Commentary: cooperation not competition: bihemispheric tDCS and fMRI show role for ipsilateral hemisphere in motor learning

Brenton Hordacre and Mitchell R. Goldsworth

Reproducibility of neuroplastic responses induced by continuous theta-burst stimulation

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Characterising activity and diet compositions for dementia prevention: protocol for the ACTIVate prospective longitudinal cohort study

Introduction Approximately 40% of late-life dementia may be prevented by addressing modifiable risk factors, including physical activity and diet. Yet, it is currently unknown how multiple lifestyle factors interact to influence cognition. The ACTIVate Study aims to (1) explore associations between 24-hour time-use and diet compositions with changes in cognition and brain function; and (2) identify duration of time-use behaviours and the dietary compositions to optimise cognition and brain function.Methods and analysis This 3-year prospective longitudinal cohort study will recruit 448 adults aged 60-70 years across Adelaide and Newcastle, Australia. Time-use data will be collected through wrist-worn activity monitors and the Multimedia Activity Recall for Children and Adults. Dietary intake will be assessed using the Australian Eating Survey food frequency questionnaire. The primary outcome will be cognitive function, assessed using the Addenbrooke's Cognitive Examination-III. Secondary outcomes include structural and functional brain measures using MRI, cerebral arterial pulse measured with diffuse optical tomography, neuroplasticity using simultaneous transcranial magnetic stimulation and electroencephalography, and electrophysiological markers of cognitive control using event-related potential and time frequency analyses. Compositional data analysis, testing for interactions between time point and compositions, will assess longitudinal associations between dependent (cognition, brain function) and independent (time-use and diet compositions) variables. Conclusions The ACTIVate Study will be the first to examine associations between time-use and diet compositions, cognition and brain function. Our findings will inform new avenues for multidomain interventions that may more effectively account for the co-dependence between activity and diet behaviours for dementia prevention. Ethics and dissemination Ethics approval has been obtained from the University of South Australia's Human Research Ethics committee (202639). Findings will be disseminated through peer-reviewed manuscripts, conference presentations, targeted media releases and community engagement events. Trial registration number >Australia New Zealand Clinical Trials Registry (ACTRN12619001659190).Ashleigh E Smith, Alexandra T Wade, Timothy Olds, Dorothea Dumuid, Michael J Breakspear, Kate Laver ... et al

The role of beta-amyloid in Alzheimer's disease-related neurodegeneration

Mitchell R. Goldsworthy and Ann-Maree Vallenc

The Role ofß-Amyloid in Alzheimer’s Disease-Related Neurodegeneration

It is currently estimated that over 35 million people worldwide have dementia, and with demographic trends of an aging global population this figure is expected to triple by 2050 (Prince and Jackson, 2009). As the leading cause of dementia, Alzheimer's disease (AD) is the source of much emotional and financial strain. Although there has been considerable research aimed at developing disease-modifying therapies that target different features of AD pathology, debate continues over which pathological features are central to disease progression. A key pathological feature of AD is the formation of neuritic plaques composed of extracellular deposits of β-amyloid (Aβ) peptides. The temporal profile of pathological features together with genetic risk factors for AD have led to the hypothesis that accumulation of Aβ oligomers during early, preclinical stages of the disease initiates a cascade of events resulting in synaptic dysfunction, neural loss and atrophy within temporoparietal and hippocampal regions, and this neurodegeneration, in turn, causes cognitive decline (Jack et al., 2010). If this hypothesis is correct, biomarkers designed to detect Aβ accumulation in preclinical populations may have an important role in the early diagnosis of AD (Sperling et al., 2011)

Inter- and intra-subject variability of motor cortex plasticity following continuous theta-burst stimulation

Background: The potential of non-invasive brain stimulation (NIBS) for studying, and inducing, functionally relevant neuroplasticity is dependent on protocols that can induce lasting, robust and reliable effects. A current limiting factor is the large inter- and intra-subject variability in NIBS-induced neuroplastic responses. There has been some study of inter-subject response variability and factors that contribute to it; however, intra-subject response variability has, so far, received little investigation. Objectives: By testing participants on multiple occasions we aimed to (1) compare inter- and intra-subject variability of neuroplastic responses induced by continuous theta-burst stimulation (cTBS); (2) determine whether the transcranial magnetic stimulation (TMS) intensity used to measure cTBS-induced neuroplastic responses contributes to response variability; (3) determine whether assessment of factors known to influence response variability can be used to explain some of the variability in cTBS-induced neuroplastic responses across experimental sessions. Methods: In three separate experimental sessions, motor-evoked potential (MEP) input–output (IO) curves were obtained before and after cTBS, and questionnaire-based assessments of physical activity and perceived stress were obtained. Results: cTBS-induced MEP suppression was greatest at the upper end of the IO curve (150–180% resting motor threshold; RMT) and most consistent across subjects and across experimental sessions when assessed with a TMS intensity of 150% RMT. The magnitude of cTBS-induced MEP suppression evoked at 150% RMT correlated with self-reported perceived stress, but not with self-reported physical activity. Conclusions: The most reliable TMS intensity to probe cTBS-induced long-term depression (LTD)-like neuroplastic responses is 150% RMT. This is unlikely to simply be a ceiling effect and, we suggest, may be due to changes in the descending volley evoked at higher stimulus intensities. The perceived stress scale appears to be sufficiently sensitive to measure the influence of subject stress on LTD-like neuroplastic responses

Probing changes in corticospinal excitability following theta burst stimulation of the human primary motor cortex

Objective: To determine whether the intensity of transcranial magnetic stimulation (TMS) used to probe changes in corticospinal excitability influences the measured plasticity response to theta burst stimulation (TBS) of the human primary motor cortex. Methods: Motor evoked potential (MEP) input/output (I/O) curves were recorded before and following continuous TBS (cTBS) (Experiment 1; n = 18) and intermittent TBS (iTBS) (Experiment 2; n = 18). Results: The magnitude and consistency of MEP depression induced by cTBS was greatest when probed using stimulus intensities at or above 150% of resting motor threshold (RMT). In contrast, facilitation of MEPs following iTBS was strongest and most consistent at 110% of RMT. Conclusions: The plasticity response to both cTBS and iTBS is influenced by the stimulus intensity used to probe the induced changes in corticospinal excitability. Significance: The results highlight the importance of the test stimulus intensity used to assess TBS-induced changes in corticospinal excitability when interpreting neuroplasticity data, and suggest that a number of test intensities may be required to reliably probe the plasticity response

Transcranial magnetic stimulation-EEG biomarkers of poststroke upper-limb motor function

Background: Motor evoked potentials obtained with transcranial magnetic stimulation (TMS) can provide valuable information to inform stroke neurophysiology and recovery but are difficult to obtain in all stroke survivors due to high stimulation thresholds. Objective: To determine whether transcranial magnetic stimulation evoked potentials (TEPs) evoked using a lower stimulus intensity, below that necessary for recording motor evoked potentials, could serve as a marker of poststroke upper-limb motor function and were different compared to healthy adults. Methods: Eight chronic stroke survivors (66 ± 21 years) and 15 healthy adults (53 ± 10 years) performed a motor function task using a customized grip-lift manipulandum. TMS was applied to the lesioned motor cortex, with TEPs recorded using simultaneous high-definition electroencephalography (EEG). Results: Stroke participants demonstrated greater hold ratio with the manipulandum. Cluster-based statistics revealed larger P30 amplitude in stroke participants, with significant clusters over frontal (P = .016) and parietal-occipital electrodes (P = .023). There was a negative correlation between the N45 peak amplitude and hold ratio in stroke participants (r = -.83, P = .02), but not controls. Conclusions: TEPs can be recorded using lower stimulus intensities in chronic stroke. The global P30 TEP response differed between stroke participants and healthy controls, with results suggesting that the TEP can be used as a biomarker of upper-limb behavior.Brenton Hordacre, Rukmini Ghosh, Mitchell R. Goldsworthy and Michael C. Riddin

Motor network connectivity predicts neuroplastic response following theta burst stimulation in healthy adults

A patterned repetitive transcranial magnetic stimulation protocol, known as continuous theta burst stimulation (cTBS), can suppress corticospinal excitability via mechanisms that appear similar to long-term depression synaptic plasticity. Despite much potential, this technique is currently limited by substantial response variability. The purpose of this study was to investigate whether baseline resting state functional connectivity is a determinant of response to cTBS. Eighteen healthy young adults participated in up to three experimental sessions. Single-pulse transcranial magnetic stimulation was used to quantify change in corticospinal excitability following cTBS. Three minutes of resting electroencephalographic activity was recorded, and functional connectivity was estimated using the debiased weighted phase lag index across different frequency bands. Partial least squares regression identified models of connectivity between a seed region (C3) and the whole scalp that maximally accounted for variance in cTBS responses. There was no group-level effect of a single cTBS train or spaced cTBS trains on corticospinal excitability (p = 0.092). A low beta frequency band model of connectivity accounted for the largest proportion of variance in spaced cTBS response (R2 = 0.50). Based on the low beta frequency model, a-priori regions of interest were identified and predicted 39% of variance in response to spaced cTBS at a subsequent session. Importantly, weaker connectivity between the seed electrode (C3) and a cluster approximating a frontocentral region was associated with greater spaced cTBS response (p = 0.02). It appears M1-frontocentral networks may have an important role in determining the effects of cTBS on corticospinal excitability.Brenton Hordacre, Mitchell R. Goldsworthy, Lynton Graetz and Michael C. Riddin

Acute aerobic exercise and neuroplasticity of the motor cortex: a systematic review

OBJECTIVES:To synthesise the existing literature investigating if acute aerobic exercise enhances the response to experimentally-induced neuroplasticity paradigms. METHODS:A systematic search of electronic databases Medline, PsycInfo and Embase was undertaken on 26 April 2018 and updated on 17 May 2019. Studies were included if they involved a bout of aerobic exercise; prescribed a bout of rest as a control condition; utilized a non-invasive brain stimulation paradigm to induce neuroplasticity; used TMS to assess neuroplasticity outcomes; participants were healthy 18-65year old males and females with no diagnosed neurological/psychological impairments. RESULTS:Eight papers (containing 12 experiments) met inclusion criteria. All studies utilized cycling or treadmill exercise as their exercise modality, and exercise intensity ranged from low intensity continuous exercise to high-intensity interval exercise. Four neuroplasticity paradigms were employed including paired associative stimulation (PAS) (n=3), continuous theta-burst stimulation (cTBS) (n=2), intermittent theta-burst stimulation (iTBS) (n=2) and transcranial direct current stimulation (n=1). Aerobic exercise enhanced neuroplastic responses (compared to rest) in seven of the 12 experiments. CONCLUSIONS:This review provides emerging evidence that acute aerobic exercise can enhance the response to experimentally-induced neuroplasticity paradigms. However, there remains great variability in the study design and reporting of effects in these studies and thus a more standardized approach is encouraged to better understand the relationship between acute aerobic exercise and neuroplasticity. Future studies should consider optimizing intensity, paradigms and duration of both exercise and neuroplasticity paradigms employed.Maddison L. Mellow, Mitchell R. Goldsworthy, Scott Coussens, Ashleigh E. Smit