Autism spectrum disorder-specific changes in white matter connectome edge density based on functionally defined nodes

IntroductionAutism spectrum disorder (ASD) is associated with both functional and microstructural connectome disruptions. We deployed a novel methodology using functionally defined nodes to guide white matter (WM) tractography and identify ASD-related microstructural connectome changes across the lifespan.MethodsWe used diffusion tensor imaging and clinical data from four studies in the national database for autism research (NDAR) including 155 infants, 102 toddlers, 230 adolescents, and 96 young adults – of whom 264 (45%) were diagnosed with ASD. We applied cortical nodes from a prior fMRI study identifying regions related to symptom severity scores and used these seeds to construct WM fiber tracts as connectome Edge Density (ED) maps. Resulting ED maps were assessed for between-group differences using voxel-wise and tract-based analysis. We then examined the association of ASD diagnosis with ED driven from functional nodes generated from different sensitivity thresholds.ResultsIn ED derived from functionally guided tractography, we identified ASD-related changes in infants (pFDR ≤ 0.001–0.483). Overall, more wide-spread ASD-related differences were detectable in ED based on functional nodes with positive symptom correlation than negative correlation to ASD, and stricter thresholds for functional nodes resulted in stronger correlation with ASD among infants (z = −6.413 to 6.666, pFDR ≤ 0.001–0.968). Voxel-wise analysis revealed wide-spread ED reductions in central WM tracts of toddlers, adolescents, and adults.DiscussionWe detected early changes of aberrant WM development in infants developing ASD when generating microstructural connectome ED map with cortical nodes defined by functional imaging. These were not evident when applying structurally defined nodes, suggesting that functionally guided DTI-based tractography can help identify early ASD-related WM disruptions between cortical regions exhibiting abnormal connectivity patterns later in life. Furthermore, our results suggest a benefit of involving functionally informed nodes in diffusion imaging-based probabilistic tractography, and underline that different age cohorts can benefit from age- and brain development-adapted image processing protocols

Cooperative Regulation of Non-Small Cell Lung Carcinoma by Nicotinic and Beta-Adrenergic Receptors: A Novel Target for Intervention

Lung cancer is the leading cause of cancer death; 80–85% of lung cancer cases are non-small cell lung cancer (NSCLC). Smoking is a documented risk factor for the development of this cancer. Although nicotine does not have the ability to initiate carcinogenic events, recent studies have implicated nicotine in growth stimulation of NSCLC. Using three NSCLC cell lines (NCI-H322, NCI-H441 and NCI-H1299), we identified the cooperation of nicotinic acetylcholine receptors (nAChRs) and β-adrenergic receptors (β-ARs) as principal regulators of these effects. Proliferation was measured by thymidine incorporation and MTT assays, and Western blots were used to monitor the upregulation of the nAChRs and activation of signaling molecules. Noradrenaline and GABA were measured by immunoassays. Nicotine-treated NSCLC cells showed significant induction of the α7nAChR and α4nAChR, along with significant inductions of p-CREB and p-ERK1/2 accompanied by increases in the stress neurotransmitter noradrenaline, which in turn led to the observed increase in DNA synthesis and cell proliferation. Effects on cell proliferation and signaling proteins were reversed by the α7nAChR antagonist α-BTX or the β-blocker propranolol. Nicotine treatment also down-regulated expression of the GABA synthesizing enzyme GAD 65 and the level of endogenous GABA, while treatment of NSCLC cells with GABA inhibited cell proliferation. Interestingly, GABA acts by reducing β-adrenergic activated cAMP signaling. Our findings suggest that nicotine-induced activation of this autocrine noradrenaline-initiated signaling cascade and concomitant deficiency in inhibitory GABA, similar to modulation of these neurotransmitters in the nicotine-addicted brain, may contribute to the development of NSCLC in smokers. Our data suggest that exposure to nicotine either by tobacco smoke or nicotine supplements facilitates growth and progression of NSCLC and that pharmacological intervention by β blocker may lower the risk for NSCLC development among smokers and could be used to enhance the clinical outcome of standard cancer therapy

Highly accurate thermal flow microsensor for continuous and quantitative measurement of cerebral blood flow

Cerebral blood flow (CBF) plays a critical role in the exchange of nutrients and metabolites at the capillary level and is tightly regulated to meet the metabolic demands of the brain. After major brain injuries, CBF normally decreases and supporting the injured brain with adequate CBF is a mainstay of therapy after traumatic brain injury. Quantitative and localized measurement of CBF is therefore critically important for evaluation of treatment efficacy and also for understanding of cerebral pathophysiology. We present here an improved thermal flow microsensor and its operation which provides higher accuracy compared to existing devices. The flow microsensor consists of three components, two stacked-up thin film resistive elements serving as composite heater/temperature sensor and one remote resistive element for environmental temperature compensation. It operates in constant-temperature mode (~2 degrees C above the medium temperature) providing 20 ms temporal resolution. Compared to previous thermal flow microsensor based on self-heating and self-sensing design, the sensor presented provides at least two-fold improvement in accuracy in the range from 0 to 200 ml/100 g/min. This is mainly achieved by using the stacked-up structure, where the heating and sensing are separated to improve the temperature measurement accuracy by minimization of errors introduced by self-heating

Endogenous methyl palmitate modulates nicotinic receptor-mediated transmission in the superior cervical ganglion

Nitric oxide (NO) is identified as the endothelium-derived relaxing factor and a neurotransmitter with a superfusion bioassay cascade technique. By using a similar technique with rat superior cervical ganglion (SCG) as donor tissue and rabbit endothelium-denuded aortic ring as detector tissue, we report here that a vasodilator, which is more potent than NO, is released in the SCG upon field electrical stimulation (FES) or addition of nicotine. Release of this vasodilator was enhanced by arginine analogs, including Nω-nitro-l-arginine (a NO synthase inhibitor), suggesting that it is not NO. Analysis by gas chromatography/mass spectrometry identified 2 saturated fatty acids, palmitic acid methyl ester (PAME) and stearic acid methyl ester (SAME), being released from the SCG upon FES in the presence of arginine analogs. Exogenous PAME but not SAME induced significant aortic dilation (EC50 = 0.19 nM), indicating that PAME is the potent vasodilator. Release of PAME and SAME was significantly diminished in chronically decentralized SCG but not denervated SCG, suggesting the preganglionic origin. Furthermore, release of both fatty acids was calcium- and myosin light chain kinase-dependent, suggesting that both were released from axoplasmic vesicular stores. Electrophysiological studies further demonstrated that PAME but not SAME inhibited nicotine-induced inward currents in cultured SCG and the α7-nicotinic acetylcholine receptor-expressing Xenopus oocytes. Endogenous PAME appears to play a role in modulation of the autonomic ganglionic transmission and to complement the vasodilator effect of NO