Involvement of the reward network is associated with apathy in cerebral small vessel disease.

INTRODUCTION: Apathy is a common yet under-recognised feature of cerebral small vessel disease (SVD), but its underlying neurobiological basis is not yet understood. We hypothesized that damage to the reward network is associated with an increase of apathy in patients with SVD. METHODS: In 114 participants with symptomatic SVD, defined as a magnetic resonance imaging confirmed lacunar stroke and confluent white matter hyperintensities, we used diffusion tensor imaging tractography to derive structural brain networks and graph theory to determine network efficiency. We determined which parts of the network correlated with apathy symptoms. We tested whether apathy was selectively associated with involvement of the reward network, compared with two "control networks" (visual and motor). RESULTS: Apathy symptoms negatively correlated with connectivity in network clusters encompassing numerous areas of the brain. Network efficiencies within the reward network correlated negatively with apathy scores; (r = - 0.344, p < 0.001), and remained significantly correlated after co-varying for the two control networks. Of the three networks tested, only variability in the reward network independently explained variance in apathetic symptoms, whereas this was not observed for the motor or visual networks. LIMITATIONS: The analysis refers only to cerebrum and not cerebellum. The apathy measure is derivative of depression measure. DISCUSSION: Our results suggest that reduced neural efficiency, particularly in the reward network, is associated with increased apathy in patients with SVD. Treatments which improve connectivity in this network may improve apathy in SVD, which in turn may improve psychiatric outcome after stroke

The benefit of minocycline on negative symptoms in early-phase psychosis in addition to standard care - extent and mechanism (BeneMin): study protocol for a randomised controlled trial.

BACKGROUND: Negative symptoms of psychosis do not respond to the traditional therapy with first- or second-generation antipsychotics and are among main causes of a decrease in quality of life observed in individuals suffering from the disorder. Minocycline, a broad-spectrum tetracyclic antibiotic displaying neuroprotective properties has been suggested as a new potential therapy for negative symptoms. In the two previous clinical trials comparing minocycline and placebo, both added to the standard care, patients receiving minocycline showed increased reduction in negative symptoms. Three routes to neuroprotection by minocycline have been identified: neuroprotection against grey matter loss, anti-inflammatory action and stabilisation of glutamate receptors. However, it is not yet certain what the extent of the benefit of minocycline in psychosis is and what its mechanism is. We present a protocol for a multi-centre double-blind randomised placebo-controlled clinical trial entitled The Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin). METHODS: After providing informed consent, 226 participants in the early phase of psychosis will be randomised to receive either 100 mg modified-release capsules of minocycline or similar capsules with placebo for 12 months in addition to standard care. The participants will be tested for outcome variables before and after the intervention period. The extent of benefit will be tested via clinical outcome measures, namely the Positive and Negative Syndrome Scale score, social and cognitive functioning scores, antipsychotic medication dose equivalent and level of weight gain. The mechanism of action of minocycline will be tested via blood screening for circulating cytokines and magnetic resonance imaging with three-dimensional T1-weighted rapid gradient-echo, proton density T2-weighted dual echo and T2*-weighted gradient echo planar imaging with N-back task and resting state. Eight research centres in UK and 15 National Health Service Trusts and Health Boards will be involved in recruiting participants, performing the study and analysing the data. DISCUSSION: The BeneMin trial can inform as to whether in minocycline we have found a new and effective therapy against negative symptoms of psychosis. The European Union Clinical Trial Register: EudraCT 2010-022463-35 with the registration finalised in July 2011. The recruitment in the trial started in January 2013 with the first patient recruited in March 2013

Genetic variation in PLEKHG1 is associated with white matter hyperintensities (n = 11,226).

OBJECTIVE: To identify novel genetic associations with white matter hyperintensities (WMH). METHODS: We performed a genome-wide association meta-analysis of WMH volumes in 11,226 individuals, including 8,429 population-based individuals from UK Biobank and 2,797 stroke patients. Replication of novel loci was performed in an independent dataset of 1,202 individuals. In all studies, WMH were quantified using validated automated or semi-automated methods. Imputation was to either the Haplotype Reference Consortium or 1,000 Genomes Phase 3 panels. RESULTS: We identified a locus at genome-wide significance in an intron of PLEKHG1 (rs275350, β [SE] = 0.071 [0.013]; p = 1.6 × 10-8), a Rho guanine nucleotide exchange factor that is involved in reorientation of cells in the vascular endothelium. This association was validated in an independent sample (overall p value, 2.4 × 10-9). The same single nucleotide polymorphism was associated with all ischemic stroke (odds ratio [OR] [95% confidence interval (CI)] 1.07 [1.03-1.12], p = 0.00051), most strongly with the small vessel subtype (OR [95% CI] 1.09 [1.00-1.19], p = 0.044). Previous associations at 17q25 and 2p16 reached genome-wide significance in this analysis (rs3744020; β [SE] = 0.106 [0.016]; p = 1.2 × 10-11 and rs7596872; β [SE] = 0.143 [0.021]; p = 3.4 × 10-12). All identified associations with WMH to date explained 1.16% of the trait variance in UK Biobank, equivalent to 6.4% of the narrow-sense heritability. CONCLUSIONS: Genetic variation in PLEKHG1 is associated with WMH and ischemic stroke, most strongly with the small vessel subtype, suggesting it acts by promoting small vessel arteriopathy.This work was supported by a British Heart Foundation Programme Grant (RG/16/4/32218). Hugh Markus is supported by a National Institute for Health Research (NIHR) Senior Investigator award, and his work is supported by the Cambridge Universities NIHR Comprehensive Biomedical Research Centre. Loes Rutten-Jacobs was supported by a British Heart Foundation Immediate Research Fellowship (FS/15/61/31626). Natalia S. Rost is in part supported by NIH/NINDS R01NS086905 and R01NS082285. The MGH WMH study was supported by the National Institutes of Health (K23NS064052 - N.R.), American Heart Association/Bugher Foundation Centers for Stroke Prevention Research (0775010N), and Deane Institute for Integrative Study of Atrial Fibrillation and Stroke. Robin Lemmens is a senior clinical investigator of FWO Flanders

Minocycline for negative symptoms of schizophrenia and possible mechanistic actions:the BeneMin RCT

Objectives: To determine the efficacy of minocycline on the negative symptoms of schizophrenia and the mechanistic role of neuroprotective, anti-inflammatory and cognitive enhancing actions. Methods: Two hundred and seven patients with a current research diagnosis of schizophrenia within 5 years of onset were randomised by a permuted blocks algorithm to minocycline (300 mg/day) or matching placebo as an adjunct to their continuing treatment. The primary efficacy outcome variable was the negative symptom subscale score from the Positive and Negative Syndrome Scales at 2, 6, 9 and 12 months. The primary mechanistic (biomarker) variables were (1) medial prefrontal grey matter volume (GMV), (2) circulating cytokine interleukin (IL) 6 concentration and (3) dorsolateral prefrontal cortex functional magnetic resonance imaging (fMRI) activations during performance of the N-back task. Movement disorder, side effects and treatment adherence were monitored throughout the study. Results: Compared with placebo, the addition of minocycline had no effect on the severity of negative symptoms [treatment effect difference –0.186, 95% confidence interval (CI) –1.225 to 0.854] across the 2-, 6-, 9- and 12-month follow-up visits. None of the mechanistic biomarkers was influenced by minocycline: left GMV –91.2 (95% CI –303.8 to 121.4), IL-6 0.072 (95% CI –0.118 to 0.262) and N-back fMRI 0.66 (95% CI –1.53 to 0.20). There were no statistically significant treatment effects on any of the secondary outcomes and no group differences at baseline. Most measures were stable over the 12 months. Twenty-five out of the 29 serious adverse events were hospital admission for worsening psychiatric state, which affected 10 minocycline-treated participants and six placebo-treated participants. Main outcome measures: The addition of minocycline to standard treatment had no benefit on the symptoms of schizophrenia in this early phase sample. There was no evidence of a progressive neuropathic or inflammatory process affecting GMV. Limitations: Although recruitment to target was achieved on time, only 43% (n = 89) of the 207 randomised patients completed 12 months of the study. However, 83% of those who started treatment remained on it and were assessed over 6 months. By contrast, no follow-up data were available for the cognitive and imaging markers in those who dropped out before the final 12-month assessments, and this reduced the power to detect treatment effects on these mechanistic variables. Patients were not selected for the presence of negative symptoms, and their initial overall psychopathology was, at most, moderate and, therefore, less likely to show treatment effects. Conclusions: The results of the study do not support the use of adjunctive minocycline for the treatment of negative or other symptoms of schizophrenia within 2–5 years of onset. More secure evidence of central inflammation is needed before further trials are conducted at other stages of psychosis. Trial registration: Current Controlled Trials ISRCTN49141214. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research partnership. The study was sponsored by Greater Manchester Mental Health NHS Foundation Trust and supported by the UK Clinical Research Network

Functional neural differences in emotional regualtion between patients with MDD and healthy controls in the context of the vulnerability factors : family history of MDD, BDNF Val66Met polymorphism

THESIS 9893Emotional regulation is a key mechanism which shows disturbances during major depressive disorder (MDD), and which may be modified by certain factors enhancing vulnerability to MDD. Two vulnerability factors were tested in this study: family history of MDD and Val66Met gene polymorphism (rs6265). In previous research, both factors have been found to have a connection to emotional regulation, and therefore to represent modifiers of vulnerability to MDD

Network neuroscience of apathy in cerebrovascular disease.

Apathy is a reduction in motivated goal-directed behavior (GDB) that is prevalent in cerebrovascular disease, providing an important opportunity to study the mechanistic underpinnings of motivation in humans. Focal lesions, such as those seen in stroke, have been crucial in developing models of brain regions underlying motivated behavior, while studies of cerebral small vessel disease (SVD) have helped define the connections between brain regions supporting such behavior. However, current lesion-based models cannot fully explain the neurobiology of apathy in stroke and SVD. To address this, we propose a network-based model which conceptualizes apathy as the result of damage to GDB-related networks. A review of the current evidence suggests that cerebrovascular disease-related pathology can lead to network changes outside of initially damaged territories, which may propagate to regions that share structural or functional connections. The presentation and longitudinal trajectory of apathy in stroke and SVD may be the result of these network changes. Distinct subnetworks might support cognitive components of GDB, the disruption of which results in specific symptoms of apathy. This network-based model of apathy may open new approaches for investigating its underlying neurobiology, and presents novel opportunities for its diagnosis and treatment

The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The antibiotic minocycline has neuroprotective and anti-inflammatory properties that could prevent or reverse progressive neuropathic changes implicated in recent-onset schizophrenia. In the BeneMin study, we aimed to replicate the benefit of minocycline on negative symptoms reported in previous pilot studies, and to understand the mechanisms involved. METHODS: In this randomised, double-blind, placebo-controlled trial, we recruited people with a schizophrenia-spectrum disorder that had begun within the past 5 years with continuing positive symptoms from 12 National Health Service (NHS) trusts. Participants were randomly assigned according to an automated permuted blocks algorithm, stratified by pharmacy, to receive minocycline (200 mg per day for 2 weeks, then 300 mg per day for the remainder of the 12-month study period) or matching placebo, which were added to their continuing treatment. The primary clinical outcome was the negative symptom subscale score of the Positive and Negative Syndrome Scales (PANSS) across follow-ups at months 2, 6, 9, and 12. The primary biomarker outcomes were medial prefrontal grey-matter volume, dorsolateral prefrontal cortex activation during a working memory task, and plasma concentration of interleukin 6. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN49141214, and the EU Clinical Trials register (EudraCT) number is 2010-022463-35I. FINDINGS: Between April 16, 2013, and April 30, 2015, we recruited 207 people and randomly assigned them to receive minocycline (n=104) or placebo (n=103). Compared with placebo, the addition of minocycline had no effect on ratings of negative symptoms (treatment effect difference -0·19, 95% CI -1·23 to 0·85; p=0·73). The primary biomarker outcomes did not change over time and were not affected by minocycline. The groups did not differ in the rate of serious adverse events (n=11 in placebo group and n=18 in the minocycline group), which were mostly due to admissions for worsening psychiatric state (n=10 in the placebo group and n=15 in the minocycline group). The most common adverse events were gastrointestinal (n=12 in the placebo group, n=19 in the minocycline group), psychiatric (n=16 in placebo group, n=8 in minocycline group), nervous system (n=8 in the placebo group, n=12 in the minocycline group), and dermatological (n=10 in the placebo group, n=8 in the minocycline group). INTERPRETATION: Minocycline does not benefit negative or other symptoms of schizophrenia over and above adherence to routine clinical care in first-episode psychosis. There was no evidence of a persistent progressive neuropathic or inflammatory process underpinning negative symptoms. Further trials of minocycline in early psychosis are not warranted until there is clear evidence of an inflammatory process, such as microgliosis, against which minocycline has known efficacy. FUNDING: National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership