism prophylaxis guidelines was assessed via inpatient chart review by an independent committee. MAIN OUTCOME MEASURES: Changes in knowledge were measured via test scores and the rate of compliance with anticoagulation guidelines. RESULTS: Multiple choice test scores of 117 residents increased significantly after reviewing the CD-ROM (from 46.7% +/- 15.1% to 77.8% +/- 15.1%, P < .005). As a control, we administered the same test at the same 2 times at a comparable institution but without the CD-ROM intervention and found that test scores did not significantly increase. Chart review revealed a rate of compliance with anticoagulation guidelines for prophylaxis of venous thromboembolism of 75% before the CD-ROM intervention, which increased to 95% after the intervention, an increase that was sustained for at least 7 months. CONCLUSIONS: These findings suggest that CD-ROM-based interventions might be useful not only in enhancing resident knowledge but also in improving the quality of care by favorably affecting clinical practice.