Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect

The histone deacetylase inhibitors (HDACi) have demonstrated anticancer efficacy across a range of malignancies, most impressively in the hematological cancers. It is uncertain whether this clinical efficacy is attributable predominantly to their ability to induce apoptosis and differentiation in the cancer cell, or to their ability to prime the cell to other pro-death stimuli such as those from the immune system. HDACi-induced apoptosis occurs through altered expression of genes encoding proteins in both intrinsic and extrinsic apoptotic pathways; through effects on the proteasome/aggresome systems; through the production of reactive oxygen species, possibly by directly inducing DNA damage; and through alterations in the tumor microenvironment. In addition HDACi increase the immunogenicity of tumor cells and modulate cytokine signaling and potentially T-cell polarization in ways that may contribute the anti-cancer effect in vivo. Here, we provide an overview of current thinking on the mechanisms of HDACi activity, with attention given to the hematological malignancies as well as scientific observations arising from the clinical trials. We also focus on the immune effects of these agents

Effects of theta transcranial alternating current stimulation (tACS) on exploration and exploitation during uncertain decision-making

Exploring ones surroundings may yield unexpected rewards, but is associated with uncertainty and risk. Alternatively, exploitation of certain outcomes is related to low risk, yet potentially better outcomes remain unexamined. As such, risk-taking behavior depends on perceived uncertainty and a trade-off between exploration-exploitation. Previously, it has been suggested that risk-taking may relate to theta activity in the prefrontal cortex. Furthermore, previous studies hinted at a relationship between a right-hemispheric bias in frontal theta asymmetry and risky behavior. In the present double-blind sham-controlled within-subject study, we applied bifrontal transcranial alternating current stimulation (tACS) at the theta frequency (5 Hz) on eighteen healthy volunteers during a gambling task. Two tACS montages with either left-right or posterior-anterior current flow were employed at an intensity of 1 mA. Results showed that, compared to sham, theta tACS increased perceived uncertainty irrespective of current flow direction. Despite this observation, no direct effect of tACS on exploration behavior and general risk-taking was observed. Furthermore, frontal theta asymmetry was more right-hemispherically biased after posterior-anterior tACS, compared to sham. Finally, we used electric field simulation to identify which regions were targeted by the tACS montages as an overlap in regions may explain why the two montages resulted in comparable outcomes. Our findings provide a first step towards understanding the relationship between frontal theta oscillations and different features of risk-taking

Effects of beta-tACS on corticospinal excitability: A meta-analysis

Over the past decade several studies have shown that transcranial alternating current stimulation (tACS) delivered at the beta (15–25 Hz) frequency range can increase corticospinal excitability of the primary motor cortex (M1). The aim of this study was to systematically quantify the effect size of beta-tACS on corticospinal excitability in healthy volunteers, as well as to identify significant outcome predictors. A meta-analysis was performed on the results of 47 experiments reported in 21 studies. Random effects modelling of the effect sizes showed that beta-tACS significantly increases M1 excitability (Ē = 0.287, 95% CI = 0.133–0.440). Further analysis showed that tACS intensities above 1 mA peak-to-peak yield a robust increase in M1 excitability, whereas intensities of 1 mA peak-to-peak and below do not induce a reliable change. Additionally, results showed an impact of tACS montages on these effects. No difference in effect size for online compared to offline application of tACS was found. In conclusion, these findings indicate that beta-tACS can increase cortical excitability if stimulation intensity is above 1 mA, yet more research is needed to titrate the stimulation parameters that yield optimal results

Frontal Beta Transcranial Alternating Current Stimulation Improves Reversal Learning

Electroencephalogram (EEG) studies suggest an association between beta (13-30 Hz) power and reversal learning performance. In search for direct evidence concerning the involvement of beta oscillations in reversal learning, transcranial alternating current stimulation (tACS) was applied in a double-blind, sham-controlled and between-subjects design. Exogenous oscillatory currents were administered bilaterally to the frontal cortex at 20 Hz with an intensity of 1 mA peak-to-peak and the effects on reward-punishment based reversal learning were evaluated in hundred-and-eight healthy volunteers. Pre- and post-tACS resting state EEG recordings were analyzed. Results showed that beta-tACS improved rule implementation during reversal learning and decreases left and right resting-state frontal theta/beta EEG ratios following tACS. Our findings provide the first behavioral and electrophysiological evidence for exogenous 20 Hz oscillatory electric field potentials administered over to the frontal cortex to improve reversal learning

Cognitive functions and underlying parameters of human brain physiology are associated with chronotype

Circadian rhythms have natural relative variations among humans known as chronotype. Chronotype or being a morning or evening person, has a specific physiological, behavioural, and also genetic manifestation. Whether and how chronotype modulates human brain physiology and cognition is, however, not well understood. Here we examine how cortical excitability, neuroplasticity, and cognition are associated with chronotype in early and late chronotype individuals. We monitor motor cortical excitability, brain stimulation-induced neuroplasticity, and examine motor learning and cognitive functions at circadian-preferred and non-preferred times of day in 32 individuals. Motor learning and cognitive performance (working memory, and attention) along with their electrophysiological components are significantly enhanced at the circadian-preferred, compared to the non-preferred time. This outperformance is associated with enhanced cortical excitability (prominent cortical facilitation, diminished cortical inhibition), and long-term potentiation/depression-like plasticity. Our data show convergent findings of how chronotype can modulate human brain functions from basic physiological mechanisms to behaviour and higher-order cognition

Transcranial direct current stimulation in attention-deficit hyperactivity disorder: A meta-analysis of neuropsychological deficits

Transcranial direct current stimulation (tDCS) is a promising method for altering cortical excitability with clinical implications in neuropsychiatric diseases. Its application in neurodevelopmental disorders especially attention-deficit hyperactivity disorder (ADHD), is in early stage and promising but its effectiveness has not been systematically examined yet. We conducted a meta-analysis on the effectiveness of tDCS on the most studied neuropsychological symptoms of ADHD, which is the first reported meta-analysis of tDCS studies on ADHD. Data from 10 randomized controlled studies (including 11 separate experiments) targeting inhibitory control, and/or working memory (WM) in ADHD were included. Results show that overall tDCS significantly improved inhibitory control. Sub-analyses further show that dorsolateral prefrontal cortex (dlPFC) (but not right inferior frontal gyrus) tDCS and anodal (but not cathodal) tDCS significantly improved inhibitory control with a small effect size. Anodal dlPFC-tDCS had the largest significant effect on inhibitory control with a small-to-medium effect size. Additionally, a significant improving effect of tDCS on inhibitory control accuracy (but not response time) and WM speed (but not accuracy) were found. Overall, this meta-analysis supports a beneficial effect of tDCS on inhibitory control and WM in ADHD with a small-to-medium effect size. TDCS seems to be a promising method for improving neuropsychological and cognitive deficits in ADHD. However, there might be a dissociation between neuropsychological deficits and clinical symptoms of ADHD and therefore, the significance of this meta-analysis for clinical purposes is limited. Future studies should systematically evaluate the role of inter-individual factors (i.e., ADHD subtype, types of the deficit) and stimulation parameters (i.e., site, polarity, intensity, duration, repetition rate) on tDCS efficacy in ADHD population and examine whether benefits are long-term

Transcranial direct current stimulation in attention-deficit hyperactivity disorder

Transcranial direct current stimulation (tDCS) is a promising method for altering cortical excitability with clinical implications in neuropsychiatric diseases. Its application in neurodevelopmental disorders especially attention-deficit hyperactivity disorder (ADHD), is in early stage and promising but its effectiveness has not been systematically examined yet. We conducted a meta-analysis on the effectiveness of tDCS on the most studied neuropsychological symptoms of ADHD, which is the first reported meta-analysis of tDCS studies on ADHD. Data from 10 randomized controlled studies (including 11 separate experiments) targeting inhibitory control, and/or working memory (WM) in ADHD were included. Results show that overall tDCS significantly improved inhibitory control. Sub-analyses further show that dorsolateral prefrontal cortex (dlPFC) (but not right inferior frontal gyrus) tDCS and anodal (but not cathodal) tDCS significantly improved inhibitory control with a small effect size. Anodal dlPFC-tDCS had the largest significant effect on inhibitory control with a small-to-medium effect size. Additionally, a significant improving effect of tDCS on inhibitory control accuracy (but not response time) and WM speed (but not accuracy) were found. Overall, this meta-analysis supports a beneficial effect of tDCS on inhibitory control and WM in ADHD with a small-to-medium effect size. TDCS seems to be a promising method for improving neuropsychological and cognitive deficits in ADHD. However, there might be a dissociation between neuropsychological deficits and clinical symptoms of ADHD and therefore, the significance of this meta-analysis for clinical purposes is limited. Future studies should systematically evaluate the role of inter-individual factors (i.e., ADHD subtype, types of the deficit) and stimulation parameters (i.e., site, polarity, intensity, duration, repetition rate) on tDCS efficacy in ADHD population and examine whether benefits are long-term

Induced neural phase precession through exogenous electric fields

Abstract The gradual shifting of preferred neural spiking relative to local field potentials (LFPs), known as phase precession, plays a prominent role in neural coding. Correlations between the phase precession and behavior have been observed throughout various brain regions. As such, phase precession is suggested to be a global neural mechanism that promotes local neuroplasticity. However, causal evidence and neuroplastic mechanisms of phase precession are lacking so far. Here we show a causal link between LFP dynamics and phase precession. In three experiments, we modulated LFPs in humans, a non-human primate, and computational models using alternating current stimulation. We show that continuous stimulation of motor cortex oscillations in humans lead to a gradual phase shift of maximal corticospinal excitability by ~90°. Further, exogenous alternating current stimulation induced phase precession in a subset of entrained neurons (~30%) in the non-human primate. Multiscale modeling of realistic neural circuits suggests that alternating current stimulation-induced phase precession is driven by NMDA-mediated synaptic plasticity. Altogether, the three experiments provide mechanistic and causal evidence for phase precession as a global neocortical process. Alternating current-induced phase precession and consequently synaptic plasticity is crucial for the development of novel therapeutic neuromodulation methods