Social Mindfulness and Psychosis: Neural response to socially mindful behavior in first-episode psychosis and patients at clinical high-risk

Background: Psychosis is characterized by problems in social functioning and trust, the assumed glue to positive social relations. But what helps building trust? A prime candidate could be social mindfulness: The ability and willingness to see and consider another person’s needs and wishes during social decision making. We investigated whether first-episode psychosis patients (FEP) and patients at clinical high-risk (CHR) show reduced social mindfulness, and examined the underlying neural mechanisms. Methods: Twenty FEP, 17 CHR and 46 healthy controls, aged 16-31, performed the social mindfulness task (SoMi) during fMRI scanning, spontaneously and after the instruction “to keep the other’s best interest in mind”. As first of two people, participants had to choose one out of four products, of which three were identical and one was unique, differing in a single aspect (e.g., color). Results: FEP tended to choose the unique item (unmindful choice) more often than controls. After instruction, all groups significantly increased the number of mindful choices compared to the spontaneous condition. FEP showed reduced activation of the caudate and medial prefrontal cortex (mPFC) during mindful, and of the anterior cingulate cortex (ACC), mPFC, and left dorso-lateral prefrontal cortex (dlPFC) during unmindful decisions. CHR showed reduced activation of the ACC compared to controls. Discussion: FEP showed a trend towards more unmindful choices. A similar increase of mindful choices after instruction indicated the ability for social mindfulness when prompted. Results suggested reduced sensitivity to the rewarding aspects of social mindfulness in FEP, and reduced consideration for the other player. FEP (and CHR to a lesser extent) might perceive unmindful choices as less incongruent with the automatic mindful responses than controls. Reduced socially mindful behavior in FEP may hinder the building of trust and cooperative interactions

Learning to trust: social feedback normalizes trust behavior in first-episode psychosis and clinical high risk

Background Psychosis is characterized by problems in social functioning that exist well before illness onset, and in individuals at clinical high risk (CHR) for psychosis. Trust is an essential element for social interactions that is impaired in psychosis. In the trust game, chronic patients showed reduced baseline trust, impaired response to positive social feedback, and attenuated brain activation in reward and mentalizing areas. We investigated whether first-episode psychosis patients (FEP) and CHR show similar abnormalities in the neural and behavioral mechanisms underlying trust. Methods Twenty-two FEP, 17 CHR, and 43 healthy controls performed two trust games, with a cooperative and an unfair partner in the fMRI scanner. Region of interest analyses were performed on mentalizing and reward processing areas, during the investment and outcome phases of the games. Results Compared with healthy controls, FEP and CHR showed reduced baseline trust, but like controls, learned to trust in response to cooperative and unfair feedback. Symptom severity was not associated with baseline trust, however in FEP associated with reduced response to feedback. The only group differences in brain activation were that CHR recruited the temporo-parietal junction (TPJ) more than FEP and controls during investment in the unfair condition. This hyper-activation in CHR was associated with greater symptom severity. Conclusions Reduced baseline trust may be associated with risk for psychotic illness, or generally with poor mental health. Feedback learning is still intact in CHR and FEP, as opposed to chronic patients. CHR however show distinct neural activation patterns of hyper-activation of the TPJ

The Influence of Trial-By-Trial Feedback on Trust in Health, First-Episode and Chronic Psychosis

Trust is crucial to establishing reciprocal, positive social interactions and seems to be compromised in psychosis. The trust game offers methods to assess an individual’s trust responses to trust-reciprocating, positive feedback. Various computational techniques have been implemented to measure trust responsiveness, mostly based on investments. Here, we propose a new method, focusing on feedback response. Psychosis patients show social dysfunction and reduced trust during early and more progressed illness stages. The present study inspects differences in feedback responsiveness of 102 first-episode psychosis patients (FEPs), 43 chronic psychosis patients (CPs), and 39 healthy controls (HCs) by adopting a novel assessment approach. Additionally, baseline trust, the trust exerted without any prior knowledge of the partner’s trustworthiness, and mean trust were examined. Participants performed a multi-round trust game, playing the investor role, and were paired with a computer, programmed to return at least the invested amount, representing a trustworthy partner. The new method detected group differences, more distinguished than the former methods. Contrary to our expectations, baseline trust was intact in patients. Relative to HCs, patients were less responsive to feedback, failing to integrate the positive information into their decision-making process. The magnitude of returns was not associated with increases in trust. This novel method showed promising results and confirmed patients’ deficits within the social interactional domain

Genetic Evaluation in a Cohort of 126 Dutch Pulmonary Arterial Hypertension Patients

Pulmonary arterial hypertension (PAH) is a severe, life-threatening disease, and in some cases is caused by genetic defects. This study sought to assess the diagnostic yield of genetic testing in a Dutch cohort of 126 PAH patients. Historically, genetic testing in the Netherlands consisted of the analysis of BMPR2 and SMAD9. These genes were analyzed in 70 of the 126 patients. A (likely) pathogenic (LP/P) variant was detected in 22 (31%) of them. After the identification of additional PAH associated genes, a next generation sequencing (NGS) panel consisting of 19 genes was developed in 2018. Additional genetic testing was offered to the 48 BMPR2 and SMAD9 negative patients, out of which 28 opted for NGS analysis. In addition, this gene panel was analyzed in 56 newly identified idiopathic (IPAH) or pulmonary veno occlusive disease (PVOD) patients. In these 84 patients, NGS panel testing revealed LP/P variants in BMPR2 (N = 4), GDF2 (N = 2), EIF2AK4 (N = 1), and TBX4 (N = 3). Furthermore, 134 relatives of 32 probands with a LP/P variant were tested, yielding 41 carriers. NGS panel screening offered to IPAH/PVOD patients led to the identification of LP/P variants in GDF2, EIF2AK4, and TBX4 in six additional patients. The identification of LP/P variants in patients allows for screening of at-risk relatives, enabling the early identification of PAH

Genetic Burden of TNNI3K in Diagnostic Testing of Patients With Dilated Cardiomyopathy and Supraventricular Arrhythmias

BACKGROUND: Genetic variants in TNNI3K (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between TNNI3K variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function. METHODS: We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including TNNI3K. We further performed burden testing of TNNI3K in the UK Biobank. For 2 novel TNNI3K variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays.RESULTS: We demonstrate enrichment of rare coding TNNI3K variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between TNNI3K missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation. CONCLUSIONS: Our findings demonstrate an increased burden of rare coding TNNI3K variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic TNNI3K variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.</p

BIO FOr CARE: biomarkers of hypertrophic cardiomyopathy development and progression in carriers of Dutch founder truncating MYBPC3 variants—design and status

Background: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by truncating variants in the MYBPC3 gene. HCM is an important cause of sudden cardiac death; however, overall prognosis is good and penetrance in genotype-positive individuals is incomplete. The underlying mechanisms are poorly understood and risk stratification remains limited. Aim: To create a nationwide cohort of carriers of truncating MYBPC3 variants for identification of predictive biomarkers for HCM development and progression. Methods: In the multicentre, observational BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort, carriers of the c.2373dupG, c.2827C > T, c.2864_2865delCT and c.3776delA MYBPC3 variants are included and prospectively undergo longitudinal blood collection. Clinical data are collected from first presentation onwards. The primary outcome constitutes a composite endpoint of HCM progression (maximum wall thickness ≥ 20 mm, septal reduction therapy, heart failure occurrence, sustained ventricular arrhythmia and sudden cardiac death). Results: So far, 250 subjects (median age 54.9 years (interquartile range 43.3, 66.6), 54.8% male) have been included. HCM was diagnosed in 169 subjects and dilated cardiomyopathy in 4. The primary outcome was met in 115 subjects. Blood samples were collected from 131 subjects. Conclusion: BIO FOr CARe is a genetically homogeneous, phenotypically heterogeneous cohort incorporating a clinical data registry and longitudinal blood collection. This provides a unique opportunity to study biomarkers for HCM development and prognosis. The established infrastructure can be extended to study other genetic variants. Other centres are invited to join our consortium

Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the ‘normativeness’ of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.publishedVersio

Applicability of corticosteroid releasing microspheres in degenerative joint diseases

Osteoarthritis (OA) and intervertebral disc (IVD) degeneration are two musculoskeletal conditions that can seriously affect the quality of life of individual patients, strain health and social care systems and thereby the economy worldwide. The prevalence of both conditions is expected to grow due to increasing life expectancy and/or incidence of risk factors. The predominant burden of musculoskeletal conditions in patients is pain, often in combination with a limitation of movement and as such affecting the quality of life. Local corticosteroid (CS) injection is a commonly applied treatment targeting inflammation and pain, especially in the osteoarthritic joint. However, locally administered CSs only provide a temporal reduction in pain, while the multiple injections that are needed for sustained effects are accompanied by several risks. Promising approaches to prolong the anti-inflammatory and analgesic effects of CS are to extend local drug exposure by a drug delivery system (DDS), while avoiding harmful peak concentrations or the side-effects that come with multiple injections. Therefore, this thesis investigated the applicability of local controlled release of corticosteroids for prolonged inhibition of inflammation, pain and degeneration in degenerative joint diseases. The controlled release of the CS triamcinolone acetonide (TAA) can be applied for the inhibition of inflammation and pain in various knee joint diseases. Chapter 2 demonstrated the characteristics of the polyesteramides (PEAs) drug delivery platform. TAA release from PEA microspheres was extended, while the potentially harmful TAA peak exposure was diminished, compared to bolus TAA. Also, local joint inflammation was successfully inhibited 7 weeks post-injection. It was seen in chapter 3 that extended CS release is not applicable in every subtype of knee joint diseases as the extended local presence worsened the tissue damage and lead to calcifications in unstable joints with ligament trauma. Chapter 4 and 5 revealed that in (stable) arthritic joints, the release of TAA by our PEA platform was extended and more superior in the reduction of inflammatory-associated pain over the conventional poly lactic-co-glycolic acid (PLGA) platform. This thesis also reported the findings regarding the applicability of controlled release of TAA in degenerated IVDs, in terms of safety and efficacy. It was found in chapter 6 that local controlled release of TAA in degenerated IVDs does not affect the tissues in and surrounding the IVD and has the potential to provide long-term analgesia. The research question of what the relation is between the retention of small molecules released by PEA microspheres and the location and disease status of the injected site was addressed in chapter 7. It was found that in tissues with a relatively low fluid exchange, such as the IVD, retention of the injected molecules was higher compared to tissues with a rapid clearance (such as the skin and knee joint). Moreover, in the IVD were the retention was delayed, it was also observed that in degenerated tissues retention was further prolonged