Structural Plasticity in Adulthood with Motor Learning and Stroke Rehabilitation.

The development of advanced noninvasive techniques to image the human brain has enabled the demonstration of structural plasticity during adulthood in response to motor learning. Understanding the basic mechanisms of structural plasticity in the context of motor learning is essential to improve motor rehabilitation in stroke patients. Here, we review and discuss the emerging evidence for motor-learning-related structural plasticity and the implications for stroke rehabilitation. In the clinical context, a few studies have started to assess the effects of rehabilitation on structural measures to understand recovery poststroke and additionally to predict intervention outcomes. Structural imaging will likely have a role in the future in providing measures that inform patient stratification for optimal outcomes.

Improving sleep after stroke: A randomised controlled trial of digital cognitive behavioural therapy for insomnia.

Stroke is frequently accompanied by long-term sleep disruption. We therefore aimed to assess the efficacy of digital cognitive behavioural therapy for insomnia to improve sleep after stroke. A parallel group randomised controlled trial was conducted remotely in participant's homes/online. Randomisation was online with minimisation of between-group differences in age and baseline Sleep Condition Indicator-8 score. In total, 86 community-dwelling stroke survivors consented, of whom 84 completed baseline assessments (39 female, mean 5.5 years post-stroke, mean 59 years old), and were randomised to digital cognitive behavioural therapy or control (sleep hygiene information). Follow-up was at post-intervention (mean 75 days after baseline) and 8 weeks later. The primary outcome was self-reported insomnia symptoms, as per the Sleep Condition Indicator-8 (range 0-32, lower numbers indicate more severe insomnia, reliable change 7 points) at post-intervention. There were significant improvements in Sleep Condition Indicator-8 for digital cognitive behavioural therapy compared with control (intention-to-treat, digital cognitive behavioural therapy n = 48, control n = 36, 5 imputed datasets, effect of group p ≤ 0.02, η p 2 = 0.07-0.12 [medium size effect], pooled mean difference = -3.35). Additionally, secondary outcomes showed shorter self-reported sleep-onset latencies and better mood for the digital cognitive behavioural therapy group, but no significant differences for self-efficacy, quality of life or actigraphy-derived sleep parameters. Cost-effectiveness analysis found that digital cognitive behavioural therapy dominates over control (non-significant cost savings and higher quality-adjusted life years). No related serious adverse events were reported to the researchers. Overall, digital cognitive behavioural therapy for insomnia effectively improves sleep after stroke. Future research is needed to assess earlier stages post-stroke, with a longer follow-up period to determine whether it should be included as part of routine post-stroke care. Clinicaltrials.gov NCT04272892.

Cerebellar GABA Change during Visuomotor Adaptation Relates to Adaptation Performance and Cerebellar Network Connectivity: A Magnetic Resonance Spectroscopic Imaging Study.

Motor adaptation is crucial for performing accurate movements in a changing environment and relies on the cerebellum. Although cerebellar involvement has been well characterized, the neurochemical changes in the cerebellum underpinning human motor adaptation remain unknown. We used a novel magnetic resonance spectroscopic imaging (MRSI) technique to measure changes in the inhibitory neurotransmitter GABA in the human cerebellum during visuomotor adaptation. Participants (n = 17, six female) used their right hand to adapt to a rotated cursor in the scanner, compared with a control task requiring no adaptation. We spatially resolved adaptation-driven GABA changes at the cerebellar nuclei and cerebellar cortex in the left and the right cerebellar hemisphere independently and found that simple right-hand movements increase GABA in the right cerebellar nuclei and decreases GABA in the left. When isolating adaptation-driven GABA changes, we found that GABA in the left cerebellar nuclei and the right cerebellar nuclei diverged, although GABA change from baseline at the right cerebellar nuclei was not different from zero at the group level. Early adaptation-driven GABA fluctuations in the right cerebellar nuclei correlated with adaptation performance. Participants showing greater GABA decrease adapted better, suggesting early GABA change is behaviorally relevant. Early GABA change also correlated with functional connectivity change in a cerebellar network. Participants showing greater decreases in GABA showed greater strength increases in cerebellar network connectivity. Results were specific to GABA, to adaptation, and to the cerebellar network. This study provides first evidence for plastic changes in cerebellar neurochemistry during motor adaptation. Characterizing these naturally occurring neurochemical changes may provide a basis for developing therapeutic interventions to facilitate human motor adaptation.SIGNIFICANCE STATEMENT Despite motor adaptation being fundamental to maintaining accurate movements, its neurochemical basis remains poorly understood, perhaps because measuring neurochemicals in the human cerebellum is technically challenging. Using a novel magnetic resonance spectroscopic imaging method, this study provides evidence for GABA changes in the left compared with the right cerebellar nuclei driven by both simple movement and motor adaptation. Although right cerebellar GABA changes were not significantly different from zero at the group level, the adaptation-driven GABA fluctuations in the right cerebellar nuclei correlated with adaptation performance and with functional connectivity change in a cerebellar network. These results show the first evidence for plastic changes in cerebellar neurochemistry during a cerebellar learning task. This provides the basis for developing therapeutic interventions that facilitate these naturally occurring changes to amplify cerebellar-dependent learning.

Self-modulation of motor cortex activity after stroke: a randomized controlled trial.

Real-time functional MRI neurofeedback allows individuals to self-modulate their ongoing brain activity. This may be a useful tool in clinical disorders that are associated with altered brain activity patterns. Motor impairment after stroke has previously been associated with decreased laterality of motor cortex activity. Here we examined whether chronic stroke survivors were able to use real-time fMRI neurofeedback to increase laterality of motor cortex activity and assessed effects on motor performance and on brain structure and function. We carried out a randomized, double-blind, sham-controlled trial (ClinicalTrials.gov: NCT03775915) in which 24 chronic stroke survivors with mild to moderate upper limb impairment experienced three training days of either Real (n = 12) or Sham (n = 12) neurofeedback. Assessments of brain structure, brain function and measures of upper-limb function were carried out before and 1 week after neurofeedback training. Additionally, measures of upper-limb function were repeated 1 month after neurofeedback training. Primary outcome measures were (i) changes in lateralization of motor cortex activity during movements of the stroke-affected hand throughout neurofeedback training days; and (ii) changes in motor performance of the affected limb on the Jebsen Taylor Test (JTT). Stroke survivors were able to use Real neurofeedback to increase laterality of motor cortex activity within (P = 0.019), but not across, training days. There was no group effect on the primary behavioural outcome measure, which was average JTT performance across all subtasks (P = 0.116). Secondary analysis found improvements in the performance of the gross motor subtasks of the JTT in the Real neurofeedback group compared to Sham (P = 0.010). However, there were no improvements on the Action Research Arm Test or the Upper Extremity Fugl-Meyer score (both P > 0.5). Additionally, decreased white-matter asymmetry of the corticospinal tracts was detected 1 week after neurofeedback training (P = 0.008), indicating that the tracts become more similar with Real neurofeedback. Changes in the affected corticospinal tract were positively correlated with participants neurofeedback performance (P = 0.002). Therefore, here we demonstrate that chronic stroke survivors are able to use functional MRI neurofeedback to self-modulate motor cortex activity in comparison to a Sham control, and that training is associated with improvements in gross hand motor performance and with white matter structural changes.

Multimodal Imaging Brain Markers in Early Adolescence Are Linked with a Physically Active Lifestyle.

The World Health Organization promotes physical exercise and a healthy lifestyle as means to improve youth development. However, relationships between physical lifestyle and human brain development are not fully understood. Here, we asked whether a human brain-physical latent mode of covariation underpins the relationship between physical activity, fitness, and physical health measures with multimodal neuroimaging markers. In 50 12-year old school pupils (26 females), we acquired multimodal whole-brain MRI, characterizing brain structure, microstructure, function, myelin content, and blood perfusion. We also acquired physical variables measuring objective fitness levels, 7 d physical activity, body mass index, heart rate, and blood pressure. Using canonical correlation analysis, we unravel a latent mode of brain-physical covariation, independent of demographics, school, or socioeconomic status. We show that MRI metrics with greater involvement in this mode also showed spatially extended patterns across the brain. Specifically, global patterns of greater gray matter perfusion, volume, cortical surface area, greater white matter extra-neurite density, and resting state networks activity covaried positively with measures reflecting a physically active phenotype (high fit, low sedentary individuals). Showing that a physically active lifestyle is linked with systems-level brain MRI metrics, these results suggest widespread associations relating to several biological processes. These results support the notion of close brain-body relationships and underline the importance of investigating modifiable lifestyle factors not only for physical health but also for brain health early in adolescence.SIGNIFICANCE STATEMENT An active lifestyle is key for healthy development. In this work, we answer the following question: How do brain neuroimaging markers relate with young adolescents' level of physical activity, fitness, and physical health? Combining advanced whole-brain multimodal MRI metrics with computational approaches, we show a robust relationship between physically active lifestyles and spatially extended, multimodal brain imaging-derived phenotypes. Suggesting a wider effect on brain neuroimaging metrics than previously thought, this work underlies the importance of studying physical lifestyle, as well as other brain-body relationships in an effort to foster brain health at this crucial stage in development.

A qualitative examination of the usability of a digital cognitive behavioral therapy for insomnia program after stroke.

OBJECTIVE: Sleep is commonly impaired after stroke. Cognitive Behavioral Therapy for Insomnia (CBT-I) is the first-line recommended treatment for sleep difficulty. "Sleepio" is a digital CBT-I program, allowing delivery of this treatment at scale. However, Sleepio has not yet been tested specifically in people with stroke. Before doing so, we wanted to explore the experience of people with stroke using the program, and potential barriers to completion. METHOD: Community dwelling survivors of stroke (n = 11, 41-78 years of age, 6 male) were given access to Sleepio. Participants discussed their experiences with the program during a semi-structured interview, which was analyzed using thematic analysis. RESULTS: We found four common themes: (1) positive and negative experiences impacted engagement with the program, (2) motivation to follow the program was proportional to perceived severity of sleep problem, (3) impractical advice for people with stroke, (4) difficulty operating the program. CONCLUSION: Sleepio can be used by some people at the chronic stage of stroke. However, some barriers to completion were highlighted, and not all suggestions were deemed practical for everyone. We therefore suggest possible adaptations which may make the program more easily usable and engaging for survivors of stroke with varying impairments.

Age-related decline in cortical inhibitory tone strengthens motor memory.

Ageing disrupts the finely tuned excitation/inhibition balance (E:I) across cortex via a natural decline in inhibitory tone (γ-amino butyric acid, GABA), causing functional decrements. However, in young adults, experimentally lowering GABA in sensorimotor cortex enhances a specific domain of sensorimotor function: adaptation memory. Here, we tested the hypothesis that as sensorimotor cortical GABA declines naturally with age, adaptation memory would increase, and the former would explain the latter. Results confirmed this prediction. To probe causality, we used brain stimulation to further lower sensorimotor cortical GABA during adaptation. Across individuals, how stimulation changed memory depended on sensorimotor cortical E:I. In those with low E:I, stimulation increased memory; in those with high E:I stimulation reduced memory. Thus, we identified a form of motor memory that is naturally strengthened by age, depends causally on sensorimotor cortex neurochemistry, and may be a potent target for motor skill preservation strategies in healthy ageing and neurorehabilitation.

Dual-task walking and automaticity after Stroke: Insights from a secondary analysis and imaging sub-study of a randomised controlled trial.

OBJECTIVE: To test the extent to which initial walking speed influences dual-task performance after walking intervention, hypothesising that slow walking speed affects automatic gait control, limiting executive resource availability. DESIGN: A secondary analysis of a trial of dual-task (DT) and single-task (ST) walking interventions comparing those with good (walking speed ⩾0.8 m s-1, n = 21) and limited (walking speed <0.79 m s-1, n = 24) capacity at baseline. SETTING: Community. SUBJECTS: Adults six-months post stroke with walking impairment. INTERVENTIONS: Twenty sessions of 30 minutes treadmill walking over 10 weeks with (DT) or without (ST) cognitive distraction. Good and limited groups were formed regardless of intervention received. MAIN MEASURES: A two-minute walk with (DT) and without (ST) a cognitive distraction assessed walking. fNIRS measured prefrontal cortex activation during treadmill walking with (DT) and without (ST) Stroop and planning tasks and an fMRI sub-study used ankle-dorsiflexion to simulate walking. RESULTS: ST walking improved in both groups (∆baseline: Good = 8.9 ± 13.4 m, limited = 5.3±8.9 m, Group × time = P < 0.151) but only the good walkers improved DT walking (∆baseline: Good = 10.4 ± 13.9 m, limited = 1.3 ± 7.7 m, Group × time = P < 0.025). fNIRS indicated increased ispilesional prefrontal cortex activation during DT walking following intervention (P = 0.021). fMRI revealed greater DT cost activation for limited walkers, and increased resting state connectivity of contralesional M1 with cortical areas associated with conscious gait control at baseline. After the intervention, resting state connectivity between ipsilesional M1 and bilateral superior parietal lobe, involved in integrating sensory and motor signals, increased in the good walkers compared with limited walkers. CONCLUSION: In individual who walk slowly it may be difficult to improve dual-task walking ability.Registration: ISRCTN50586966.

Structural Variability in the Human Brain Reflects Fine-Grained Functional Architecture at the Population Level.

Human brain structure topography is thought to be related in part to functional specialization. However, the extent of such relationships is unclear. Here, using a data-driven, multimodal approach for studying brain structure across the lifespan (N = 484, n = 260 females), we demonstrate that numerous structural networks, covering the entire brain, follow a functionally meaningful architecture. These gray matter networks (GMNs) emerge from the covariation of gray matter volume and cortical area at the population level. We further reveal fine-grained anatomical signatures of functional connectivity. For example, within the cerebellum, a structural separation emerges between lobules that are functionally connected to distinct, mainly sensorimotor, cognitive and limbic regions of the cerebral cortex and subcortex. Structural modes of variation also replicate the fine-grained functional architecture seen in eight well defined visual areas in both task and resting-state fMRI. Furthermore, our study shows a structural distinction corresponding to the established segregation between anterior and posterior default-mode networks (DMNs). These fine-grained GMNs further cluster together to form functionally meaningful larger-scale organization. In particular, we identify a structural architecture bringing together the functional posterior DMN and its anticorrelated counterpart. In summary, our results demonstrate that the relationship between structural and functional connectivity is fine-grained, widespread across the entire brain, and driven by covariation in cortical area, i.e. likely differences in shape, depth, or number of foldings. These results suggest that neurotrophic events occur during development to dictate that the size and folding pattern of distant, functionally connected brain regions should vary together across subjects.SIGNIFICANCE STATEMENT Questions about the relationship between structure and function in the human brain have engaged neuroscientists for centuries in a debate that continues to this day. Here, by investigating intersubject variation in brain structure across a large number of individuals, we reveal modes of structural variation that map onto fine-grained functional organization across the entire brain, and specifically in the cerebellum, visual areas, and default-mode network. This functionally meaningful structural architecture emerges from the covariation of gray matter volume and cortical folding. These results suggest that the neurotrophic events at play during development, and possibly evolution, which dictate that the size and folding pattern of distant brain regions should vary together across subjects, might also play a role in functional cortical specialization.

Neural basis of induced phantom limb pain relief.

OBJECTIVE: Phantom limb pain (PLP) is notoriously difficult to treat, partly due to an incomplete understanding of PLP-related disease mechanisms. Noninvasive brain stimulation (NIBS) is used to modulate plasticity in various neuropathological diseases, including chronic pain. Although NIBS can alleviate neuropathic pain (including PLP), both disease and treatment mechanisms remain tenuous. Insight into the mechanisms underlying both PLP and NIBS-induced PLP relief is needed for future implementation of such treatment and generalization to related conditions. METHODS: We used a within-participants, double-blind, and sham-controlled design to alleviate PLP via task-concurrent NIBS over the primary sensorimotor missing hand cortex (S1/M1). To specifically influence missing hand signal processing, amputees performed phantom hand movements during anodal transcranial direct current stimulation. Brain activity was monitored using neuroimaging during and after NIBS. PLP ratings were obtained throughout the week after stimulation. RESULTS: A single session of intervention NIBS significantly relieved PLP, with effects lasting at least 1 week. PLP relief associated with reduced activity in the S1/M1 missing hand cortex after stimulation. Critically, PLP relief and reduced S1/M1 activity correlated with preceding activity changes during stimulation in the mid- and posterior insula and secondary somatosensory cortex (S2). INTERPRETATION: The observed correlation between PLP relief and decreased S1/M1 activity confirms our previous findings linking PLP with increased S1/M1 activity. Our results further highlight the driving role of the mid- and posterior insula, as well as S2, in modulating PLP. Lastly, our novel PLP intervention using task-concurrent NIBS opens new avenues for developing treatment for PLP and related pain conditions. ANN NEUROL 2019;85:59-73.

A critical evaluation of systematic reviews assessing the effect of chronic physical activity on academic achievement, cognition and the brain in children and adolescents: a systematic review.

BACKGROUND: International and national committees have started to evaluate the evidence for the effects of physical activity on neurocognitive health in childhood and adolescence to inform policy. Despite an increasing body of evidence, such reports have shown mixed conclusions. We aimed to critically evaluate and synthesise the evidence for the effects of chronic physical activity on academic achievement, cognitive performance and the brain in children and adolescents in order to guide future research and inform policy. METHODS: MedLine, Embase, PsycINFO, Cochrane Library, Web of Science, and ERIC electronic databases were searched from inception to February 6th, 2019. Articles were considered eligible for inclusion if they were systematic reviews with or without meta-analysis, published in peer-reviewed (English) journals. Reviews had to be on school-aged children and/or adolescents that reported on the effects of chronic physical activity or exercise interventions, with cognitive markers, academic achievement or brain markers as outcomes. Reviews were selected independently by two authors and data were extracted using a pre-designed data extraction template. The quality of reviews was assessed using AMSTAR-2 criteria. RESULTS: Of 908 retrieved, non-duplicated articles, 19 systematic reviews met inclusion criteria. One high-quality review reported inconsistent evidence for physical activity-related effects on cognitive- and academic performance in obese or overweight children and adolescents. Eighteen (critically) low-quality reviews presented mixed favourable and null effects, with meta-analyses showing small effect sizes (0.1-0.3) and high heterogeneity. Low-quality reviews suggested physical activity-related brain changes, but lacked an interpretation of these findings. Systematic reviews varied widely in their evidence synthesis, rarely took intervention characteristics (e.g. dose), intervention fidelity or study quality into account and suspected publication bias. Reviews consistently reported that there is a lack of high-quality studies, of studies that include brain imaging outcomes, and of studies that include adolescents or are conducted in South American and African countries. CONCLUSIONS: Inconsistent evidence exists for chronic physical activity-related effects on cognitive-, academic-, and brain outcomes. The field needs to refocus its efforts towards improving study quality, transparency of reporting and dissemination, and is urged to differentiate between intervention characteristics for its findings to have a meaningful impact on policy.

Effects of gender, activity type, class location and class composition on physical activity levels experienced during physical education classes in British secondary schools: a pilot cross-sectional study.

BACKGROUND: Pupils in secondary schools do not meet the targets for physical activity levels during physical education (PE) sessions, and there is a lack of data on the vigorous physical activity domain (VPA) in PE known to be positively associated with cardio metabolic health While PE session intensity depends on a variety of factors, the large majority of studies investigating these factors have not taken into account the nested structure of this type of data set. Therefore, the aim of this study was to investigate the relationship between various factors (gender, activity type, class location and class composition) and various activity levels during PE classes in secondary schools, using a multi-level statistical approach. METHODS: Year eight (12-13 years old) adolescents (201 boys and 106 girls) from six schools were fitted with accelerometers during one PE session each, to determine the percentage (%) of the PE session time spent in sedentary (SPA), light (LPA), moderate (MPA), vigorous (VPA) and moderate-to-vigorous (MVPA) intensity levels. Two- and three-level (pupils, n = 307; classes, n = 13, schools, n = 6) mixed-effect models were used to assess the relationship between accelerometer-measured physical activity levels (% of class time spent in various activity levels) and gender, activity type, class location and composition. RESULTS: Participants engaged in MVPA and VPA for 30.7 ± 1.2% and 11.5 ± 0.8% of PE classes, respectively. Overall, no significant association between gender or class composition and PA was shown. A significant relationship between activity type and PA was observed, with Artistic classes significantly less active than Fitness classes for VPA (5.4 ± 4.5 vs. 12.5 ± 7.1%, p = 0.043, d:1.19). We also found a significant association between class location and PA, with significantly less time spent in SPA (24.8 ± 4.8% vs. 30.0 ± 3.4%, p = 0.042, d:0.77) and significantly more time spent in VPA (12.4 ± 3.7% vs. 7.6 ± 2.0%, p = 0.022, d:1.93) and MVPA (32.3 ± 6.7% vs.24.8 ± 3.8%, p = 0.024, d:1.33) in outdoors vs. indoors classes. CONCLUSIONS: The results suggest that class location and activity type could be associated with the intensity of PA in PE. It is essential to take into account the clustered nature of this type of data in similar studies if the sample size allows it.

Perceptions of active and inactive prototypes are associated with objective measures of physical activity in adolescents.

The benefits of physical activity are known, but the proportion of adolescents meeting daily activity guidelines remains low. The Theory of Planned Behaviour (TPB), which assumes reasoned intentions explain actions, is a useful framework for predicting activity, but it leaves variance unexplained. The Prototype Willingness Model (PWM) which builds on the TPB, proposes a reasoned action pathway and a second social reactive pathway in which perceptions of social images, or prototypes, explain actions via behavioural willingness. We explored whether variables in the PWM's social reactive pathway explained variance in an objective measure of daily activity, over and above the reasoned action path. Participants aged 12-13 (n = 205) were invited to complete measures of constructs in the PWM and to wear an accelerometer for the next seven days. Overall, 126 students (65 males) participated. Reasoned intentions, attitudes and subjective norms explained 12.8% of variance in activity. Prototype perceptions and willingness explained an additional 13.1% of variance. Participants' perceived similarity to active prototypes, and unfavourable perceptions of inactive prototypes, significantly predicted activity. There were no significant differences between sexes on psychological variables. These findings highlight the importance of targeting prototype perceptions to encourage physical activity in this age group.

Modulating Regional Motor Cortical Excitability with Noninvasive Brain Stimulation Results in Neurochemical Changes in Bilateral Motor Cortices.

Learning a novel motor skill is dependent both on regional changes within the primary motor cortex (M1) contralateral to the active hand and also on modulation between and within anatomically distant but functionally connected brain regions. Interregional changes are particularly important in functional recovery after stroke, when critical plastic changes underpinning behavioral improvements are observed in both ipsilesional and contralesional M1s. It is increasingly understood that reduction in GABA in the contralateral M1 is necessary to allow learning of a motor task. However, the physiological mechanisms underpinning plasticity within other brain regions, most importantly the ipsilateral M1, are not well understood. Here, we used concurrent two-voxel magnetic resonance spectroscopy to simultaneously quantify changes in neurochemicals within left and right M1s in healthy humans of both sexes in response to transcranial direct current stimulation (tDCS) applied to left M1. We demonstrated a decrease in GABA in both the stimulated (left) and nonstimulated (right) M1 after anodal tDCS, whereas a decrease in GABA was only observed in nonstimulated M1 after cathodal stimulation. This GABA decrease in the nonstimulated M1 during cathodal tDCS was negatively correlated with microstructure of M1:M1 callosal fibers, as quantified by diffusion MRI, suggesting that structural features of these fibers may mediate GABA decrease in the unstimulated region. We found no significant changes in glutamate. Together, these findings shed light on the interactions between the two major network nodes underpinning motor plasticity, offering a potential framework from which to optimize future interventions to improve motor function after stroke.SIGNIFICANCE STATEMENT Learning of new motor skills depends on modulation both within and between brain regions. Here, we use a novel two-voxel magnetic resonance spectroscopy approach to quantify GABA and glutamate changes concurrently within the left and right primary motor cortex (M1) during three commonly used transcranial direct current stimulation montages: anodal, cathodal, and bilateral. We also examined how the neurochemical changes in the unstimulated hemisphere were related to white matter microstructure between the two M1s. Our results provide insights into the neurochemical changes underlying motor plasticity and may therefore assist in the development of further adjunct therapies.

Relating diffusion tensor imaging measurements to microstructural quantities in the cerebral cortex in multiple sclerosis.

To investigate whether the observed anisotropic diffusion in cerebral cortex may reflect its columnar cytoarchitecture and myeloarchitecture, as a potential biomarker for disease-related changes, we compared postmortem diffusion magnetic resonance imaging scans of nine multiple sclerosis brains with histology measures from the same regions. Histology measurements assessed the cortical minicolumnar structure based on cell bodies and associated axon bundles in dorsolateral prefrontal cortex (Area 9), Heschl's gyrus (Area 41), and primary visual cortex (V1). Diffusivity measures included mean diffusivity, fractional anisotropy of the cortex, and three specific measures that may relate to the radial minicolumn structure: the angle of the principal diffusion direction in the cortex, the component that was perpendicular to the radial direction, and the component that was parallel to the radial direction. The cellular minicolumn microcircuit features were correlated with diffusion angle in Areas 9 and 41, and the axon bundle features were correlated with angle in Area 9 and to the parallel component in V1 cortex. This may reflect the effect of minicolumn microcircuit organisation on diffusion in the cortex, due to the number of coherently arranged membranes and myelinated structures. Several of the cortical diffusion measures showed group differences between MS brains and control brains. Differences between brain regions were also found in histology and diffusivity measurements consistent with established regional variation in cytoarchitecture and myeloarchitecture. Therefore, these novel measures may provide a surrogate of cortical organisation as a potential biomarker, which is particularly relevant for detecting regional changes in neurological disorders.

The role of diffusion MRI in neuroscience.

Diffusion-weighted imaging has pushed the boundaries of neuroscience by allowing us to examine the white matter microstructure of the living human brain. By doing so, it has provided answers to fundamental neuroscientific questions, launching a new field of research that had been largely inaccessible. We briefly summarize key questions that have historically been raised in neuroscience concerning the brain's white matter. We then expand on the benefits of diffusion-weighted imaging and its contribution to the fields of brain anatomy, functional models and plasticity. In doing so, this review highlights the invaluable contribution of diffusion-weighted imaging in neuroscience, presents its limitations and proposes new challenges for future generations who may wish to exploit this powerful technology to gain novel insights.

Artificial limb representation in amputees.

The human brain contains multiple hand-selective areas, in both the sensorimotor and visual systems. Could our brain repurpose neural resources, originally developed for supporting hand function, to represent and control artificial limbs? We studied individuals with congenital or acquired hand-loss (hereafter one-handers) using functional MRI. We show that the more one-handers use an artificial limb (prosthesis) in their everyday life, the stronger visual hand-selective areas in the lateral occipitotemporal cortex respond to prosthesis images. This was found even when one-handers were presented with images of active prostheses that share the functionality of the hand but not necessarily its visual features (e.g. a 'hook' prosthesis). Further, we show that daily prosthesis usage determines large-scale inter-network communication across hand-selective areas. This was demonstrated by increased resting state functional connectivity between visual and sensorimotor hand-selective areas, proportional to the intensiveness of everyday prosthesis usage. Further analysis revealed a 3-fold coupling between prosthesis activity, visuomotor connectivity and usage, suggesting a possible role for the motor system in shaping use-dependent representation in visual hand-selective areas, and/or vice versa. Moreover, able-bodied control participants who routinely observe prosthesis usage (albeit less intensively than the prosthesis users) showed significantly weaker associations between degree of prosthesis observation and visual cortex activity or connectivity. Together, our findings suggest that altered daily motor behaviour facilitates prosthesis-related visual processing and shapes communication across hand-selective areas. This neurophysiological substrate for prosthesis embodiment may inspire rehabilitation approaches to improve usage of existing substitutionary devices and aid implementation of future assistive and augmentative technologies.

Transcranial direct current stimulation for promoting motor function in cerebral palsy: a review.

Transcranial direct current stimulation (tDCS) has the potential to improve motor function in a range of neurological conditions, including Cerebral Palsy (CP). Although there have been many studies assessing tDCS in adult stroke, the literature regarding the efficacy of tDCS in CP is more limited. This review therefore focuses on the neurophysiological and clinical findings in children and adolescents with CP. Initial studies applying anodal tDCS to promote lower limb function are promising, with improvements in gait, mobility and balance reported. However, the results of upper limb studies are mixed and more research is needed. Studies investigating neurophysiological changes or predictors of response are also lacking. Large-scale longitudinal studies are needed for the lower limb to ascertain whether the initial pilot results translate into clinically meaningful improvements. Future studies of the upper limb should focus on determining the optimal stimulation parameters and consider tailoring stimulation to the individual based on the (re)organisation of their motor system.

Investigating the Stability of Fine-Grain Digit Somatotopy in Individual Human Participants.

Studies of human primary somatosensory cortex (S1) have placed a strong emphasis on the cortical representation of the hand and the propensity for plasticity therein. Despite many reports of group differences and experience-dependent changes in cortical digit somatotopy, relatively little work has considered the variability of these maps across individuals and to what extent this detailed functional architecture is dynamic over time. With the advent of 7 T fMRI, it is increasingly feasible to map such detailed organization noninvasively in individual human participants. Here, we extend the ability of ultra-high-field imaging beyond a technological proof of principle to investigate the intersubject variability of digit somatotopy across participants and the stability of this organization across a range of intervals. Using a well validated phase-encoding paradigm and an active task, we demonstrate the presence of highly reproducible maps of individual digits in S1, sharply contrasted by a striking degree of intersubject variability in the shape, extent, and relative position of individual digit representations. Our results demonstrate the presence of very stable fine-grain somatotopy of the digits in human S1 and raise the issue of population variability in such detailed functional architecture of the human brain. These findings have implications for the study of detailed sensorimotor plasticity in the context of both learning and pathological dysfunction. The simple task and 10 min scan required to derive these maps also raises the potential for this paradigm as a tool in the clinical setting. SIGNIFICANCE STATEMENT: We applied ultra-high-resolution fMRI at 7 T to map sensory digit representations in the human primary somatosensory cortex (S1) at the level of individual participants across multiple time points. The resulting fine-grain maps of individual digits in S1 reveal the stability in this fine-grain functional organization over time, contrasted with the variability in these maps across individuals.

Using diffusion imaging to study human connectional anatomy.

Diffusion imaging can be used to estimate the routes taken by fiber pathways connecting different regions of the living brain. This approach has already supplied novel insights into in vivo human brain anatomy. For example, by detecting where connection patterns change, one can define anatomical borders between cortical regions or subcortical nuclei in the living human brain for the first time. Because diffusion tractography is a relatively new technique, however, it is important to assess its validity critically. We discuss the degree to which diffusion tractography meets the requirements of a technique to assess structural connectivity and how its results compare to those from the gold-standard tract tracing methods in nonhuman animals. We conclude that although tractography offers novel opportunities it also raises significant challenges to be addressed by further validation studies to define precisely the limitations and scope of this exciting new technique.