Chamberlain, S. R. | bioRxiv Science

bioRxiv2018

Transdiagnostic variations in impulsivity and compulsivity in obsessive-compulsive disorder and gambling disorder correlate with effective connectivity in cortical-striatal-thalamic-cortical circuits.

BackgroundIndividual differences in impulsivity and compulsivity is thought to underlie vulnerability to a broad range of disorders and are closely tied to cortical-striatal-thalamic-cortical (CSTC) function. However, whether impulsivity and compulsivity in clinical disorders is continuous with the healthy population and explains CSTC dysfunction across different disorders remains unclear.\n\nMethodsWe characterized the relationship between CSTC effective connectivity, estimated using dynamic causal modelling of functional magnetic resonance imaging data, and dimensional phenotypes of impulsivity and compulsivity in two symptomatically distinct but phenotypically related disorders, obsessive-compulsive disorder (OCD) and gambling disorder (GD). 487 online participants provided data for modelling of dimensional phenotypes. These data were combined with 34 OCD patients, 22 GD patients, and 39 healthy controls, who underwent functional magnetic resonance imaging.\n\nResultsThree core dimensions were identified: disinhibition, impulsivity, and compulsivity. Patients scores on these dimensions were continuously distributed with the healthy participants, supporting a continuum model of psychopathology. Across all participants, higher disinhibition correlated with lower bottom-up connectivity in the dorsal circuit and increased bottom-up connectivity in the ventral circuit, and higher compulsivity correlated with reduced bottom-up connectivity in the dorsal circuit. Similar changes in effective connectivity were observed with increasing clinical severity that were not accounted for by phenotypic variation, demonstrating convergence towards behaviourally and clinically relevant changes in brain dynamics. Effective connectivity did not differ as a function of traditional diagnostic labels.\n\nConclusionsCSTC dysfunction across OCD and GD is better characterized by dimensional phenotypes than diagnostic comparisons, supporting investigation of quantitative liability phenotypes.

neuroscience↗

bioRxiv2017

Treatment-resistant depression and peripheral C-reactive protein

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSDysregulation of the peripheral innate immune system has been implicated in the pathophysiology of major depressive disorder (MDD), and may partly account for why many patients do not experience symptomatic improvement. Elevated CRP has been demonstrated in meta-analysis for MDD compared to healthy volunteers, but little is known about whether this is the case for particular clinical phenotypes of the disorder, as opposed to MDD in general.\n\nAdded value of this studyThis study recruited a large cohort of MDD patients, stratified by prior exposure to monoamine reuptake inhibitor treatment. MDD participants were carefully screened for physical comorbidity, and were compared to healthy volunteers matched for age, sex, body mass indices, and cigarette smoking status. Using group-wise comparisons and the innovative statistical approach of partial least squares, we demonstrated that elevated CRP was associated with treatment-resistance, childhood adversity, and specific depressive and anxious symptoms.\n\nImplications of all the available evidenceCRP is significantly increased \"on average\" in MDD patients, However, CRP was most abnormally increased in the subgroup of patients with treatment-resistant depression. High BMI, high scores on vegetative symptoms of depression, low scores on calmness, and a history of childhood adversity, were all predictive of increased CRP. In future, stratification of MDD patients using pro-inflammatory biomarkers, like CRP, may be valuable for sample enrichment and targeted treatment interventions.\n\nAbstractO_ST_ABSBackgroundC_ST_ABSC-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.\n\nMethodsWe recruited 102 treatment-resistant, depressed MDD patients, 48 treatment-responsive, non-depressed MDD patients, 48 depressed but un-medicated patients, and 54 healthy volunteers. High sensitivity CRP in peripheral venous blood, body mass index (BMI), and questionnaire assessments of depression, anxiety, and childhood trauma, were measured. Group differences in CRP were estimated, before and after correction for BMI. Partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes.\n\nOutcomesCompared to healthy volunteers, BMI-corrected CRP was significantly elevated in treatment-resistant patients (P = 0.007; Cohens d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two factor solution that accounted for 34.7% of variation in clinical measures, and for 36.0% of variation in CRP. The clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were: vegetative depressive symptoms, BMI, state anxiety, and feeling unloved as a child or wishing for a different childhood.\n\nInterpretationPeripheral CRP was elevated in MDD, especially in treatment-resistant cases. Other phenotypes associated with elevated CRP included childhood adversity, and specific depressive and anxious symptoms. We suggest that MDD patients stratified for pro-inflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.\n\nFundingWellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimers Disease (NIMA) Consortium.

neuroscience↗