A new class of silica-supported chromo-fluorogenic chemosensors for anion recognition based on a selenourea scaffold

[EN] The first example of a chemosensor (L) containing a selenourea moiety is described here. L is able to colorimetrically sense the presence of CN- and S2- in H2O: MeCN (75 : 25, v/v). Moreover, when L is loaded into functionalised mesoporous silica nanoparticles an increase in the selectivity towards S2- occurs via a selective fluorescence response.The authors thank the financial support from the Fondazione Banco di Sardegna, the Spanish Government, European FEDER funds (project MAT2015-64139-C4-1-R) and the Generalitat Valenciana (project PROMETEOII/2014/047). A. Llopis-Lorente is grateful to the "La Caixa'' Banking Foundation for his PhD fellowship. Dr Tiziana Pivetta is gratefully acknowledged for help with the interpretation of the mass spectra.Casula, A.; Llopis-Lorente, A.; Garau, A.; Isaia, F.; Kubicki, M.; Lippolis, V.; Sancenón Galarza, F.... (2017). A new class of silica-supported chromo-fluorogenic chemosensors for anion recognition based on a selenourea scaffold. 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White matter microstructural perturbations after total sleep deprivation in depression

BackgroundTotal sleep deprivation (TSD) transiently reverses depressive symptoms in a majority of patients with depression. How TSD modulates diffusion tensor imaging (DTI) measures of white matter (WM) microstructure, which may be linked with TSD’s rapid antidepressant effects, remains uncharacterized.MethodsPatients with depression (N = 48, mean age = 33, 26 women) completed diffusion-weighted imaging and Hamilton Depression Rating (HDRS) and rumination scales before and after >24 h of TSD. Healthy controls (HC) (N = 53, 23 women) completed the same assessments at baseline, and after receiving TSD in a subset of HCs (N = 15). Tract based spatial statistics (TBSS) investigated voxelwise changes in fractional anisotropy (FA) across major WM pathways pre-to-post TSD in patients and HCs and between patients and HCs at baseline. Post hoc analyses tested for TSD effects for other diffusion metrics, and the relationships between change in diffusion measures with change in mood and rumination symptoms.ResultsSignificant improvements in mood and rumination occurred in patients with depression (both p < 0.001), but not in HCs following TSD. Patients showed significant (p < 0.05, corrected) decreases in FA values in multiple WM tracts, including the body of the corpus callosum and anterior corona radiata post-TSD. Significant voxel-level changes in FA were not observed in HCs who received TSD (p > 0.05). However, differential effects of TSD between HCs and patients were found in the superior corona radiata, frontal WM and the posterior thalamic radiation (p < 0.05, corrected). A significant (p < 0.05) association between change in FA and axial diffusivity within the right superior corona radiata and improvement in rumination was found post-TSD in patients.ConclusionTotal sleep deprivation leads to rapid microstructural changes in WM pathways in patients with depression that are distinct from WM changes associated with TSD observed in HCs. WM tracts including the superior corona radiata and posterior thalamic radiation could be potential biomarkers of the rapid therapeutic effects of TSD. Changes in superior corona radiata FA, in particular, may relate to improvements in maladaptive rumination

Longitudinal trajectory of response to electroconvulsive therapy associated with transient immune response & white matter alteration post-stimulation

Research suggests electroconvulsive therapy (ECT) induces an acute neuroinflammatory response and changes in white matter (WM) structural connectivity. However, whether these processes are related, either to each other or to eventual treatment outcomes, has yet to be determined. We examined the relationship between levels of peripheral pro-inflammatory cytokines and diffusion imaging-indexed changes in WM microstructure in individuals with treatment-resistant depression (TRD) who underwent ECT. Forty-two patients were assessed at baseline, after their second ECT (T2), and after completion of ECT (T3). A Montgomery Åsberg Depression Rating Scale improvement of >50% post-ECT defined ECT-responders (n = 19) from non-responders (n = 23). Thirty-four controls were also examined. Tissue-specific fractional anisotropy (FAt) was estimated using diffusion imaging data and the Free-Water method in 17 WM tracts. Inflammatory panels were evaluated from peripheral blood. Cytokines were examined to characterize the association between potential ECT-induced changes in an inflammatory state and WM microstructure. Longitudinal trajectories of both measures were also examined separately for ECT-responders and non-responders. Patients exhibited elevated Interleukin-8 (IL-8) levels at baseline compared to controls. In patients, correlations between IL-8 and FAt changes from baseline to T2 were significant in the positive direction in the right superior longitudinal fasciculus (R-SLF) and right cingulum (R-CB) (psig = 0.003). In these tracts, linear mixed-effects models revealed that trajectories of IL-8 and FAt were significantly positively correlated across all time points in responders, but not non-responders (R-CB-p = .001; R-SLF-p = 0.008). Our results suggest that response to ECT in TRD may be mediated by IL-8 and WM microstructure

Transcranial direct current stimulation (tDCS) in depression induces structural plasticity

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique involving administration of well-tolerated electrical current to the brain through scalp electrodes. TDCS may improve symptoms in neuropsychiatric disorders, but mixed results from recent clinical trials underscore the need to demonstrate that tDCS can modulate clinically relevant brain systems over time in patients. Here, we analyzed longitudinal structural MRI data from a randomized, double-blind, parallel-design clinical trial in depression (NCT03556124, N = 59) to investigate whether serial tDCS individually targeted to the left dorso-lateral prefrontal cortex (DLPFC) can induce neurostructural changes. Significant (FWEc p < 0.05) treatment-related gray matter changes were observed with active high-definition (HD) tDCS relative to sham tDCS within the left DLPFC stimulation target. No changes were observed with active conventional tDCS. A follow-up analysis within individual treatment groups revealed significant gray matter increases with active HD-tDCS in brain regions functionally connected with the stimulation target, including the bilateral DLPFC, bilateral posterior cingulate cortex, subgenual anterior cingulate cortex, and the right hippocampus, thalamus and left caudate brain regions. Integrity of blinding was verified, no significant differences in stimulation-related discomfort were observed between treatment groups, and tDCS treatments were not augmented by any other adjunct treatments. Overall, these results demonstrate that serial HD-tDCS leads to neurostructural changes at a predetermined brain target in depression and suggest that such plasticity effects may propagate over brain networks

A novel technique for accurate electrode placement over cortical targets for transcranial electrical stimulation (tES) clinical trials.

Objective. We present an easy-to-implement technique for accurate electrode placement over repeated transcranial electrical stimulation (tES) sessions across participants and time. tES is an emerging, non-invasive neuromodulation technique that delivers electrical stimulation using scalp electrodes.Approach.The tES electrode placement technique was developed during an exploratory clinical trial aimed at targeting a specific MNI-atlas cortical coordinate inN= 59 depressed participants (32 F, mean age: 31.1 ± 8.3 SD). Each participant completed 12 sessions of active or sham stimulation, administered using high-definition (HD) or conventional sized electrode montages placed according to the proposed technique. Neuronavigation data measuring the distances between the identified and the intended stimulation site, simulations, and cerebral blood flow (CBF) data at baseline and post-treatment were acquired to evaluate the targeting characteristics of the proposed technique.Main results.Neuronavigation measurements indicate accurate electrode placement to within 1 cm of the stimulation target on average across repeated sessions. Simulations predict that these placement characteristics result in minimal electric field differences at the stimulation target (>0.90 correlation, and <10% change in the modal electric field and targeted volume). Additionally, significant changes in %CBF (relative to baseline) under the stimulation target in the active stimulation group relative to sham confirmed that the proposed placement technique introduces minimal bias in the spatial location of the cortical coordinate ultimately targeted. Finally, we show proof of concept that the proposed technique provides similar accuracy of electrode placement at other cortical targets.Significance.For voxel-level cortical targets, existing techniques based on cranial landmarks are suboptimal. Our results show that the proposed electrode placement approach provides high consistency for the accurate targeting of such specific cortical regions. Overall, the proposed technique now enables the accurate targeting of locations not accessible with the existing 10-20 system such as scalp-projections of clinically-relevant cortical coordinates identified by brain mapping studies. Clinical trial ID: NCT03556124

Hippocampal subregions and networks linked with antidepressant response to electroconvulsive therapy.

Electroconvulsive therapy (ECT) has been repeatedly linked to hippocampal plasticity. However, it remains unclear what role hippocampal plasticity plays in the antidepressant response to ECT. This magnetic resonance imaging (MRI) study tracks changes in separate hippocampal subregions and hippocampal networks in patients with depression (n = 44, 23 female) to determine their relationship, if any, with improvement after ECT. Voxelwise analyses were restricted to the hippocampus, amygdala, and parahippocampal cortex, and applied separately for responders and nonresponders to ECT. In analyses of arterial spin-labeled (ASL) MRI, nonresponders exhibited increased cerebral blood flow (CBF) in bilateral anterior hippocampus, while responders showed CBF increases in right middle and left posterior hippocampus. In analyses of gray matter volume (GMV) using T1-weighted MRI, GMV increased throughout bilateral hippocampus and surrounding tissue in nonresponders, while responders showed increased GMV in right anterior hippocampus only. Using CBF loci as seed regions, BOLD-fMRI data from healthy controls (n = 36, 19 female) identified spatially separable neurofunctional networks comprised of different brain regions. In graph theory analyses of these networks, functional connectivity within a hippocampus-thalamus-striatum network decreased only in responders after two treatments and after index. In sum, our results suggest that the location of ECT-related plasticity within the hippocampus may differ according to antidepressant outcome, and that larger amounts of hippocampal plasticity may not be conducive to positive antidepressant response. More focused targeting of hippocampal subregions and/or circuits may be a way to improve ECT outcome

Hippocampal subregions and networks linked with antidepressant response to electroconvulsive therapy.

Electroconvulsive therapy (ECT) has been repeatedly linked to hippocampal plasticity. However, it remains unclear what role hippocampal plasticity plays in the antidepressant response to ECT. This magnetic resonance imaging (MRI) study tracks changes in separate hippocampal subregions and hippocampal networks in patients with depression (n = 44, 23 female) to determine their relationship, if any, with improvement after ECT. Voxelwise analyses were restricted to the hippocampus, amygdala, and parahippocampal cortex, and applied separately for responders and nonresponders to ECT. In analyses of arterial spin-labeled (ASL) MRI, nonresponders exhibited increased cerebral blood flow (CBF) in bilateral anterior hippocampus, while responders showed CBF increases in right middle and left posterior hippocampus. In analyses of gray matter volume (GMV) using T1-weighted MRI, GMV increased throughout bilateral hippocampus and surrounding tissue in nonresponders, while responders showed increased GMV in right anterior hippocampus only. Using CBF loci as seed regions, BOLD-fMRI data from healthy controls (n = 36, 19 female) identified spatially separable neurofunctional networks comprised of different brain regions. In graph theory analyses of these networks, functional connectivity within a hippocampus-thalamus-striatum network decreased only in responders after two treatments and after index. In sum, our results suggest that the location of ECT-related plasticity within the hippocampus may differ according to antidepressant outcome, and that larger amounts of hippocampal plasticity may not be conducive to positive antidepressant response. More focused targeting of hippocampal subregions and/or circuits may be a way to improve ECT outcome

Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression.

Subanesthetic ketamine is found to induce fast-acting and pronounced antidepressant effects, even in treatment resistant depression (TRD). However, it remains unclear how ketamine modulates neural function at the brain systems-level to regulate emotion and behavior. Here, we examined treatment-related changes in the inhibitory control network after single and repeated ketamine therapy in TRD. Forty-seven TRD patients (mean age = 38, 19 women) and 32 healthy controls (mean age = 35, 18 women) performed a functional magnetic resonance imaging (fMRI) response inhibition task at baseline, and 37 patients completed the fMRI task and symptom scales again 24 h after receiving both one and four 0.5 mg/kg intravenous ketamine infusions. Analyses of fMRI data addressed effects of diagnosis, time, and differences between treatment remitters and non-remitters. Significant decreases in brain activation were observed in the inhibitory control network, including in prefrontal and parietal regions, and visual cortex following serial ketamine treatment, p < 0.05 corrected. Remitters were distinguished from non-remitters by having lower functional activation in the supplementary motor area (SMA) prior to treatment, which normalized towards controls following serial ketamine treatment. Results suggest that ketamine treatment leads to neurofunctional plasticity in executive control networks including the SMA during a response-inhibitory task. SMA changes relate to reductions in depressive symptoms, suggesting modulation of this network play an important role in therapeutic response. In addition, early changes in the SMA network during response inhibition appear predictive of overall treatment outcome, and may serve as a biomarker of treatment response

In-vivo imaging of targeting and modulation of depression-relevant circuitry by transcranial direct current stimulation: a randomized clinical trial.

Recent clinical trials of transcranial direct current stimulation (tDCS) in depression have shown contrasting results. Consequently, we used in-vivo neuroimaging to confirm targeting and modulation of depression-relevant neural circuitry by tDCS. Depressed participants (N = 66, Baseline Hamilton Depression Rating Scale (HDRS) 17-item scores ≥14 and <24) were randomized into Active/Sham and High-definition (HD)/Conventional (Conv) tDCS groups using a double-blind, parallel design, and received tDCS individually targeted at the left dorsolateral prefrontal cortex (DLPFC). In accordance with Ampere's Law, tDCS currents were hypothesized to induce magnetic fields at the stimulation-target, measured in real-time using dual-echo echo-planar-imaging (DE-EPI) MRI. Additionally, the tDCS treatment trial (consisting of 12 daily 20-min sessions) was hypothesized to induce cerebral blood flow (CBF) changes post-treatment at the DLPFC target and in the reciprocally connected anterior cingulate cortex (ACC), measured using pseudo-continuous arterial spin labeling (pCASL) MRI. Significant tDCS current-induced magnetic fields were observed at the left DLPFC target for both active stimulation montages (Brodmann's area (BA) 46: pHD = 0.048, Cohen's dHD = 0.73; pConv = 0.018, dConv = 0.86; BA 9: pHD = 0.011, dHD = 0.92; pConv = 0.022, dConv = 0.83). Significant longitudinal CBF increases were observed (a) at the left DLPFC stimulation-target for both active montages (pHD = 3.5E-3, dHD = 0.98; pConv = 2.8E-3, dConv = 1.08), and (b) at ACC for the HD-montage only (pHD = 2.4E-3, dHD = 1.06; pConv = 0.075, dConv = 0.64). These results confirm that tDCS-treatment (a) engages the stimulation-target, and (b) modulates depression-relevant neural circuitry in depressed participants, with stronger network-modulations induced by the HD-montage. Although not primary outcomes, active HD-tDCS showed significant improvements of anhedonia relative to sham, though HDRS scores did not differ significantly between montages post-treatment

Single and repeated ketamine treatment induces perfusion changes in sensory and limbic networks in major depressive disorder

Ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depressive disorder (MDD). Yet, how single and repeated ketamine treatment induces brain systems-level neuroplasticity underlying symptom improvement is unknown. Advanced multiband imaging (MB) pseudo-continuous arterial spin labeling (pCASL) perfusion MRI data was acquired from patients with treatment resistant depression (TRD) (N = 22, mean age=35.2 ± 9.95 SD, 27% female) at baseline, and 24 h after receiving single, and four subanesthetic (0.5 mg/kg) intravenous ketamine infusions. Changes in global and regional CBF were compared across time points, and relationships with overall mood, anhedonia and apathy were examined. Comparisons between patients at baseline and controls (N = 18, mean age=36.11 ± 14.5 SD, 57% female) established normalization of treatment effects. Results showed increased regional CBF in the cingulate and primary and higher-order visual association regions after first ketamine treatment. Baseline CBF in the fusiform, and acute changes in CBF in visual areas were related to symptom improvement after single and repeated ketamine treatment, respectively. In contrast, after serial infusion therapy, decreases in regional CBF were observed in the bilateral hippocampus and right insula with ketamine treatment. Findings demonstrate that neurophysiological changes occurring with single and repeated ketamine treatment follow both a regional and temporal pattern including sensory and limbic regions. Initial changes are observed in the posterior cingulate and precuneus and primary and higher-order visual areas, which relate to clinical responses. However, repeated exposure to ketamine, though not relating to clinical outcome, appears to engage deeper limbic structures and insula. ClinicalTrials.gov: Biomarkers of Fast Acting Therapies in Major Depression, https://clinicaltrials.gov/ct2/show/NCT02165449, NCT02165449