Resting State fMRI Functional Connectivity Analysis Using Dynamic Time Warping

Traditional resting-state network concept is based on calculating linear dependence of spontaneous low frequency fluctuations of the BOLD signals of different brain areas, which assumes temporally stable zero-lag synchrony across regions. However, growing amount of experimental findings suggest that functional connectivity exhibits dynamic changes and a complex time-lag structure, which cannot be captured by the static zero-lag correlation analysis. Here we propose a new approach applying Dynamic Time Warping (DTW) distance to evaluate functional connectivity strength that accounts for non-stationarity and phase-lags between the observed signals. Using simulated fMRI data we found that DTW captures dynamic interactions and it is less sensitive to linearly combined global noise in the data as compared to traditional correlation analysis. We tested our method using resting-state fMRI data from repeated measurements of an individual subject and showed that DTW analysis results in more stable connectivity patterns by reducing the within-subject variability and increasing robustness for preprocessing strategies. Classification results on a public dataset revealed a superior sensitivity of the DTW analysis to group differences by showing that DTW based classifiers outperform the zero-lag correlation and maximal lag cross-correlation based classifiers significantly. Our findings suggest that analysing resting-state functional connectivity using DTW provides an efficient new way for characterizing functional networks

Cognitive subtypes in recent onset psychosis: distinct neurobiological fingerprints?

In schizophrenia, neurocognitive subtypes can be distinguished based on cognitive performance and they are associated with neuroanatomical alterations. We investigated the existence of cognitive subtypes in shortly medicated recent onset psychosis patients, their underlying gray matter volume patterns and clinical characteristics. We used a K-means algorithm to cluster 108 psychosis patients from the multi-site EU PRONIA (Prognostic tools for early psychosis management) study based on cognitive performance and validated the solution independently (N = 53). Cognitive subgroups and healthy controls (HC; n = 195) were classified based on gray matter volume (GMV) using Support Vector Machine classification. A cognitively spared (N = 67) and impaired (N = 41) subgroup were revealed and partially independently validated (N-spared = 40, N-impaired = 13). Impaired patients showed significantly increased negative symptomatology (p(fdr) = 0.003), reduced cognitive performance (p(fdr) < 0.001) and general functioning (p(fdr) < 0.035) in comparison to spared patients. Neurocognitive deficits of the impaired subgroup persist in both discovery and validation sample across several domains, including verbal memory and processing speed. A GMV pattern (balanced accuracy = 60.1%, p = 0.01) separating impaired patients from HC revealed increases and decreases across several fronto-temporal-parietal brain areas, including basal ganglia and cerebellum. Cognitive and functional disturbances alongside brain morphological changes in the impaired subgroup are consistent with a neurodevelopmental origin of psychosis. Our findings emphasize the relevance of tailored intervention early in the course of psychosis for patients suffering from the likely stronger neurodevelopmental character of the disease

Resisting Sleep Pressure:Impact on Resting State Functional Network Connectivity

In today's 24/7 society, sleep restriction is a common phenomenon which leads to increased levels of sleep pressure in daily life. However, the magnitude and extent of impairment of brain functioning due to increased sleep pressure is still not completely understood. Resting state network (RSN) analyses have become increasingly popular because they allow us to investigate brain activity patterns in the absence of a specific task and to identify changes under different levels of vigilance (e.g. due to increased sleep pressure). RSNs are commonly derived from BOLD fMRI signals but studies progressively also employ cerebral blood flow (CBF) signals. To investigate the impact of sleep pressure on RSNs, we examined RSNs of participants under high (19 h awake) and normal (10 h awake) sleep pressure with three imaging modalities (arterial spin labeling, BOLD, pseudo BOLD) while providing confirmation of vigilance states in most conditions. We demonstrated that CBF and pseudo BOLD signals (measured with arterial spin labeling) are suited to derive independent component analysis based RSNs. The spatial map differences of these RSNs were rather small, suggesting a strong biological substrate underlying these networks. Interestingly, increased sleep pressure, namely longer time awake, specifically changed the functional network connectivity (FNC) between RSNs. In summary, all FNCs of the default mode network with any other network or component showed increasing effects as a function of increased 'time awake'. All other FNCs became more anti-correlated with increased 'time awake'. The sensorimotor networks were the only ones who showed a within network change of FNC, namely decreased connectivity as function of 'time awake'. These specific changes of FNC could reflect both compensatory mechanisms aiming to fight sleep as well as a first reduction of consciousness while becoming drowsy. We think that the specific changes observed in functional network connectivity could imply an impairment of information transfer between the affected RSNs

An open science resource for establishing reliability and reproducibility in functional connectomics

Efforts to identify meaningful functional imaging-based biomarkers are limited by the ability to reliably characterize inter-individual differences in human brain function. Although a growing number of connectomics-based measures are reported to have moderate to high test-retest reliability, the variability in data acquisition, experimental designs, and analytic methods precludes the ability to generalize results. The Consortium for Reliability and Reproducibility (CoRR) is working to address this challenge and establish test-retest reliability as a minimum standard for methods development in functional connectomics. Specifically, CoRR has aggregated 1,629 typical individuals’ resting state fMRI (rfMRI) data (5,093 rfMRI scans) from 18 international sites, and is openly sharing them via the International Data-sharing Neuroimaging Initiative (INDI). To allow researchers to generate various estimates of reliability and reproducibility, a variety of data acquisition procedures and experimental designs are included. Similarly, to enable users to assess the impact of commonly encountered artifacts (for example, motion) on characterizations of inter-individual variation, datasets of varying quality are included

Prefrontal transcranial direct current stimulation for treatment of schizophrenia with predominant negative symptoms: a double-blind, sham-controlled proof-of-concept study

Negative symptoms are highly relevant in the long-term course of schizophrenia and are an important target domain for the development of novel interventions. Recently, transcranial direct current stimulation (tDCS) of the prefrontal cortex has been investigated as a treatment option in schizophrenia. In this proof-of-concept study, 20 schizophrenia patients with predominantly negative symptoms were randomized to either 10 sessions of add-on active (2 mA, 20min) or sham tDCS (anode: left DLPFC/F3; cathode: right supraorbital/F4). Primary outcome measure was the change in the Scale for the Assessment of Negative Symptoms (SANS) sum score; secondary outcomes included reduction in Positive and Negative Syndrome Scale (PANSS) scores and improvement of depressive symptoms, cognitive processing speed, and executive functioning. Sixteen patients underwent 4 functional connectivity magnetic resonance imaging (fcMRI) scans (pre and post 1st and pre and post 10th tDCS) to investigate changes in resting state network connectivity after tDCS. Per-protocol analysis showed a significantly greater decrease in SANS score after active (−36.1%) than after sham tDCS (−0.7%). PANSS sum scores decreased significantly more with active (−23.4%) than with sham stimulation (−2.2%). Explorative analysis of fcMRI data indicated changes in subgenual cortex and dorsolateral prefrontal cortex (DLPFC) connectivity within frontal-thalamic-temporo-parietal networks. The results of this first proof-of-concept study indicate that prefrontal tDCS may be a promising intervention for treatment of schizophrenia with predominant negative symptoms. Large-scale randomized controlled studies are needed to further establish prefrontal tDCS as novel treatment for negative symptoms in schizophrenia

Variations in radioiodine ablation: decision-making after total thyroidectomy.

The role of radioiodine treatment following total thyroidectomy for differentiated thyroid cancer is changing. The last major revision of the American Thyroid Association (ATA) Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer in 2015 changed treatment recommendations dramatically in comparison with the European Association of Nuclear Medicine (EANM) 2008 guidelines. We hypothesised that there is marked variability between the different treatment regimens used today. We analysed decision-making in all Swiss hospitals offering radioiodine treatment to map current practice within the community and identify consensus and discrepancies. RESULTS AND CONCLUSION: We demonstrated that for low-risk DTC patients after thyroidectomy, some institutions offered only follow-up, while RIT with significant activities is recommended in others. For intermediate- and high-risk patients, radioiodine treatment is generally recommended. Dosing and treatment preparation (recombinant human thyroid stimulation hormone (rhTSH) vs. thyroid hormone withdrawal (THW)) vary significantly among centres

Activated Protein C Protects Against Diabetic Nephropathy By Inhibiting Endothelial And Podocyte Apoptosis

Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally linked to nephropathy. Thrombomodulin-dependent APC formation mediates cytoprotection in diabetic nephropathy by inhibiting glomerular apoptosis. APC prevents glucose-induced apoptosis in endothelial cells and podocytes, the cellular components of the glomerular filtration barrier. APC modulates the mitochondrial apoptosis pathway via the protease-activated receptor PAR-1 and the endothelial protein C receptor EPCR in glucose-stressed cells. These experiments establish a new pathway, in which hyperglycemia impairs endothelial thrombomodulin- dependent APC formation. Loss of thrombomodulin-dependent APC formation interrupts cross-talk between the vascular compartment and podocytes, causing glomerular apoptosis and diabetic nephropathy. Conversely, maintaining high APC levels during long-term diabetes protects against diabetic nephropathy. © 2007 Nature Publishing Group.131113491358Renal Data System: USRDS 1998 Annual Data Report (NIH Publ. No. 98-3176) (US Government Printing Office, Washington, DC, 1998)Wendt, T.M., RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy (2003) Am. J. Pathol, 162, pp. 1123-1137Haraldsson, B., Sorensson, J., Why do we not all have proteinuria? An update of our current understanding of the glomerular barrier (2004) News Physiol. Sci, 19, pp. 7-10Dalla Vestra, M., Is podocyte injury relevant in diabetic nephropathy? Studies in patients with type 2 diabetes (2003) Diabetes, 52, pp. 1031-1035Meyer, T.W., Bennett, P.H., Nelson, R.G., Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria (1999) Diabetologia, 42, pp. 1341-1344Esmon, C.T. Inflammation and the activated protein C anticoagulant pathway. Semin. Thromb. Hemost. 32 (Suppl. 1), 49-60 (2006)Riewald, M., Petrovan, R.J., Donner, A., Mueller, B.M., Ruf, W., Activation of endothelial cell protease activated receptor 1 by the protein C pathway (2002) Science, 296, pp. 1880-1882Cheng, T., Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective (2003) Nat. Med, 9, pp. 338-342Feistritzer, C., Riewald, M., Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation (2005) Blood, 105, pp. 3178-3184Finigan, J.H., Activated protein C mediates novel lung endothelial barrier enhancement: Role of sphingosine 1-phosphate receptor transactivation (2005) J. Biol. Chem, 280, pp. 17286-17293Borcea, V., Influence of ramipril on the course of plasma thrombomodulin in patients with diabetes mellitus (1999) Vasa, 28, pp. 172-180Fujiwara, Y., Tagami, S., Kawakami, Y., Circulating thrombomodulin and hematological alterations in type 2 diabetic patients with retinopathy (1998) J. Atheroscler. Thromb, 5, pp. 21-28Weiler-Guettler, H., A targeted point mutation in thrombomodulin generates viable mice with a prethrombotic state (1998) J. Clin. Invest, 101, pp. 1983-1991Hall, S.W., Nagashima, M., Zhao, L., Morser, J., Leung, L.L., Thrombin interacts with thrombomodulin, protein C, and thrombin-activatable fibrinolysis inhibitor via specific and distinct domains (1999) J. Biol. Chem, 274, pp. 25510-25516Festa, A., Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: The Insulin Resistance Atherosclerosis Study (2000) Kidney Int, 58, pp. 1703-1710Isermann, B., The thrombomodulin-protein C system is essential for the maintenance of pregnancy (2003) Nat. Med, 9, pp. 331-337Mosnier, L.O., Griffin, J.H., Inhibition of staurosporine-induced apoptosis of endothelial cells by activated protein C requires protease-activated receptor-1 and endothelial cell protein C receptor (2003) Biochem. J, 373, pp. 65-70Tewari, M., Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase (1995) Cell, 81, pp. 801-809Wang, J., Minocycline up-regulates Bcl-2 and protects against cell death in mitochondria (2004) J. Biol. Chem, 279, pp. 19948-19954Kelly, K.J., Minocycline inhibits apoptosis and inflammation in a rat model of ischemic renal injury (2004) Am. J. Physiol. Renal Physiol, 287, pp. F760-F766Brownlee, M., Biochemistry and molecular cell biology of diabetic complications (2001) Nature, 414, pp. 813-820Zou, M.H., Shi, C., Cohen, R.A., High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/prostaglandin H(2) receptor-mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells (2002) Diabetes, 51, pp. 198-203Yamaji, K., Activated protein C, a natural anticoagulant protein, has antioxidant properties and inhibits lipid peroxidation and advanced glycation end products formation (2005) Thromb. Res, 115, pp. 319-325Riewald, M., Ruf, W., Protease-activated receptor-1 signaling by activated protein C in cytokine-perturbed endothelial cells is distinct from thrombin signaling (2005) J. Biol. Chem, 280, pp. 19808-19814Goligorsky, M.S., Chen, J., Brodsky, S., Workshop: Endothelial cell dysfunction leading to diabetic nephropathy: focus on nitric oxide (2001) Hypertension, 37, pp. 744-748Endemann, D.H., Schiffrin, E.L., Endothelial dysfunction (2004) J. Am. Soc. Nephrol, 15, pp. 1983-1992Murata, I., Apoptotic cell loss following cell proliferation in renal glomeruli of Otsuka Long-Evans Tokushima Fatty rats, a model of human type 2 diabetes (2002) Am. J. Nephrol, 22, pp. 587-595Kumar, D., Robertson, S., Burns, K.D., Evidence of apoptosis in human diabetic kidney (2004) Mol. Cell. Biochem, 259, pp. 67-70Baba, K., Involvement of apoptosis in patients with diabetic nephropathy: A study on plasma soluble Fas levels and pathological findings (2004) Nephrology (Carlton), 9, pp. 94-99Liaw, P.C., Patients with severe sepsis vary markedly in their ability to generate activated protein C (2004) Blood, 104, pp. 3958-3964Macias, W.L., New insights into the protein C pathway: Potential implications for the biological activities of drotrecogin alfa (activated) (2005) Crit. Care, 9 (SUPPL. 4), pp. S38-S45Glaser, C.B., Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation (1992) J. Clin. Invest, 90, pp. 2565-2573Boehme, M.W., Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: In vivo and in vitro studies (1996) Immunology, 87, pp. 134-140Mosnier, L.O., Gale, A.J., Yegneswaran, S., Griffin, J.H., Activated protein C variants with normal cytoprotective but reduced anticoagulant activity (2004) Blood, 104, pp. 1740-1744Bernard, G.R., Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis (2003) Crit. Care, 7, pp. 155-163Taylor, F.B., Kinasewitz, G., Activated protein C in sepsis (2004) J. Thromb. Haemost, 2, pp. 708-717Chae, S.S., Proia, R.L., Hla, T., Constitutive expression of the S1P1 receptor in adult tissues (2004) Prostaglandins Other Lipid Mediat, 73, pp. 141-150Virag, L., Szabo, C., The therapeutic potential of poly(ADP-ribose) polymerase inhibitors (2002) Pharmacol. Rev, 54, pp. 375-429Cipriani, G., Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction (2005) J. Biol. Chem, 280, pp. 17227-17234Alano, C.C., Kauppinen, T.M., Valls, A.V., Swanson, R.A., Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations (2006) Proc. Natl. Acad. Sci. USA, 103, pp. 9685-9690Szabo, C., Biser, A., Benko, R., Bottinger, E., Susztak, K., Poly(ADP-ribose) polymerase inhibitors ameliorate nephropathy of type 2 diabetic Leprdb/db mice (2006) Diabetes, 55, pp. 3004-3012Kiss, L., The pathogenesis of diabetic complications: The role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity (2005) Mem. Inst. Oswaldo Cruz, 100 (SUPPL. 1), pp. 29-37Richardson, M.A., Gerlitz, B., Grinnell, B.W., Enhancing protein C interaction with thrombin results in a clot-activated anticoagulant (1992) Nature, 360, pp. 261-264Chen, M., Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease (2000) Nat. Med, 6, pp. 797-801Isermann, B., Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis (2001) J. Clin. Invest, 108, pp. 537-546Kerlin, B.A., Survival advantage associated with heterozygous Factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia (2003) Blood, 102, pp. 3085-3092Calkin, A.C., PPAR-α and -γ agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse (2006) Nephrol. Dial. Transplant, 21, pp. 2399-2405Mundel, P., Rearrangements of the cytoskeleton and cell contacts induce process formation during differentiation of conditionally immortalized mouse podocyte cell lines (1997) Exp. Cell Res, 236, pp. 248-258Asanuma, K., Synaptopodin regulates the actin-bundling activity of alpha-actinin in an isoform-specific manner (2005) J. Clin. Invest, 115, pp. 1188-119

Variations in radioiodine ablation: decision-making after total thyroidectomy.

BACKGROUND The role of radioiodine treatment following total thyroidectomy for differentiated thyroid cancer is changing. The last major revision of the American Thyroid Association (ATA) Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer in 2015 changed treatment recommendations dramatically in comparison with the European Association of Nuclear Medicine (EANM) 2008 guidelines. We hypothesised that there is marked variability between the different treatment regimens used today. METHODS We analysed decision-making in all Swiss hospitals offering radioiodine treatment to map current practice within the community and identify consensus and discrepancies. RESULTS AND CONCLUSION: We demonstrated that for low-risk DTC patients after thyroidectomy, some institutions offered only follow-up, while RIT with significant activities is recommended in others. For intermediate- and high-risk patients, radioiodine treatment is generally recommended. Dosing and treatment preparation (recombinant human thyroid stimulation hormone (rhTSH) vs. thyroid hormone withdrawal (THW)) vary significantly among centres