White matter fibre density in the brain's inhibitory control network is associated with falling in low activity older adults.

Recent research has indicated that the relationship between age-related cognitive decline and falling may be mediated by the individual's capacity to quickly cancel or inhibit a motor response. This longitudinal investigation demonstrates that higher white matter fibre density in the motor inhibition network paired with low physical activity was associated with falling in elderly participants. We measured the density of white matter fibre tracts connecting key nodes in the inhibitory control network in a large sample (n = 414) of older adults. We modelled their self-reported frequency of falling over a 4-year period with white matter fibre density in pathways corresponding to the direct and hyperdirect cortical-subcortical loops implicated in the inhibitory control network. Only connectivity between right inferior frontal gyrus and right subthalamic nucleus was associated with falling as measured cross-sectionally. The connectivity was not, however, predictive of future falling when measured 2 and 4 years later. Higher white matter fibre density was associated with falling, but only in combination with low levels of physical activity. No such relationship existed for selected control brain regions that are not implicated in the inhibitory control network. Albeit statistically robust, the direction of this effect was counterintuitive (more dense connectivity associated with falling) and warrants further longitudinal investigation into whether white matter fibre density changes over time in a manner correlated with falling, and mediated by physical activity.

A method to assess response inhibition during a balance recovery step.

BACKGROUND: Correlations between falls and individual differences in inhibitory control, suggest the ability to suppress automatic, but unwanted, action is important in fall prevention. Response inhibition has been a topic of considerable interest in the cognitive neuroscience community for many decades, bringing a wealth of techniques that could potentially inform assessment of reactive balance. For example, the stop signal task is a popular method to quantify inhibitory control ability. RESEARCH QUESTION: Can we apply the stop signal task to measure response inhibition in a balance recovery task? METHODS: Twenty healthy, young adults completed a novel reactive balance test that required occasional suppression of a balance recovery step. Participants were released from a supported lean ('Go' cue) requiring them to quickly step forward to regain balance. On some trials, a tone ('Stop' cue) instructed participants to suppress a step and relax into a harness. Step trials were more frequent (80%) than stop trials (20%) to bias a rapid stepping response. The stop tone was presented at various delays following cable release, to manipulate task difficulty (i.e., longer delays make step suppression difficult). Individual differences in inhibitory control were determined using lift off times from force plates, and by contrasting muscle activation in failed compared to successful stop trials. RESULTS: Most participants were able to successfully suppress a balance recovery step on occasion, allowing for accurate estimation of individual differences in inhibitory control. The successful suppression of a balance recovery step was more likely in the group (n = 10) where shorter stop signal delays were used (i.e., the task was easier). SIGNIFICANCE: While balance assessments often stress reflexive action, there is a need for methods that evaluate response inhibition. The present study leveraged a well-established cognitive test of inhibitory control to develop a method to quantify stopping ability in a reactive balance context.

Challenges and Opportunities for the Future of Brain-Computer Interface in Neurorehabilitation.

Brain-computer interfaces (BCIs) provide a unique technological solution to circumvent the damaged motor system. For neurorehabilitation, the BCI can be used to translate neural signals associated with movement intentions into tangible feedback for the patient, when they are unable to generate functional movement themselves. Clinical interest in BCI is growing rapidly, as it would facilitate rehabilitation to commence earlier following brain damage and provides options for patients who are unable to partake in traditional physical therapy. However, substantial challenges with existing BCI implementations have prevented its widespread adoption. Recent advances in knowledge and technology provide opportunities to facilitate a change, provided that researchers and clinicians using BCI agree on standardisation of guidelines for protocols and shared efforts to uncover mechanisms. We propose that addressing the speed and effectiveness of learning BCI control are priorities for the field, which may be improved by multimodal or multi-stage approaches harnessing more sensitive neuroimaging technologies in the early learning stages, before transitioning to more practical, mobile implementations. Clarification of the neural mechanisms that give rise to improvement in motor function is an essential next step towards justifying clinical use of BCI. In particular, quantifying the unknown contribution of non-motor mechanisms to motor recovery calls for more stringent control conditions in experimental work. Here we provide a contemporary viewpoint on the factors impeding the scalability of BCI. Further, we provide a future outlook for optimal design of the technology to best exploit its unique potential, and best practices for research and reporting of findings.

Relationship between Speed of Response Inhibition and Ability to Suppress a Step in Midlife and Older Adults.

In young adults, performance on a test of response inhibition was recently found to be correlated with performance on a reactive balance test where automated stepping responses must occasionally be inhibited. The present study aimed to determine whether this relationship holds true in older adults, wherein response inhibition is typically deficient and the control of postural equilibrium presents a greater challenge. Ten participants (50+ years of age) completed a seated cognitive test (stop signal task) followed by a reactive balance test. Reactive balance was assessed using a modified lean-and-release system where participants were required to step to regain balance following perturbation, or suppress a step if an obstacle was present. The stop signal task is a standardized cognitive test that provides a measure of the speed of response inhibition called the Stop Signal Reaction Time (SSRT). Muscle responses in the legs were compared between conditions where a step was allowed or blocked to quantify response inhibition of the step. The SSRT was significantly related to leg muscle suppression during balance recovery in the stance leg. Thus, participants that were better at inhibiting their responses in the stop signal task were also better at inhibiting an unwanted leg response in favor of grasping a supportive handle. The relationship between a seated cognitive test using finger responses and leg muscle suppression when a step was blocked indicates a context-independent, generalized capacity for response inhibition. This suggests that a simple cognitive test such as the stop signal task could be used clinically to predict an individual's capacity for adapting balance reactions and fall risk. The present results provide support for future studies, with larger samples, to verify this relationship between stop signal reaction time and leg response during balance recovery.

Volume of ß-Bursts, But Not Their Rate, Predicts Successful Response Inhibition.

In humans, impaired response inhibition is characteristic of a wide range of psychiatric diseases and of normal aging. It is hypothesized that the right inferior frontal cortex (rIFC) plays a key role by inhibiting the motor cortex via the basal ganglia. The electroencephalography (EEG)-derived ß-rhythm (15-29 Hz) is thought to reflect communication within this network, with increased right frontal ß-power often observed before successful response inhibition. Recent literature suggests that averaging spectral power obscures the transient, burst-like nature of ß-activity. There is evidence that the rate of ß-bursts following a Stop signal is higher when a motor response is successfully inhibited. However, other characteristics of ß-burst events, and their topographical properties, have not yet been examined. Here, we used a large human (male and female) EEG Stop Signal task (SST) dataset (n = 218) to examine averaged normalized ß-power, ß-burst rate, and ß-burst "volume" (which we defined as burst duration × frequency span × amplitude). We first sought to optimize the ß-burst detection method. In order to find predictors across the whole scalp, and with high temporal precision, we then used machine learning to (1) classify successful versus failed stopping and to (2) predict individual stop signal reaction time (SSRT). ß-burst volume was significantly more predictive of successful and fast stopping than ß-burst rate and normalized ß-power. The classification model generalized to an external dataset (n = 201). We suggest ß-burst volume is a sensitive and reliable measure for investigation of human response inhibition.SIGNIFICANCE STATEMENT The electroencephalography (EEG)-derived ß-rhythm (15-29 Hz) is associated with the ability to inhibit ongoing actions. In this study, we sought to identify the specific characteristics of ß-activity that contribute to successful and fast inhibition. In order to search for the most relevant features of ß-activity, across the whole scalp and with high temporal precision, we employed machine learning on two large datasets. Spatial and temporal features of ß-burst "volume" (duration × frequency span × amplitude) predicted response inhibition outcomes in our data significantly better than ß-burst rate and normalized ß-power. These findings suggest that multidimensional measures of ß-bursts, such as burst volume, can add to our understanding of human response inhibition.

Neuronal response variability as a product of divisive normalization; neurobiological implications at a macroscale level.

The occurrence of neuronal spikes recorded directly from sensory cortex is highly irregular within and between presentations of an invariant stimulus. The traditional solution has been to average responses across many trials. However, with this approach, response variability is downplayed as noise, so it is assumed that statistically controlling it will reveal the brain's true response to a stimulus. A mounting body of evidence suggests that this approach is inadequate. For example, experiments show that response variability itself varies as a function of stimulus dimensions like contrast and state dimensions like attention. In other words, response variability has structure, is therefore potentially informative and should be incorporated into models which try to explain neural encoding. In this article we provide commentary on a recently published study by Coen-Cagli and Solomon that incorporates spike variability in a quantitative model, by explaining it as a function of divisive normalization. We consider the potential role of neural oscillations in this process as a potential bridge between the current microscale findings and response variability at the mesoscale/macroscale level.

Muscle-specific modulation of indirect inputs to primary motor cortex during action observation.

Single-pulse transcranial magnetic stimulation (spTMS) studies report that movement observation facilitates corticospinal excitability in primary motor cortex (M1) in a muscle-specific manner. However, motor evoked potentials (MEPs) elicited by spTMS are known to reflect the summation of several descending volleys in corticospinal neurons which are evoked via mono- and polysynaptic inputs (so-called indirect waves or I-waves). It is unclear which of these components contribute to the muscle-specific modulation of M1 during action observation. The interactions between different I-waves are reflected in the facilitatory peaks elicited with a short-intracortical facilitation (SICF) protocol when two pulses are sent to M1 at precise intervals (i.e., 1.3, 2.5 or 4.1 ms). Here, we explored the modulation of early and late SICF peaks during action observation by measuring highly specific MEP amplitude changes measured in two muscles (index, FDI and little finger, ADM) while participants observed two different actions (precision and whole-hand grip). Our results demonstrate that both early (1.3 ms) and late (2.5 and 4.1 ms) SICF peaks are modulated in the context of movement observation. However, only the second peak (ISI 2.5 ms) was significantly associated with the muscle-specific modulation of corticospinal excitability as measured with spTMS. This late SICF peak is believed to reflect the activity cortico-cortical pathways involved in the facilitation of muscle-specific representations in M1. Thus, our findings suggest that movement observation leads to widespread activation of different neural circuits within M1, including those mediating cortico-cortical communication.

Author Correction: Deep sleep maintains learning efficiency of the human brain.

This corrects the article DOI: 10.1038/ncomms15405.

Repetitive reaching training combined with transcranial Random Noise Stimulation in stroke survivors with chronic and severe arm paresis is feasible: a pilot, triple-blind, randomised case series.

BACKGROUND: Therapy that combines repetitive training with non-invasive brain stimulation is a potential avenue to enhance upper limb recovery after stroke. This study aimed to investigate the feasibility of transcranial Random Noise Stimulation (tRNS), timed to coincide with the generation of voluntary motor commands, during reaching training. METHODS: A triple-blind pilot RCT was completed. Four stroke survivors with chronic (6-months to 5-years) and severe arm paresis, not taking any medications that had the potential to alter cortical excitability, and no contraindications to tRNS or MRI were recruited. Participants were randomly allocated to 12 sessions of reaching training over 4-weeks with active or sham tRNS delivered over the lesioned hemisphere motor representation. tRNS was triggered to coincide with a voluntary movement attempt, ceasing after 5-s. At this point, peripheral nerve stimulation enabled full range reaching. To determine feasibility, we considered adverse events, training outcomes, clinical outcomes, corticospinal tract (CST) structural integrity, and reflections on training through in-depth interviews from each individual case. RESULTS: Two participants received active and two sham tRNS. There were no adverse events. All training sessions were completed, repetitive practice performed and clinically relevant improvements across motor outcomes demonstrated. The amount of improvement varied across individuals and appeared to be independent of group allocation and CST integrity. CONCLUSION: Reaching training that includes tRNS timed to coincide with generation of voluntary motor commands is feasible. Clinical improvements were possible even in the most severely affected individuals as evidenced by CST integrity. TRIAL REGISTRATION: This study was registered on the Australian and New Zealand Clinical Trials Registry (ANZCTR) http://www.ANZCTR.org.au/ACTRN12614000952640.aspx . Registration date 4 September 2014, first participant date 9 September 2014.

Deep sleep maintains learning efficiency of the human brain.

It is hypothesized that deep sleep is essential for restoring the brain's capacity to learn efficiently, especially in regions heavily activated during the day. However, causal evidence in humans has been lacking due to the inability to sleep deprive one target area while keeping the natural sleep pattern intact. Here we introduce a novel approach to focally perturb deep sleep in motor cortex, and investigate the consequences on behavioural and neurophysiological markers of neuroplasticity arising from dedicated motor practice. We show that the capacity to undergo neuroplastic changes is reduced by wakefulness but restored during unperturbed sleep. This restorative process is markedly attenuated when slow waves are selectively perturbed in motor cortex, demonstrating that deep sleep is a requirement for maintaining sustainable learning efficiency.

Structural and Functional Cortical Connectivity Mediating Cross Education of Motor Function.

Cross-education (CE) is the process whereby training with one limb leads to subsequent improvement in performance by the opposite untrained limb. We used multimodal neuroimaging in humans to investigate the mediating neural mechanisms by relating quantitative estimates of functional and structural cortical connectivity to individual levels of interlimb transfer. Resting-state (rs)-fMRI and diffusion weighted imaging (DWI) scans were undertaken before unilateral ballistic wrist flexion training. The rs-fMRI sequence was repeated immediately afterward. The increase in performance of the untrained limb was 83.6% of that observed for the trained limb and significantly greater than that of a control group who undertook no training. Functional connectivity in the resting motor network between right and left supplementary motor areas (SMA) was elevated after training. These changes were not, however, correlated with individual levels of transfer. Analysis of the DWI data using constrained spherical deconvolution-based tractography indicated that fractional anisotropy and apparent fiber density in tracts connecting bilateral SMA were negatively correlated with and predictive of transfer. The findings suggest that interhemispheric interactions between bilateral SMA play an instrumental role in CE and that the structural integrity of the connecting white matter pathways influences the level of transfer.SIGNIFICANCE STATEMENT Strength or skill training with one limb also brings about improvements in the performance of the opposite, untrained limb. This phenomenon, termed cross-education (CE), has obvious potential for the rehabilitation of functional capacity that has been lost through brain insult or musculoskeletal injury. The neural mechanisms that give rise to CE are, however, poorly understood. We used a combination of neuroimaging methods to investigate the pathways in the human brain that mediate CE. We determined that the supplementary motor area (SMA) plays an important role in the interlimb transfer of performance gains and demonstrate that the quality of the white matter fibers connecting right and left SMA predicts the benefit that an individual derives from CE.

Transcallosal connectivity of the human cortical motor network.

The organisational and architectural configuration of white matter pathways connecting brain regions has ramifications for all facets of the human condition, including manifestations of incipient neurodegeneration. Although diffusion tensor imaging (DTI) has been used extensively to visualise white matter connectivity, due to the widespread presence of crossing fibres, the lateral projections of the corpus callosum are not normally detected using this methodology. Detailed knowledge of the transcallosal connectivity of the human cortical motor network has, therefore, remained elusive. We employed constrained spherical deconvolution (CSD) tractography-an approach that is much less susceptible to the influence of crossing fibres, in order to derive complete in vivo characterizations of white matter pathways connecting specific motor cortical regions to their counterparts and other loci in the opposite hemisphere. The revealed patterns of connectivity closely resemble those derived from anatomical tracing in primates. It was established that dorsal premotor cortex (PMd) and supplementary motor area (SMA) have extensive interhemispheric connectivity-exhibiting both dense homologous projections, and widespread structural relations with every other region in the contralateral motor network. Through this in vivo portrayal, the importance of non-primary motor regions for interhemispheric communication is emphasised. Additionally, distinct connectivity profiles were detected for the anterior and posterior subdivisions of primary motor cortex. The present findings provide a comprehensive representation of transcallosal white matter projections in humans, and have the potential to inform the development of models and hypotheses relating structural and functional brain connectivity.

What Do TMS-Evoked Motor Potentials Tell Us About Motor Learning?

Thirty years ago, the first magnetic device capable of stimulating the human brain without discomfort through the intact skull was unveiled in Sheffield, England (Barker et al. in Lancet 1:1106-1107, 1985). Since that time, transcranial magnetic stimulation (TMS) has become the tool of choice for many scientists investigating human motor control and learning. In light of the fact that there are limits to the information that can be provided by any experimental technique, we first make the case that the necessarily restricted explanatory scope of the TMS technique-and the motor-evoked potentials to which it gives rise, is not yet reflected adequately in the research literature. We also argue that this inattention, coupled with the pervasive adoption of TMS as an investigative tool, may be restricting the elaboration of knowledge concerning the neural processes that mediate human motor learning. In order to make these points, we use as an exemplar the study of cross-education-the interlimb transfer of functional capacity.

Interhemispheric sensorimotor integration; an upper limb phenomenon?

Somatosensory information from the limbs reaches the contralateral Primary Sensory Cortex (S1) with a delay of 23ms for finger, and 40ms for leg (somatosensory N20/N40). Upon arrival of this input in the cortex, motor evoked potentials (MEPs) elicited by Transcranial Magnetic Stimulation (TMS) are momentarily inhibited. This phenomenon is called 'short latency afferent inhibition (SAI)' and can be used as a tool for investigating sensorimotor interactions in the brain. We used SAI to investigate the process of sensorimotor integration in the hemisphere ipsilateral to the stimulated limb. We hypothesized that ipsilateral SAI would occur with a delay following the onset of contralateral SAI, to allow for transcallosal conduction of the signal. We electrically stimulated the limb either contralateral or ipsilateral to the hemisphere receiving TMS, using a range of different interstimulus intervals (ISI). We tested the First Dorsal Interosseous (FDI) muscle in the hand, and Tibialis Anterior (TA) in the lower leg, in three separate experiments. Ipsilateral SAI was elicited in the upper limb (FDI) at all ISIs that were greater than N20+18ms (all p<.05) but never at any earlier timepoint. No ipsilateral SAI was detected in the lower limb (TA) at any of the tested ISIs. The delayed onset timing of ipsilateral SAI suggests that transcallosal communication mediates this inhibitory process for the upper limb. The complete absence of ipsilateral SAI in the lower limb warrants consideration of the potential limb-specific differences in demands for bilateral sensorimotor integration.

Neural Adaptations Associated with Interlimb Transfer in a Ballistic Wrist Flexion Task.

Cross education is the process whereby training of one limb gives rise to increases in the subsequent performance of its opposite counterpart. The execution of many unilateral tasks is associated with increased excitability of corticospinal projections from primary motor cortex (M1) to the opposite limb. It has been proposed that these effects are causally related. Our aim was to establish whether changes in corticospinal excitability (CSE) arising from prior training of the opposite limb determine levels of interlimb transfer. We used three vision conditions shown previously to modulate the excitability of corticospinal projections to the inactive (right) limb during wrist flexion movements performed by the training (left) limb. These were: (1) mirrored visual feedback of the training limb; (2) no visual feedback of either limb; and (3) visual feedback of the inactive limb. Training comprised 300 discrete, ballistic wrist flexion movements executed as rapidly as possible. Performance of the right limb on the same task was assessed prior to, at the mid point of, and following left limb training. There was no evidence that variations in the excitability of corticospinal projections (assessed by transcranial magnetic stimulation (TMS)) to the inactive limb were associated with, or predictive of, the extent of interlimb transfer that was expressed. There were however associations between alterations in muscle activation dynamics observed for the untrained limb, and the degree of positive transfer that arose from training of the opposite limb. The results suggest that the acute adaptations that mediate the bilateral performance gains realized through unilateral practice of this ballistic wrist flexion task are mediated by neural elements other than those within M1 that are recruited at rest by single-pulse TMS.

Neural pathways mediating cross education of motor function.

Cross education is the process whereby training of one limb gives rise to enhancements in the performance of the opposite, untrained limb. Despite interest in this phenomenon having been sustained for more than a century, a comprehensive explanation of the mediating neural mechanisms remains elusive. With new evidence emerging that cross education may have therapeutic utility, the need to provide a principled evidential basis upon which to design interventions becomes ever more pressing. Generally, mechanistic accounts of cross education align with one of two explanatory frameworks. Models of the "cross activation" variety encapsulate the observation that unilateral execution of a movement task gives rise to bilateral increases in corticospinal excitability. The related conjecture is that such distributed activity, when present during unilateral practice, leads to simultaneous adaptations in neural circuits that project to the muscles of the untrained limb, thus facilitating subsequent performance of the task. Alternatively, "bilateral access" models entail that motor engrams formed during unilateral practice, may subsequently be utilized bilaterally-that is, by the neural circuitry that constitutes the control centers for movements of both limbs. At present there is a paucity of direct evidence that allows the corresponding neural processes to be delineated, or their relative contributions in different task contexts to be ascertained. In the current review we seek to synthesize and assimilate the fragmentary information that is available, including consideration of knowledge that has emerged as a result of technological advances in structural and functional brain imaging. An emphasis upon task dependency is maintained throughout, the conviction being that the neural mechanisms that mediate cross education may only be understood in this context.

Vision modulates corticospinal suppression in a functionally specific manner during movement of the opposite limb.

The effect of vision on the excitability of corticospinal projections to the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles of right human forearm was investigated before and during discrete movement of the opposite limb. An external force opposed the initial phase of the movement (wrist flexion) and assisted the reverse phase, so that recruitment of the wrist extensors was minimized. Three conditions were used as follows: viewing the inactive right limb (Vision), viewing the mirror image of the moving left limb (Mirror), and with vision of the right limb occluded (No Vision). Transcranial magnetic stimulation was delivered to the left motor cortex: before, at the onset of, or during the left limb movement to obtain motor evoked potentials (MEPs) in the muscles of the right forearm. At and following movement onset, MEPs obtained in the right FCR were smaller in the Vision condition than in the Mirror and No Vision conditions. A distinct pattern of variation was obtained for the ECR. In all conditions, MEPs in this muscle were elevated upon or following movement of the opposite limb. An additional analysis of ipsilateral silent periods indicated that interhemispheric inhibition plays a role in mediating these effects. Activity-dependent changes in corticospinal output to a resting limb during discrete actions of the opposite limb are thus directly contingent upon where one looks. Furthermore, the extent to which vision exerts an influence upon projections to specific muscles varies in accordance with the functional contribution of their homologs to the intended action.