Cross-sectional associations between 24-hour time-use composition, grey matter volume and cognitive function in healthy older adults.

BACKGROUND: Increasing physical activity (PA) is an effective strategy to slow reductions in cortical volume and maintain cognitive function in older adulthood. However, PA does not exist in isolation, but coexists with sleep and sedentary behaviour to make up the 24-hour day. We investigated how the balance of all three behaviours (24-hour time-use composition) is associated with grey matter volume in healthy older adults, and whether grey matter volume influences the relationship between 24-hour time-use composition and cognitive function. METHODS: This cross-sectional study included 378 older adults (65.6 ± 3.0 years old, 123 male) from the ACTIVate study across two Australian sites (Adelaide and Newcastle). Time-use composition was captured using 7-day accelerometry, and T1-weighted magnetic resonance imaging was used to measure grey matter volume both globally and across regions of interest (ROI: frontal lobe, temporal lobe, hippocampi, and lateral ventricles). Pairwise correlations were used to explore univariate associations between time-use variables, grey matter volumes and cognitive outcomes. Compositional data analysis linear regression models were used to quantify associations between ROI volumes and time-use composition, and explore potential associations between the interaction between ROI volumes and time-use composition with cognitive outcomes. RESULTS: After adjusting for covariates (age, sex, education), there were no significant associations between time-use composition and any volumetric outcomes. There were significant interactions between time-use composition and frontal lobe volume for long-term memory (p = 0.018) and executive function (p = 0.018), and between time-use composition and total grey matter volume for executive function (p = 0.028). Spending more time in moderate-vigorous PA was associated with better long-term memory scores, but only for those with smaller frontal lobe volume (below the sample mean). Conversely, spending more time in sleep and less time in sedentary behaviour was associated with better executive function in those with smaller total grey matter volume. CONCLUSIONS: Although 24-hour time use was not associated with total or regional grey matter independently, total grey matter and frontal lobe grey matter volume moderated the relationship between time-use composition and several cognitive outcomes. Future studies should investigate these relationships longitudinally to assess whether changes in time-use composition correspond to changes in grey matter volume and cognition.

Metaplastic neuromodulation via transcranial direct current stimulation has no effect on corticospinal excitability and neuromuscular fatigue.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation tool with potential for managing neuromuscular fatigue, possibly due to alterations in corticospinal excitability. However, inconsistencies in intra- and inter- individual variability responsiveness to tDCS limit its clinical use. Emerging evidence suggests harnessing homeostatic metaplasticity induced via tDCS may reduce variability and boost its outcomes, yet little is known regarding its influence on neuromuscular fatigue in healthy adults. We explored whether cathodal tDCS (ctDCS) prior to exercise combined with anodal tDCS (atDCS) could augment corticospinal excitability and attenuate neuromuscular fatigue. 15 young healthy adults (6 males, 22 ± 4 years) participated in four pseudo-randomised neuromodulation sessions: sham stimulation prior and during exercise, sham stimulation prior and atDCS during exercise, ctDCS prior and atDCS during exercise, ctDCS prior and sham stimulation during exercise. The exercise constituted an intermittent maximal voluntary contraction (MVC) of the right first dorsal interosseous (FDI) for 10 min. Neuromuscular fatigue was quantified as an attenuation in MVC force, while motor evoked potential (MEP) amplitude provided an assessment of corticospinal excitability. MEP amplitude increased during the fatiguing exercise, whilst across time, force decreased. There were no differences in MEP amplitudes or force between neuromodulation sessions. These outcomes highlight the ambiguity of harnessing metaplasticity to ameliorate neuromuscular fatigue in young healthy individuals.

Does predictive cueing of presentation time modulate alpha power and facilitate visual working memory performance in younger and older adults?

Selective attention and working memory (WM) are vulnerable to age-related decline. Older adults perform worse on, and are less able to modulate alpha power (8-12 Hz) than younger adults in tasks involving cues about 'where' or 'when' a memory set will appear. However, no study has investigated whether alpha power is modulated by cues predicting the presentation time of a memory set. Here, we recorded electroencephalography while 24 younger (18-33 years) and 23 older (60-77 years) adults completed a modified delay match-to-sample task where participants were cued to the duration of a memory set (0.1 s or 0.5 s). We found: (1) predictive cues increased WM storage; (2) no differences in preparatory alpha power between predictive and neutral cue types, but preparatory alpha suppression was weaker in older adults; (3) retention period oscillatory power differed between presentation times, but these differences were no longer present when comparing trial types from the onset of the memory set; and (4) oscillatory power in the preparatory and retention periods were unrelated to performance. Our results suggest that preparatory alpha power is not modulated by predictive cues towards presentation time, however, reductions in alpha/beta power during visual WM retention may be linked to encoding, rather than retention.

Examining motor evoked potential amplitude and short-interval intracortical inhibition on the up-going and down-going phases of a transcranial alternating current stimulation (tacs) imposed alpha oscillation.

Many brain regions exhibit rhythmical activity thought to reflect the summed behaviour of large populations of neurons. The endogenous alpha rhythm has been associated with phase-dependent modulation of corticospinal excitability. However, whether exogenous alpha rhythm, induced using transcranial alternating current stimulation (tACS) also has a phase-dependent effect on corticospinal excitability remains unknown. Here, we triggered transcranial magnetic stimuli (TMS) on the up- or down-going phase of a tACS-imposed alpha oscillation and measured motor evoked potential (MEP) amplitude and short-interval intracortical inhibition (SICI). There was no significant difference in MEP amplitude or SICI when TMS was triggered on the up- or down-going phase of the tACS-imposed alpha oscillation. The current study provides no evidence of differences in corticospinal excitability or GABAergic inhibition when targeting the up-going (peak) and down-going (trough) phase of the tACS-imposed oscillation.

The Role of Alpha Power in the Suppression of Anticipated Distractors During Verbal Working Memory.

As working memory (WM) is limited in capacity, it is important to direct neural resources towards processing task-relevant information while ignoring distractors. Neural oscillations in the alpha frequency band (8-12 Hz) have been suggested to play a role in the inhibition of task-irrelevant information during WM, although results are mixed, possibly due to differences in the type of WM task employed. Here, we examined the role of alpha power in suppression of anticipated distractors of varying strength using a modified Sternberg task where the encoding and retention periods were temporally separated. We recorded EEG while 20 young adults completed the task and found: (1) slower reaction times in strong distractor trials compared to weak distractor trials; (2) increased alpha power in posterior regions from baseline prior to presentation of a distractor regardless of condition; and (3) no differences in alpha power between strong and weak distractor conditions. Our results suggest that parieto-occipital alpha power is increased prior to a distractor. However, we could not find evidence that alpha power is further modulated by distractor strength.

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.

Simulation of electromyographic recordings following transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is a technique that enables noninvasive manipulation of neural activity and holds promise in both clinical and basic research settings. The effect of TMS on the motor cortex is often measured by electromyography (EMG) recordings from a small hand muscle. However, the details of how TMS generates responses measured with EMG are not completely understood. We aim to develop a biophysically detailed computational model to study the potential mechanisms underlying the generation of EMG signals following TMS. Our model comprises a feed-forward network of cortical layer 2/3 cells, which drive morphologically detailed layer 5 corticomotoneuronal cells, which in turn project to a pool of motoneurons. EMG signals are modeled as the sum of motor unit action potentials. EMG recordings from the first dorsal interosseous muscle were performed in four subjects and compared with simulated EMG signals. Our model successfully reproduces several characteristics of the experimental data. The simulated EMG signals match experimental EMG recordings in shape and size, and change with stimulus intensity and contraction level as in experimental recordings. They exhibit cortical silent periods that are close to the biological values and reveal an interesting dependence on inhibitory synaptic transmission properties. Our model predicts several characteristics of the firing patterns of neurons along the entire pathway from cortical layer 2/3 cells down to spinal motoneurons and should be considered as a viable tool for explaining and analyzing EMG signals following TMS. NEW & NOTEWORTHY A biophysically detailed model of EMG signal generation following transcranial magnetic stimulation (TMS) is proposed. Simulated EMG signals match experimental EMG recordings in shape and amplitude. Motor-evoked potential and cortical silent period properties match experimental data. The model is a viable tool to analyze, explain, and predict EMG signals following TMS.

Resting state functional connectivity measures correlate with the response to anodal transcranial direct current stimulation.

Responses to non-invasive brain stimulation are highly variable between subjects. Resting state functional connectivity was investigated as a marker of plasticity induced by anodal transcranial direct current stimulation (tDCS). Twenty-six healthy adults (15 male, 26.4 ± 6.5 years) were tested. Experiment 1 investigated whether functional connectivity could predict modulation of corticospinal excitability following anodal tDCS. Experiment 2 determined test-retest reliability of connectivity measures. Three minutes of electroencephalography was recorded and connectivity was quantified with the debiased weighted phase lag index. Anodal (1 mA, 20 min) or sham tDCS was applied to the left primary motor cortex (M1), with a change in motor evoked potential amplitude recorded from the right first dorsal interosseous used as a marker of tDCS response. Connectivity in the high beta frequency (20-30 Hz) between an electrode approximating the left M1 (C3) and electrodes overlying the left parietal cortex was a strong predictor of tDCS response (cross-validated R2  = 0.69). Similar relationships were observed for alpha (8-13 Hz; R2  = 0.64), theta (4-7 Hz; R2  = 0.53), and low beta (14-19 Hz; R2  = 0.58) frequencies, however, test-retest reliability of connectivity measures was strongest for the high beta frequency model (ICC = 0.65; good reliability). Further investigation of the high beta model found that greater connectivity between C3 and a cluster of electrodes approximately overlying the left parietal cortex was associated with stronger responses to anodal (rho = 0.61, P = 0.03), but not sham tDCS (rho = 0.43, P = 0.14). Functional connectivity is a strong predictor of the neuroplastic response to tDCS and may be one important characteristic to assist targeted tDCS application.

Combined transcranial alternating current stimulation and continuous theta burst stimulation: a novel approach for neuroplasticity induction.

Non-invasive brain stimulation can induce functionally relevant plasticity in the human cortex, making it potentially useful as a therapeutic tool. However, the induced changes are highly variable between individuals, potentially limiting research and clinical utility. One factor that might contribute to this variability is the level of cortical inhibition at the time of stimulation. The alpha rhythm (~ 8-13 Hz) recorded with electroencephalography (EEG) is thought to reflect pulsatile cortical inhibition; therefore, targeting non-invasive brain stimulation to particular phases of the alpha rhythm may provide an approach to enhance plasticity induction. Transcranial alternating current stimulation (tACS) has been shown to entrain cortical oscillations in a frequency-specific manner. We investigated whether the neuroplastic response to continuous theta burst stimulation (cTBS) was enhanced by timing bursts of stimuli to the peak or the trough of a tACS-imposed alpha rhythm. While motor evoked potentials (MEPs) were unaffected when cTBS was applied in-phase with the peak of the tACS-imposed oscillation, MEP depression was enhanced when cTBS was applied in-phase with the trough. This enhanced MEP depression was dependent on the individual peak frequency of the endogenous alpha rhythm recorded with EEG prior to stimulation, and was strongest in those participants classified as non-responders to standard cTBS. These findings suggest that tACS may be used in combination with cTBS to enhance the plasticity response. Furthermore, the peak frequency of endogenous alpha, as measured with EEG, may be used as a simple marker to pre-select those individuals likely to benefit from this approach.

Resistant Against De-depression: LTD-Like Plasticity in the Human Motor Cortex Induced by Spaced cTBS.

The long-term depression (LTD)-like changes in human primary motor cortex (M1) excitability induced by continuous theta burst stimulation (cTBS) are subject to reversal (i.e., de-depression) following behavioral engagement of M1, limiting its therapeutic potential under behaviorally relevant conditions. Experiments in animals suggest that the repeated, spaced application of stimulation trains may consolidate synaptic plasticity, making it resistant to reversal by physiological activity. Although there is evidence that repeated cTBS prolongs LTD-like M1 neuroplasticity in humans, whether these effects are resistant to de-depression has not been tested. We investigated whether the neuroplastic effects of paired cTBS trains were resistant to de-depression by a sustained, submaximal voluntary contraction of the hand muscles. In the absence of cTBS, voluntary contraction had no effect on motor evoked potentials (MEPs) recorded from the right first dorsal interosseous muscle. While the LTD-like MEP depression induced by a single cTBS was abolished by subsequent voluntary contraction, paired cTBS induced MEP depression that was resistant to reversal. This MEP depression was also resistant to reversal when an experimental de-depression protocol was used instead of a voluntary contraction. Our findings suggest that repeated cTBS applications consolidate LTD-like M1 neuroplasticity, which may have important implications for the clinical application of cTBS.

Can noninvasive brain stimulation enhance function in the ageing brain?

Advancing age is associated with cognitive and motor performance deficits and a reduced capacity for plasticity. Zimerman and colleagues (Zimerman M, Nitsch M, Giraux P, Gerloff C, Cohen LG, Hummel FC. Ann Neurol 73: 10-15, 2013) have recently shown that noninvasive brain stimulation can enhance behavioral improvements following training on a motor sequence task in older adults. The work is of high clinical importance given the rapidly growing ageing population and the accompanying costs to health systems globally.

Day differences in the cortisol awakening response predict day differences in synaptic plasticity in the brain.

The cortisol awakening response (CAR) is the most prominent, dynamic and variable part of the circadian pattern of cortisol secretion. Despite this, its precise purpose is unknown. Aberrant patterns of the CAR are associated with impaired physical and mental health and reduced cognitive function, suggesting that it may have a pervasive role or roles. It has been suggested that the CAR primes the brain for the expected demands of the day but the mechanisms underlying this process are unknown. We examined temporal covariation of the CAR and rapid transcranial magnetic stimulation (rTMS)-induced long term depression (LTD)-like responses in the motor cortex. Plasticity was evaluated across 180 measures from five time points on four sessions across nine healthy researcher participants, mean age 25 ± 2.5 years. Plasticity estimates were obtained in the afternoon after measurement of the CAR on 4 days, at least 3 days apart. As both CAR magnitude and rTMS-induced responses are variable across days, we hypothesized that days with larger than individual average CARs would be associated with a greater than individual average plasticity response. This was confirmed by mixed regression modelling where variation in the CAR predicted variation in rTMS-induced responses (df: 1, 148.24; F: 10.41; p = 0.002). As the magnitude of the CAR is regulated by the "master" circadian CLOCK, and synaptic plasticity is known to be modulated by peripheral "slave" CLOCK genes, we suggest that the CAR may be a mediator between the master and peripheral circadian systems to entrain daily levels of synaptic plasticity.

The influence of a single bout of aerobic exercise on short-interval intracortical excitability.

Regular physical activity can have positive effects on brain function and plasticity. Indeed, there is some limited evidence that even a single bout of exercise may promote plasticity within the cortex. However, the mechanisms by which exercise acutely promotes plasticity are not clear. To further explore the effects of acute exercise on cortical function, we examined whether a single bout of exercise was associated with changes in cortical excitability and inhibition. Using standard techniques, cortical stimulus-response curves [90% resting motor threshold (RMT)-150% RMT] were investigated in nine subjects (four females, 31.1 ± 11.7 years) and short-interval intracortical inhibition (SICI) [interstimulus interval 2 ms and 3 ms, conditioning intensities of 80% active motor threshold (AMT) and 90% AMT] in 13 subjects (six females, 28.4 ± 5.1 years) before and at 0 and 15 min following 30 min of ergometer cycling at low-moderate or moderate-high intensity. There were no changes in cortical excitability following exercise but less SICI at both 0 and 15 min post-exercise (F [2, 24] = 7.7, P = 0.003). These findings show that a short period of exercise can transiently reduce SICI. Such a change in inhibition after exercise may contribute to the development of a cortical environment that would be more optimal for plasticity and may partially explain previous findings of enhanced neuroplasticity following low-intensity exercise.

The interaction between metaplastic neuromodulation and fatigue in multiple sclerosis.

BACKGROUND AND OBJECTIVE: Neuromuscular fatigue contributes to decrements in quality of life in Multiple Sclerosis (MS), yet available treatments demonstrate limited efficacy. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique which presents promise in managing fatigue, possibly related to its capacity to modulate corticospinal excitability. There is evidence for capitalising on metaplasticity using tDCS for improving outcomes. However, this remains to be explored with fatigue in people with MS (pwMS). We investigated cathodal tDCS (ctDCS) priming on anodal tDCS (atDCS)-induced corticospinal excitability and fatigue modulation in pwMS. METHODS: 15 pwMS and 15 healthy controls completed fatiguing exercise whilst receiving either ctDCS or sham (stDCS) primed atDCS to the motor cortex. We assessed change in contraction force and motor evoked potential (MEP) amplitude across time to represent changes in fatigue and corticospinal excitability. RESULTS AND CONCLUSION: ctDCS primed atDCS induced MEP elevation in healthy participants but not in pwMS, possibly indicating impaired metaplasticity in pwMS. No tDCS-mediated change in the magnitude of fatigue was observed, implying that development of fatigue may not rely on changes in corticospinal excitability. SIGNIFICANCE: These findings expand understanding of tDCS effects in pwMS, highlighting differences that may be relevant in the disease pathophysiology.

The effects of age and biological sex on the association between I-wave recruitment and the response to cTBS: An exploratory study.

The neuroplastic response to continuous theta burst stimulation (cTBS) is inherently variable. The measurement of I-wave latencies has been shown to strongly predict the magnitude and direction of the response to cTBS, whereby longer latencies are associated with stronger long-term depression-like responses. However, potential differences in this association relating to age and sex have not been explored. We performed cTBS and measured I-wave recruitment (via MEP latencies) in 66 participants (31 female) ranging in age from 11 to 78 years. The influence of age and sex on the association between I-wave recruitment and the response to cTBS was tested using linear regression models. In contrast to previous studies, there was not a significant association between I-wave latencies and cTBS response at the group level (p = 0.142, R2 = 0.033). However, there were interactions between I-waves and both age and sex when predicting cTBS response. Subgroup analysis revealed that preferential late I-wave recruitment predicted cTBS response in adolescent females, but not in adolescent or adult males or adult females. These data suggest that the generalisability of I-wave measurement in predicting the response to cTBS may be lower than initially believed. Prediction models should include age and sex, rather than I-wave latencies alone, as our findings suggest that, while each factor alone is not a strong predictor, these factors interact to influence the response to cTBS.

Finding synaptic couplings from a biophysical model of motor evoked potentials after theta-burst transcranial magnetic stimulation.

OBJECTIVE: We aimed to use measured input-output (IO) data to identify the best fitting model for motor evoked potentials. METHODS: We analyzed existing IO data before and after intermittent and continuous theta-burst stimulation (iTBS & cTBS) from a small group of subjects (18 for each). We fitted individual synaptic couplings and sensitivity parameters using variations of a biophysical model. A best performing model was selected and analyzed. RESULTS: cTBS gives a broad reduction in MEPs for amplitudes larger than resting motor threshold (RMT). Close to threshold, iTBS gives strong potentiation. The model captures individual IO curves. There is no change to the population average synaptic weights post TBS but the change in excitatory-to-excitatory synaptic coupling is strongly correlated with the experimental post-TBS response relative to baseline. CONCLUSIONS: The model describes population-averaged and individual IO curves, and their post-TBS change. Variation among individuals is accounted for with variation in synaptic couplings, and variation in sensitivity of neural response to stimulation. SIGNIFICANCE: The best fitting model could be applied more broadly and validation studies could elucidate underlying biophysical meaning of parameters.

Corrigendum: Twenty-four-hour time-use composition and cognitive function in older adults: cross-sectional findings of the ACTIVate study.

[This corrects the article DOI: 10.3389/fnhum.2022.1051793.].

The application of spaced theta burst protocols induces long-lasting neuroplastic changes in the human motor cortex.

There is some limited evidence suggesting that the spaced application of repetitive transcranial magnetic stimulation (rTMS) protocols may extend the duration of induced neuroplastic changes. However, this has yet to be demonstrated in the human primary motor cortex (M1). We evaluated whether the paired application of an inhibitory rTMS protocol [continuous theta burst stimulation (cTBS)] at 10-min intervals prolonged the duration of induced M1 plasticity. Motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous muscle before and following single and paired cTBS protocols applied with two intensities: 80% of active motor threshold (AMT(80)) and 70% of resting motor threshold (RMT(70)). Single cTBS protocols did not significantly influence MEP amplitudes. Whereas paired trains applied at AMT(80) had no effect on MEP amplitudes, paired cTBS trains at RMT(70) significantly reduced them. MEP amplitudes remained suppressed for at least 2 h following the second train. Control experiments suggested that the contraction used to establish active motor threshold prior to cTBS application may be responsible for blocking the effect of paired cTBS trains at AMT(80). The results suggest that the spaced application of cTBS protocols may be an effective approach for establishing long-lasting M1 neuroplasticity only in the absence of prior voluntary motor activation. These findings may have important implications for the therapeutic application of rTMS.

How are combinations of physical activity, sedentary behaviour and sleep related to cognitive function in older adults? A systematic review.

The relationships between cognitive function and each of physical activity, sleep and sedentary behaviour in older adults are well documented. However, these three "time use" behaviours are co-dependent parts of the 24-hour day (spending time in one leaves less time for the others), and their best balance for cognitive function in older adults is still largely unknown. This systematic review summarises the existing evidence on the associations between combinations of two or more time-use behaviours and cognitive function in older adults. Embase, Pubmed, PsycInfo, Medline and Emcare databases were searched in March 2020 and updated in May 2021, returning a total of 25,289 papers for screening. A total of 23 studies were included in the synthesis, spanning >23,000 participants (mean age 71 years). Findings support previous evidence that spending more time in physical activity and limiting sedentary behaviour is broadly associated with better cognitive outcomes in older adults. Higher proportions of moderate-vigorous physical activity in the day were most frequently associated with better cognitive function. Some evidence suggests that certain types of sedentary behaviour may be positively associated with cognitive function, such as reading or computer use. Sleep duration appears to share an inverted U-shaped relationship with cognition, as too much or too little sleep is negatively associated with cognitive function. This review highlights considerable heterogeneity in methodological and statistical approaches, and encourages a more standardised, transparent approach to capturing important daily behaviours in older adults. Investigating all three time-use behaviours together against cognitive function using suitable statistical methodology is strongly recommended to further our understanding of optimal 24-hour time use for brain function in aging.