Short-Interval Cortical Inhibition and Intracortical Facilitation during Submaximal Voluntary Contractions Changes with Fatigue

This study determined whether short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) change during a sustained submaximal isometric contraction. On 2 days, 12 participants (6 men, 6 women) performed brief (7-s) elbow flexor contractions before and after a 10-min fatiguing contraction; all contractions were performed at the level of integrated electromyographic activity (EMG) which produced 25 % maximal unfatigued torque. During the brief 7-s and 10-min submaximal contractions, single (test) and paired (conditioning–test) transcranial magnetic stimuli were applied over the motor cortex (5 s apart) to elicit motor-evoked potentials (MEPs) in biceps brachii. SICI and ICF were elicited on separate days, with a conditioning–test interstimulus interval of 2.5 and 15 ms, respectively. On both days, integrated EMG remained constant while torque fell during the sustained contraction by ~51.5 % from control contractions, perceived effort increased threefold, and MVC declined by 21–22 %. For SICI, the conditioned MEP during control contractions (74.1 ± 2.5 % of unconditioned MEP) increased (less inhibition) during the sustained contraction (last 2.5 min: 86.0 ± 5.1 %; P \u3c 0.05). It remained elevated in recovery contractions at 2 min (82.0 ± 3.8 %; P \u3c 0.05) and returned toward control at 7-min recovery (76.3 ± 3.2 %). ICF during control contractions (conditioned MEP 129.7 ± 4.8 % of unconditioned MEP) decreased (less facilitation) during the sustained contraction (last 2.5 min: 107.6 ± 6.8 %; P \u3c 0.05) and recovered to 122.8 ± 4.3 % during contractions after 2 min of recovery. Both intracortical inhibitory and facilitatory circuits become less excitable with fatigue when assessed during voluntary activity, but their different time courses of recovery suggest different mechanisms for the fatigue-related changes of SICI and ICF

Cognition and brain iron deposition in whole grey matter regions and hippocampal subfields

ACKNOWLEDGEMENTS We are grateful to the Aberdeen Children of the 1950's (ACONF) subset of Generation Scotland GS:SFHS who took part in the STRADL study, supported and funded by the Wellcome Trust Strategic Award ‘Stratifying Resilience and Depression Longitudinally’ (STRADL) [104036/Z/14/Z]. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. HS is supported by the Roland Sutton Academic Trust [0076/R/19]. We also thank the STRADL project team. Research Funding Chief Scientist Office. Grant Number: CZD/16/6 Roland Sutton Academic Trust. Grant Number: 0076/R/19 Scottish Funding Council. Grant Number: HR03006 Wellcome Trust. Grant Number: 104036/Z/14/ZPeer reviewedPublisher PD

Structural brain complexity and cognitive decline in late life : A longitudinal study in the Aberdeen 1936 Birth Cohort

Copyright © 2014 Elsevier Inc. All rights reserved.Peer reviewedPostprin

Differential effects of nutritional folic acid deficiency and moderate hyperhomocysteinemia on aortic plaque formation and genome-wide DNA methylation in vascular tissue from ApoE-/- mice

Low folate intake is associated with vascular disease. Causality has been attributed to hyperhomocysteinemia. However, human intervention trials have failed to show the benefit of homocysteine-lowering therapies. Alternatively, low folate may promote vascular disease by deregulating DNA methylation. We investigated whether folate could alter DNA methylation and atherosclerosis in ApoE null mice. Mice were fed one of six diets (n = 20 per group) for 16 weeks. Basal diets were either control (C; 4% lard) or high fat (HF; 21% lard and cholesterol, 0.15%) with different B-vitamin compositions: (1) folic acid and B-vitamin replete, (2) folic acid deficient (−F), (3) folic acid, B6 and B12 deficient (−F−B). −F diets decreased plasma (up to 85%; P < 0.05), whole blood (up to 70%; P < 0.05), and liver folate (up to 65%; P < 0.05) and hepatic SAM/SAH (up to 80%; P < 0.05). −F−B diets reduced plasma (up to 76%; P < 0.05), whole blood (up to 72%; P < 0.05), and liver B12 (up to 39%; P < 0.05) and hepatic SAM/SAH (up to 90%; P < 0.05). −F increased homocysteine 2-fold, while −F−B increased homocysteine 3.6- and 6.8-fold in the C and HF groups (P < 0.05). Plaque formation was increased 2-fold (P < 0.0001) in mice fed a HF diet. Feeding a HF–F diet increased lesion formation by 17% (P < 0.05). There was no change in 5-methyldeoxycytidine in liver or vascular tissue (aorta, periadventitial tissue and heart). These data suggest that atherogenesis is not associated with genome-wide epigenetic changes in this animal model

Validation and comparison of two automated methods to quantify brain white matter hyperintensities of presumed vascular origin

Funding Data collection was funded by grants from the Alzheimer’s Research Trust (now Alzheimer’s Research UK, grant reference: ART/SPG2003B), Alzheimer’s Research UK (grant reference: ARUK-SB2012B-2), the University of Aberdeen Development Trust (grant reference RGB3109) and NHS Grampian and the Chief Scientist’s Office (grant reference: CAF/08/08). JMJW is funded by the University of Aberdeen Development Trust and TauRx Therapeutics Ltd. CP is funded by Royal Surrey County Hospital NHS Foundation Trust. CJM, ADM, and GDW are funded by the Scottish Funding Council.Peer reviewedPublisher PD

Cognitive Test Scores and Progressive Cognitive Decline in the Aberdeen 1921 and 1936 Birth Cohorts

Acknowledgments: We remain grateful to the kindness of the staff at the Scottish Council for Research in Education who allowed us access to their archive and remained supportive and gracious throughout our collaboration. We thank the many people of Aberdeen who volunteered generously and committed to the long-term success of this program. We thank Victoria Bourne, who made substantial contributions to study design, data collection, data analysis and hypothesis generation. Jen Herbert (deceased) recruited the ABC36 participants, collected data (sessions I and II) and, through her encouragement and professionalism, ensured the continued involvement of many participants. She was much loved by participants and the study team. Funding: The Aberdeen Birth Cohort 1921 and 1936 research program was established in 1997 with funding from the Henry Smith (Kensington Estates) Charity and continued by The UK Biotechnology and Biological Sciences Research Council (1999–2002), The Wellcome Trust (2001–2006), The Scottish Government (2000–2002), the Medical Research Council (2003), Alzheimer Research UK (2002–2005) and the University of Aberdeen Development Trust (2007–2010, 2014).Peer reviewedPublisher PD

Circulating asymmetric dimethylarginine and cognitive decline : A 4‐year follow‐up study of the 1936 Aberdeen Birth Cohort

ACKNOWLEDGEMENTS The authors gratefully acknowledge all participants of the ABC36 study. They acknowledge their colleagues, Prof Lawrence Whalley, Prof Ian Deary and the late Prof John Starr who developed the study. F.T. acknowledges support by the Rural and Environment Science and Analytical Services Division of the Scottish government (RESAS). Funding Information NHS Grampian R&D Endowments. Grant Number: 11/08 Scottish government Rural and Environment Science and Analytical Services DivisionPeer reviewedPublisher PD

Genetic dissection of a model complex trait using the Drosophila Synthetic Population Resource

Genetic dissection of complex, polygenic trait variation is a key goal of medical and evolutionary genetics. Attempts to identify genetic variants underlying complex traits have been plagued by low mapping resolution in traditional linkage studies, and an inability to identify variants that cumulatively explain the bulk of standing genetic variation in genome-wide association studies (GWAS). Thus, much of the heritability remains unexplained for most complex traits. Here we describe a novel, freely available resource for the Drosophila community consisting of two sets of recombinant inbred lines (RILs), each derived from an advanced generation cross between a different set of eight highly inbred, completely resequenced founders. The Drosophila Synthetic Population Resource (DSPR) has been designed to combine the high mapping resolution offered by multiple generations of recombination, with the high statistical power afforded by a linkage-based design. Here, we detail the properties of the mapping panel of >1600 genotyped RILs, and provide an empirical demonstration of the utility of the approach by genetically dissecting alcohol dehydrogenase (ADH) enzyme activity. We confirm that a large fraction of the variation in this classic quantitative trait is due to allelic variation at the Adh locus, and additionally identify several previously unknown modest-effect trans-acting QTL (quantitative trait loci). Using a unique property of multiparental linkage mapping designs, for each QTL we highlight a relatively small set of candidate causative variants for follow-up work. The DSPR represents an important step toward the ultimate goal of a complete understanding of the genetics of complex traits in the Drosophila model system.This work was supported by the following NIH R01 grants: RR024862 to S.J.M. and A.D.L., GM085260 to S.J.M., GM085251 to A.D.L., GM078338 to S.S., and GM074244 to K.W.B

The influence of residual force enhancement on spinal and supraspinal excitability

Background Following active muscle lengthening, there is an increase in steady-state isometric force as compared with a purely isometric contraction at the same muscle length and level of activation. This fundamental property of skeletal muscle is known as residual force enhancement (RFE). While the basic mechanisms contributing to this increase in steady-state isometric force have been well documented, changes in central nervous system (CNS) excitability for submaximal contractions during RFE are unclear. The purpose of this study was to investigate spinal and supraspinal excitability in the RFE isometric steady-state following active lengthening of the ankle dorsiflexor muscles. Methods A total of 11 male participants (20–28 years) performed dorsiflexions at a constant level of electromyographic activity (40% of maximum). Half of the contractions were purely isometric (8 s at an ankle angle of 130°), and the other half were during the RFE isometric steady-state following active lengthening (2 s isometric at 90°, a 1 s lengthening phase at 40°/s, and 5 s at 130°). Motor evoked potentials (MEPs), cervicomedullary motor evoked potentials (CMEPs), and compound muscle action potentials (M-waves) were recorded from the tibialis anterior during the purely isometric contraction and RFE isometric steady-state. Results Compared to the purely isometric condition, following active lengthening, there was 10% RFE (p 0.05). Discussion These results indicate that spinal excitability is reduced during submaximal voluntary contractions in the RFE state with no change in supraspinal excitability. These findings may have further implications to everyday life offering insight into how the CNS optimizes control of skeletal muscle following submaximal active muscle lengthening

UBC-Nepal Expedition: An experimental overview of the 2016 University of British Columbia Scientific Expedition to Nepal Himalaya

The University of British Columbia Nepal Expedition took place over several months in the fall of 2016 and was comprised of an international team of 37 researchers. This paper describes the objectives, study characteristics, organization and management of this expedition, and presents novel blood gas data during acclimatization in both lowlanders and Sherpa. An overview and framework for the forthcoming publications is provided. The expedition conducted 17 major studies with two principal goals—to identify physiological differences in: 1) acclimatization; and 2) responses to sustained high-altitude exposure between lowland natives and people of Tibetan descent. We performed observational cohort studies of human responses to progressive hypobaric hypoxia (during ascent), and to sustained exposure to 5050 m over 3 weeks comparing lowlander adults (n = 30) with Sherpa adults (n = 24). Sherpa were tested both with (n = 12) and without (n = 12) descent to Kathmandu. Data collected from lowlander children (n = 30) in Canada were compared with those collected from Sherpa children (n = 57; 3400–3900m). Studies were conducted in Canada (344m) and the following locations in Nepal: Kathmandu (1400m), Namche Bazaar (3440m), Kunde Hospital (3480m), Pheriche (4371m) and the Ev-K2-CNR Research Pyramid Laboratory (5050m). The core studies focused on the mechanisms of cerebral blood flow regulation, the role of iron in cardiopulmonary regulation, pulmonary pressures, intra-ocular pressures, cardiac function, neuromuscular fatigue and function, blood volume regulation, autonomic control, and micro and macro vascular function. A total of 335 study sessions were conducted over three weeks at 5050m. In addition to an overview of this expedition and arterial blood gas data from Sherpa, suggestions for scientists aiming to perform field-based altitude research are also presented. Together, these findings will contribute to our understanding of human acclimatization and adaptation to the stress of residence at high-altitude