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The reproducibility of connectivity metrics was also analyzed in the repeat subjects. In addition, functional connectivity density (FCD), a data-driven approach that counts the number of significant connections, both within a local cluster and globally, with each voxel was analyzed. Regardless of the standard or advanced denoising technique, all seed-based RSFC was significantly higher for MBME compared to MB. Much more GM ROI combinations showed significantly higher RSFC for MBME vs. MB. Reproducibility, evaluated using the dice coefficient was significantly higher for MBME relative to MB data. Finally, FCD was also higher for MBME vs. MB data. This study showed higher RSFC for MBME vs. MB data using selected seed-based, whole GM ROI-based, and data-driven approaches. Reproducibility found also higher for MBME data. Taken together, these results indicate that MBME is a promising technique for rs-fMRI.Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the default-mode network (DMN), a constellation of inter-connected regions that displays altered FC in depressive disorders. In this study, we investigated the effects of psilocybin on FC across the entire brain with a view to investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin- relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene expression maps and viral tracer projection fields revealed two distinct effects of psilocybin it increased FC between 5-HT-associated networks and cortical areas, including elements of the murine DMN, thalamus, and midbrain; it decreased FC within dopamine (DA)-associated striatal networks. These results suggest that interactions between 5-HT- and DA-regulated neural networks contribute to the neural and therefore psychological effects of psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural connectivity can assist in the interpretation of pharmaco-fMRI findings.Functional MRI responses are localized to the synaptic sites of evoked inhibitory neurons, but it is unknown whether, or by what mechanisms, these neurons initiate functional hyperemia. Here, the neuronal origins of these hemodynamic responses were investigated by fMRI or local field potential and blood flow measurements during topical application of pharmacological agents when GABAergic granule cells in the rat olfactory bulb were synaptically targeted. First, to examine if postsynaptic activation of these inhibitory neurons was required for neurovascular coupling, we applied an NMDA receptor antagonist during cerebral blood volume-weighted fMRI acquisition and found that responses below the drug application site (up to ~1.5 mm) significantly decreased within ~30 min. Similarly, large decreases in granule cell postsynaptic activities and blood flow responses were observed when AMPA or NMDA receptor antagonists were applied. Second, inhibition of nitric oxide synthase preferentially decreased the initial, fast component of the blood flow response, while inhibitors of astrocyte-specific glutamate transporters and vasoactive intestinal peptide receptors did not decrease blood flow responses. Third, inhibition of GABA release with a presynaptic GABAB receptor agonist caused less reduction of neuronal and blood flow responses compared to the postsynaptic glutamate receptor antagonists. click here In conclusion, local hyperemia by synaptically-evoked inhibitory neurons was primarily driven by their postsynaptic activities, possibly through NMDA receptor-dependent calcium signaling that was not wholly dependent on nitric oxide.Detecting neuroplasticity in global brain circuits in vivo is key for understanding myriad processes such as memory, learning, and recovery from injury. Functional Magnetic Resonance Imaging (fMRI) is instrumental for such in vivo mappings, yet it typically relies on mapping changes in spatial extent of activation or via signal amplitude modulations, whose interpretation can be highly ambiguous. Importantly, a central aspect of neuroplasticity involves modulation of neural activity timing properties. We thus hypothesized that this temporal dimension could serve as a new marker for neuroplasticity. To detect fMRI signals more associated with the underlying neural dynamics, we developed an ultrafast fMRI (ufMRI) approach facilitating high spatiotemporal sensitivity and resolution in distributed neural pathways. When neuroplasticity was induced in the mouse visual pathway via dark rearing, ufMRI indeed mapped temporal modulations in the entire visual pathway. Our findings therefore suggest a new dimension for exploring neuroplasticity in vivo.Recombinant adeno-associated virus (AAV) is the leading vector for gene therapy in the retina. As non-pathogenic, non-integrating, replication deficient vector, the recombinant virus efficiently transduces all key retinal cell populations. Successful testing of AAV vectors in clinical trials of inherited retinal diseases led to the recent approval of voretigene neparvovec (Luxturna) for the treatment of RPE65 mutation-associated retinal dystrophies. However, studies applying AAV-mediated retinal gene therapy independently reported intraocular inflammation and/or loss of efficacy after initial functional improvements. Both observations might be explained by targeted removal of transduced cells via anti-viral defence mechanisms. AAV has been shown to activate innate pattern recognition receptors (PRRs) such as toll-like receptor (TLR)-2 and TLR-9 resulting in the release of inflammatory cytokines and type I interferons. The vector can also induce capsid-specific and transgene-specific T cell responses and neutralizing anti-AAV antibodies which both limit the therapeutic effect. However, the target organ of retinal gene therapy, the eye, is known as an immune-privileged site. It is characterized by suppression of inflammation and promotion of immune tolerance which might prevent AAV-induced immune responses. This review evaluates AAV-related immune responses, toxicity and inflammation in studies of retinal gene therapy, identifies influencing variables of these responses and discusses potential strategies to modulate immune reactions to AAV vectors to increase the safety and efficacy of ocular gene therapy.