Salience and default mode network coupling predicts cognition in aging and Parkinson’s disease

OBJECTIVES: Cognitive impairment is common in Parkinson’s disease (PD). Three neurocognitive networks support efficient cognition: the salience network, the default mode network, and the central executive network. The salience network is thought to switch between activating and deactivating the default mode and central executive networks. Anti-correlated interactions between the salience and default mode networks in particular are necessary for efficient cognition. Our previous work demonstrated altered functional coupling between the neurocognitive networks in non-demented individuals with PD compared to age-matched control participants. Here, we aim to identify associations between cognition and functional coupling between these neurocognitive networks in the same group of participants. METHODS: We investigated the extent to which intrinsic functional coupling among these neurocognitive networks is related to cognitive performance across three neuropsychological domains: executive functioning, psychomotor speed, and verbal memory. Twenty-four non-demented individuals with mild to moderate PD and 20 control participants were scanned at rest and evaluated on three neuropsychological domains. RESULTS: PD participants were impaired on tests from all three domains compared to control participants. Our imaging results demonstrated that successful cognition across healthy aging and Parkinson’s disease participants was related to anti-correlated coupling between the salience and default mode networks. Individuals with poorer performance scores across groups demonstrated more positive salience network/default-mode network coupling. CONCLUSIONS: Successful cognition relies on healthy coupling between the salience and default mode networks, which may become dysfunctional in PD. These results can help inform non-pharmacological interventions (repetitive transcranial magnetic stimulation) targeting these specific networks before they become vulnerable in early stages of Parkinson’s disease.Published versio

An Increase in Tobacco Craving Is Associated with Enhanced Medial Prefrontal Cortex Network Coupling

Craving is a key aspect of drug dependence that is thought to motivate continued drug use. Numerous brain regions have been associated with craving, suggesting that craving is mediated by a distributed brain network. Whether an increase in subjective craving is associated with enhanced interactions among brain regions was evaluated using resting state functional magnetic imaging (fMRI) in nicotine dependent participants. We focused on craving-related changes in the orbital and medial prefrontal cortex (OMPFC) network, which also included the subgenual anterior cingulate cortex (sgACC) extending into the ventral striatum. Brain regions in the OMPFC network are not only implicated in addiction and reward, but, due to their rich anatomic interconnections, may serve as the site of integration across craving-related brain regions. Subjective craving and resting state fMRI were evaluated twice with an ∼1 hour delay between the scans. Cigarette craving was significantly increased at the end, relative to the beginning of the scan session. Enhanced craving was associated with heightened coupling between the OMPFC network and other cortical, limbic, striatal, and visceromotor brain regions that are both anatomically interconnected with the OMPFC, and have been implicated in addiction and craving. This is the first demonstration confirming that an increase in craving is associated with enhanced brain region interactions, which may play a role in the experience of craving

199 Baricitinib in patients with systemic lupus erythematosus: results from a phase 2, randomized, double-blind, placebo-controlled study

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Mapping and Functional Characterisation of a CTCF-Dependent Insulator Element at the 3′ Border of the Murine Scl Transcriptional Domain

The Scl gene encodes a transcription factor essential for haematopoietic development. Scl transcription is regulated by a panel of cis-elements spread over 55 kb with the most distal 3′ element being located downstream of the neighbouring gene Map17, which is co-regulated with Scl in haematopoietic cells. The Scl/Map17 domain is flanked upstream by the ubiquitously expressed Sil gene and downstream by a cluster of Cyp genes active in liver, but the mechanisms responsible for delineating the domain boundaries remain unclear. Here we report identification of a DNaseI hypersensitive site at the 3′ end of the Scl/Map17 domain and 45 kb downstream of the Scl transcription start site. This element is located at the boundary of active and inactive chromatin, does not function as a classical tissue-specific enhancer, binds CTCF and is both necessary and sufficient for insulator function in haematopoietic cells in vitro. Moreover, in a transgenic reporter assay, tissue-specific expression of the Scl promoter in brain was increased by incorporation of 350 bp flanking fragments from the +45 element. Our data suggests that the +45 region functions as a boundary element that separates the Scl/Map17 and Cyp transcriptional domains, and raise the possibility that this element may be useful for improving tissue-specific expression of transgenic constructs

GA4GH: International policies and standards for data sharing across genomic research and healthcare.

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

The involvement of type IV phosphodiesterases in cocaine-induced sensitization and subsequent pERK expression in the mouse nucleus accumbens

Abstract Rationale Cocaine exposure produces sensitization that is partly mediated by cyclic adenosine monophosphate (cAMP) pathways within the nucleus accumbens (NAc). Type IV phosphodiesterases (PDE4s) break down cAMP and are required for cocaine-induced conditioned place preference. Whether PDE4 disruption attenuates induction of behavioral sensitization to cocaine and subsequent NAc expression of phosphorylated extracellular signal-regulated kinase (ERK), which is involved in cocaine-induced sensitization, is unknown. Objectives The objective of this study was to determine whether inhibition of PDE4s prevents cocaine-induced locomotor sensitization and if reduced behavioral sensitization is accompanied by decreased expression of phosphorylated ERK (pERK) within the NAc. Methods Mice were administered the PDE4 inhibitor, rolipram, or vehicle before or after five daily injections of cocaine or saline, and activity was monitored on days 1 and 5. After nine drug-free days, locomotor sensitization was tested. Some subjects were sacrificed following testing for behavioral sensitization to measure pERK expression in the NAc. Results PDE4 inhibition, during the induction of sensitization, reduced behavioral sensitization only if rolipram (1.0 mg/kg) was administered before cocaine. Re-exposure to the cocainepaired environment following a 9-day drug-free period enhanced pERK expression in the NAc core and shell. Rolipram did not alter pERK induction despite blocking behavioral sensitization. Conclusions Rolipram given during, but not following, cocaine treatment prevents development of locomotor sensitization to cocaine but does not affect subsequent pERK activation induced by exposure to a cocaine-paired context or following a cocaine challenge. Although PDE4 inhibition during the induction of sensitization blocks the locomotor component of sensitization, other long-term changes induced by repeated cocaine treatment remain

Sex differences in default mode and dorsal attention network engagement

Focusing on sex differences is necessary to fully understand basic neurobiological processes such as the engagement of large-scale brain networks involved in attention. Prior work suggests that women show enhanced attention during tasks of reward/punishment relative to men. Yet, sex differences in the engagement of neural networks sub serving internal and external focus has been unexplored in regard to reward and punishment. Using data from a large sample (n = 190) of healthy participants from the Human Connectome Project, we investigated sex differences in default mode network (DMN), dorsal attention network (DAN), and frontal parietal network (FPN) activation during exposure to reward and punishment. To determine if sex differences are specific to valenced stimuli, we analyzed network activation during working memory. Results indicate that, relative to men, women have increased suppression of the DMN and greater activation of the DAN during exposure to reward and punishment. Given the relative roles of these networks in internal (DMN) and external (DAN) attention, this pattern of activation suggests that women have enhanced external attention to reward and punishment. In contrast, there were no sex differences in network activation during working memory, indicating that this sex difference is specific to the processing of reward and punishment. These findings suggest a neurobiological explanation for prior work showing women have greater sensitivity to reward/punishment and are more prone to psychiatric disorders characterized by enhanced attention to such stimuli. Furthermore, given the large sample from the Human Connectome Project, the current findings provide general implications for the study of sex as a biological variable in investigation of reward processes