Driving human motor cortical oscillations leads to behaviorally relevant changes in local GABAA inhibition: a tACS-TMS study

Beta and gamma oscillations are the dominant oscillatory activity in the human motor cortex (M1). However, their physiological basis and precise functional significance remain poorly understood. Here, we used transcranial magnetic stimulation (TMS) to examine the physiological basis and behavioral relevance of driving beta and gamma oscillatory activity in the human M1 using transcranial alternating current stimulation (tACS). tACS was applied using a sham-controlled crossover design at individualized intensity for 20 min and TMS was performed at rest (before, during, and after tACS) and during movement preparation (before and after tACS). We demonstrated that driving gamma frequency oscillations using tACS led to a significant, duration-dependent decrease in local resting-state GABAA inhibition, as quantified by short interval intracortical inhibition. The magnitude of this effect was positively correlated with the magnitude of GABAA decrease during movement preparation, when gamma activity in motor circuitry is known to increase. In addition, gamma tACS-induced change in GABAA inhibition was closely related to performance in a motor learning task such that subjects who demonstrated a greater increase in GABAA inhibition also showed faster short-term learning. The findings presented here contribute to our understanding of the neurophysiological basis of motor rhythms and suggest that tACS may have similar physiological effects to endogenously driven local oscillatory activity. Moreover, the ability to modulate local interneuronal circuits by tACS in a behaviorally relevant manner provides a basis for tACS as a putative therapeutic intervention.SIGNIFICANCE STATEMENT Gamma oscillations have a vital role in motor control. Using a combined tACS-TMS approach, we demonstrate that driving gamma frequency oscillations modulates GABAA inhibition in the human motor cortex. Moreover, there is a clear relationship between the change in magnitude of GABAA inhibition induced by tACS and the magnitude of GABAA inhibition observed during task-related synchronization of oscillations in inhibitory interneuronal circuits, supporting the hypothesis that tACS engages endogenous oscillatory circuits. We also show that an individual's physiological response to tACS is closely related to their ability to learn a motor task. These findings contribute to our understanding of the neurophysiological basis of motor rhythms and their behavioral relevance and offer the possibility of developing tACS as a therapeutic tool

Post-stroke upper limb recovery is correlated with dynamic resting-state network connectivity

Motor recovery is still limited for people with stroke especially those with greater functional impairments. In order to improve outcome, we need to understand more about the mechanisms underpinning recovery. Task-unbiased, blood-flow independent post-stroke neural activity can be acquired from resting brain electrophysiological recordings, and offers substantial promise to investigate physiological mechanisms, but behaviourally-relevant features of resting-state sensorimotor network dynamics have not yet been identified. Thirty-seven people with subcortical ischemic stroke and unilateral hand paresis of any degree were longitudinally evaluated at 3 weeks (early subacute) and 12 weeks (late subacute) after stroke. Resting-state magnetoencephalography and clinical scores of motor function were recorded and compared with matched controls. Magnetoencephalography data were decomposed using a data-driven Hidden Markov Model into 10 time-varying resting-state networks. People with stroke showed statistically significantly improved Action Research Arm Test and Fugl-Meyer upper extremity scores between 3 weeks and 12 weeks after stroke (both p < 0.001). Hidden Markov Model analysis revealed a primarily alpha-band ipsilesional resting-state sensorimotor network which had a significantly increased life-time (the average time elapsed between entering and exiting the network) and fractional occupancy (the occupied percentage among all networks) at 3 weeks after stroke when compared to controls. The life-time of the ipsilesional resting-state sensorimotor network positively correlated with concurrent motor scores in people with stroke who had not fully recovered. Specifically, this relationship was observed only in ipsilesional rather in contralesional sensorimotor network, default mode network or visual network. The ipsilesional sensorimotor network metrics were not significantly different from controls at 12 weeks after stroke. The increased recruitment of alpha-band ipsilesional resting-state sensorimotor network at subacute stroke served as functionally correlated biomarkers exclusively in people with stroke with not fully recovered hand paresis, plausibly reflecting functional motor recovery processes

Prebiotic fructans have greater impact on luminal microbiology and CD3+ T cells in healthy siblings than patients with Crohn’s disease : a pilot study investigating the potential for primary prevention of inflammatory bowel disease

Funding This work was supported by a clinical research fellowship granted by the charity Core (Guts UK) (CRH). FMF and PL received financial support from the Scottish Government Rural and Environment Science and Analytical Services. Acknowledgments The authors would like to acknowledge BENEO-Orafti, Teinen, Belgium who provided the oligofructose-enriched inulin. The authors would like to thank the patients and the siblings who generously participated in this study.Peer reviewedPostprin

A CD3-Specific Antibody Reduces Cytokine Production and Alters Phosphoprotein Profiles in Intestinal Tissues From Patients With Inflammatory Bowel Disease

NOTICE: this is the author’s version of a work that was accepted for publication in Gastroenterology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in GASTROENTEROLOGY, 10.1053/j.gastro.2014.03.04

Dietary intake of inulin-type fructans in active and inactive Crohn’s disease and healthy controls: a case-control study

Background and Aims: Prebiotic inulin-type fructans are widely consumed in the diet and may have contrasting effects in Crohn’s disease by stimulating gut microbiota and/or by generating functional gastrointestinal symptoms. The aim of this study was to measure fructan and oligofructose intakes in patients with active and inactive Crohn’s disease compared with healthy controls. Methods: Patients with active Crohn’s disease (n=98), inactive Crohn’s (n=99) and healthy controls (n=106) were recruited to a case-control study. Dietary intake of inulin-type fructans was measured using a specific food frequency questionnaire and was compared between the three groups and between patients with different disease phenotypes (Montreal classification). Associations between intakes and disease activity (Harvey Bradshaw Index, HBI) were also undertaken. Results: Patients with active Crohn’s disease had lower fructan intakes (median 2.9 g/d, IQR 1.8) than those with inactive Crohn’s (3.6 g/d, 2.1, P=0.036) or controls (3.9 g/d, 2.1, P=0.003) and lower oligofructose intakes (2.8 g/d, 1.8) than inactive Crohn’s (3.5 g/d, 2.2, P=0.048) or controls (3.8 g/d, 2.1, P=0.003). There were no differences in intakes related to disease site or behaviour. There were negative correlations between HBI wellbeing score and fructan intake (ρ=-0.154, P=0.03) and oligofructose intake (ρ=-0.156, P=0.028) and for the HBI abdominal pain score and fructan (ρ=-0.164, P=0.021) and oligofructose intake (ρ=-0.157, P=0.027). Conclusions: Patients with active Crohn’s disease consume lower quantities of fructans and oligofructose than their inactive counterparts and healthy controls. The impact of lower intakes of prebiotic fructans on gut microbiota are unknown and warrant further research

Created mangrove wetlands store belowground carbon and surface elevation change enables them to adjust to sea-level rise

Mangrove wetlands provide ecosystem services for millions of people, most prominently by providing storm protection, food and fodder. Mangrove wetlands are also valuable ecosystems for promoting carbon (C) sequestration and storage. However, loss of mangrove wetlands and these ecosystem services are a global concern, prompting the restoration and creation of mangrove wetlands as a potential solution. Here, we investigate soil surface elevation change, and its components, in created mangrove wetlands over a 25 year developmental gradient. All created mangrove wetlands were exceeding current relative sea-level rise rates (2.6 mm yr(-1)), with surface elevation change of 4.2-11.0 mm yr(-1) compared with 1.5-7.2 mm yr(-1) for nearby reference mangroves. While mangrove wetlands store C persistently in roots/soils, storage capacity is most valuable if maintained with future sea-level rise. Through empirical modeling, we discovered that properly designed creation projects may not only yield enhanced C storage, but also can facilitate wetland persistence perennially under current rates of sea-level rise and, for most sites, for over a century with projected medium accelerations in sea-level rise (IPCC RCP 6.0). Only the fastest projected accelerations in sea-level rise (IPCC RCP 8.5) led to widespread submergence and potential loss of stored C for created mangrove wetlands before 2100

IL-21 conditions antigen-presenting human γδ T-cells to promote IL-10 expression in naïve and memory CD4+ T-cells

Direct interaction between T-cells exerts a major influence on tissue immunity and inflammation across multiple body sites including the human gut, which is highly enriched in ‘unconventional’ lymphocytes such as γδ T-cells. We previously reported that microbial activation of human Vγ9/Vδ2+ γδ T-cells in the presence of the mucosal damage-associated cytokine IL-15 confers the ability to promote epithelial barrier defence, specifically via induction of IL-22 expression in conventional CD4+ T-cells. In the current report, we assessed whether other cytokines enriched in the gut milieu also functionally influence microbe-responsive Vγ9/Vδ2 T-cells. When cultured in the presence of IL-21, Vγ9/Vδ2 T-cells acquired the ability to induce expression of the immunoregulatory cytokine IL-10 in both naïve and memory CD4+ T-cells, at levels surpassing those induced by monocytes or monocyte-derived DCs. These findings identify an unexpected influence of IL-21 on Vγ9/Vδ2 T-cell modulation of CD4+ T-cell responses. Further analyses suggested a possible role for CD30L and/or CD40L reverse signalling in mediating IL-10 induction by IL-21 conditioned Vγ9/Vδ2 T-cells. Our findings indicate that the local microenvironment exerts a profound influence on Vγ9/Vδ2 T-cell responses to microbial challenge, leading to induction of distinct functional profiles among CD4+ T-cells that may influence inflammatory events at mucosal surfaces. Targeting these novel pathways may offer therapeutic benefit in disorders such as inflammatory bowel disease

Gut Homing Receptors on CD8 T Cells Are Retinoic Acid Dependent and Not Maintained by Liver Dendritic or Stellate Cells

BACKGROUND & AIMS: Lymphocytes primed by intestinal dendritic cells (DC) express the gut-homing receptors CCR9 and α4β7, which recognize CCL25 and mucosal addressin cell-adhesion molecule-1 in the intestine promoting the development of regional immunity. In mice, imprinting of CCR9 and α4β7 is dependent on retinoic acid during T-cell activation. Tissue specificity is lost in primary sclerosing cholangitis (PSC), an extraintestinal manifestation of inflammatory bowel disease, when ectopic expression of mucosal addressin cell-adhesion molecule-1 and CCL25 in the liver promotes recruitment of CCR9+α4β7+ T cells to the liver. We investigated the processes that control enterohepatic T-cell migration and whether the ability to imprint CCR9 and α4β7 is restricted to intestinal DCs or can under some circumstances be acquired by hepatic DCs in diseases such as PSC. METHODS: Human and murine DCs from gut, liver, or portal lymph nodes and hepatic stellate cells were used to activate CD8 T cells. Imprinting of CCR9 and α4β7 and functional migration responses were determined. Crossover activation protocols assessed plasticity of gut homing. RESULTS: Activation by gut DCs imprinted high levels of functional CCR9 and α4β7 on naïve CD8 T cells, whereas hepatic DCs and stellate cells proved inferior. Imprinting was RA dependent and demonstrated plasticity. CONCLUSIONS: Imprinting and plasticity of gut-homing human CD8 T cells requires primary activation or reactivation by gut DCs and is retinoic acid dependent. The inability of liver DCs to imprint gut tropism implies that α4β7+CCR9+ T cell that infiltrate the liver in PSC are primed in the gut

A role for gut-associated lymphoid tissue in shaping the human B cell repertoire

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