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Summary Background: Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing - termed ���kick and kill��� - have been explored as a strategy towards an HIV cure. RIVER is the first randomized trial to determine the impact of ART alone versus ART plus ���kick-and-kill��� on markers of the HIV reservoir. Methods: RIVER (Trial registration: NCT02336074) was an open-label, multicenter, 1:1 randomized controlled trial of ART-only (control) versus ART plus the histone deacetylase inhibitor vorinostat (the ���kick���) and replication-deficient viral vector vaccines encoding conserved HIV sequences ChAdV63.HIVconsv-prime, MVA.HIVconsv-boost T-cell vaccination (the ���kill���) (ART+V+V; intervention) in HIV-positive adults treated in recent HIV-infection. The primary endpoint was total HIV DNA in peripheral blood CD4+ T-cells at weeks 16 and 18 post-randomization. Secondary endpoints included safety, alternative measures of the HIV reservoir including quantitative viral outgrowth, HIV-specific T-cell frequencies, and CD8+ T-cell mediated viral inhibition. Findings: Between December 2015 and November 2017, 60 HIV-positive male participants were randomized (computer-based and stratified by time since diagnosis; 30 participants in each trial arm) and completed the study interventions, with no loss-to-follow-up. There were no intervention-related serious adverse events. Mean total HIV DNA at weeks 16 and 18 was 3.02 log10 copies HIV DNA/106 CD4+ T-cells in the control and 3.06 log10 copies HIV DNA/106 CD4+ T-cells in the intervention arm, with no statistically significant difference (mean difference of 0.04 (95%CI -0.03, 0.11) log10 total HIV DNA copies/106 CD4+ T-cells (p=0.26)). Interpretation: This ���kick-and-kill��� approach conferred no significant benefit compared to ART alone on measures of the HIV reservoir. Although this does not disprove the ���kick and kill��� strategy, for future trials significant enhancement of both ���kick��� and ���kill��� agents will be required., Medical Research Council (MR/L00528X/1).

Oscillatory neural activity is a fundamental characteristic of the mammalian brain spanning multiple levels of spatial and temporal scale. Current theories of neural oscillations and analysis techniques employed to investigate their functional significance are based on an often implicit assumption: In the absence of experimental manipulation, the spectral content of any given EEG- or MEG-recorded neural oscillator remains approximately stationary over the course of a typical experimental session (~1 hour), spontaneously fluctuating only around its dominant frequency. Here, we examined this assumption for ongoing neural oscillations in the alpha-band (8:13 Hz). We found that alpha peak frequency systematically decreased over time, while alpha-power increased. Intriguingly, these systematic changes showed partial independence of each other: Statistical source separation (independent component analysis) revealed that while some alpha components displayed concomitant power increases and peak frequency decreases, other components showed either unique power increases or frequency decreases. Interestingly, we also found these components to differ in frequency. Components that showed mixed frequency/power changes oscillated primarily in the lower alpha-band (~8-10Hz), while components with unique changes oscillated primarily in the higher alpha-band (~9-13Hz). Our findings provide novel clues on the time-varying intrinsic properties of large-scale neural networks as measured by M/EEG, with implications for the analysis and interpretation of studies that aim at identifying functionally relevant oscillatory networks or at driving them through external stimulation.

The Salience Network (SN) and its interactions are important for cognitive control. We have previously shown that structural damage to the SN is associated with abnormal functional connectivity between the SN and Default Mode Network (DMN), abnormal DMN deactivation, and impaired response inhibition, which is an important aspect of cognitive control. This suggests that stimulating the SN might enhance cognitive control. Here, we tested whether non-invasive transcranial direct current stimulation (TDCS) could be used to modulate activity within the SN and enhance cognitive control. TDCS was applied to the right inferior frontal gyrus/anterior insula cortex during performance of the Stop Signal Task (SST) and concurrent functional (f)MRI. Anodal TDCS improved response inhibition. Furthermore, stratification of participants based on SN structural connectivity showed that it was an important influence on both behavioural and physiological responses to anodal TDCS. Participants with high fractional anisotropy within the SN showed improved SST performance and increased activation of the SN with anodal TDCS, whilst those with low fractional anisotropy within the SN did not. Cathodal stimulation of the SN produced activation of the right caudate, an effect which was not modulated by SN structural connectivity. Our results show that stimulation targeted to the SN can improve response inhibition, supporting the causal influence of this network on cognitive control and confirming it as a target to produce cognitive enhancement. Our results also highlight the importance of structural connectivity as a modulator of network to TDCS, which should guide the design and interpretation of future stimulation studies.