Multimodal neuroimaging correlates of physical-cognitive covariation in Chilean adolescents. The Cogni-Action Project.

Health-related behaviours have been related to brain structural features. In developing settings, such as Latin America, high social inequality has been inversely associated with several health-related behaviours affecting brain development. Understanding the relationship between health behaviours and brain structure in such settings is particularly important during adolescence when critical habits are acquired and ingrained. In this cross-sectional study, we carry out a multimodal analysis identifying a brain region associated with health-related behaviours (i.e., adiposity, fitness, sleep problems and others) and cognitive/academic performance, independent of socioeconomic status in a large sample of Chilean adolescents. Our findings suggest that the relationship between health behaviours and cognitive/academic performance involves a particular brain phenotype that could play a mediator role. These findings fill a significant gap in the literature, which has largely focused on developed countries and raise the possibility of promoting healthy behaviours in adolescence as a means to influence brain structure and thereby cognitive/academic achievement, independently of socioeconomic factors. By highlighting the potential impact on brain structure and cognitive/academic achievement, policymakers could design interventions that are more effective in reducing health disparities in developing countries.

Motor learning in developmental coordination disorder: behavioral and neuroimaging study.

Developmental coordination disorder (DCD) is characterized by motor learning deficits that are poorly understood within whole-body activities context. Here we present results of one of the largest non-randomized interventional trials combining brain imaging and motion capture techniques to examine motor skill acquisition and its underpinning mechanisms in adolescents with and without DCD. A total of 86 adolescents with low fitness levels (including 48 with DCD) were trained on a novel stepping task for a duration of 7 weeks. Motor performance during the stepping task was assessed under single and dual-task conditions. Concurrent cortical activation in the prefrontal cortex (PFC) was measured using functional near-infrared spectroscopy (fNIRS). Additionally, structural and functional magnetic resonance imaging (MRI) was conducted during a similar stepping task at the beginning of the trial. The results indicate that adolescents with DCD performed similarly to their peers with lower levels of fitness in the novel stepping task and demonstrated the ability to learn and improve motor performance. Both groups showed significant improvements in both tasks and under single- and dual-task conditions at post-intervention and follow-up compared to baseline. While both groups initially made more errors in the Stroop task under dual-task conditions, at follow-up, a significant difference between single- and dual-task conditions was observed only in the DCD group. Notably, differences in prefrontal activation patterns between the groups emerged at different time points and task conditions. Adolescents with DCD exhibited distinct prefrontal activation responses during the learning and performance of a motor task, particularly when complexity was increased by concurrent cognitive tasks. Furthermore, a relationship was observed between MRI brain structure and function measures and initial performance in the novel stepping task. Overall, these findings suggest that strategies that address task and environmental complexities, while simultaneously enhancing brain activity through a range of tasks, offer opportunities to increase the participation of adolescents with low fitness in physical activity and sports.

Serotonin regulation of behavior via large-scale neuromodulation of serotonin receptor networks.

Although we understand how serotonin receptors function at the single-cell level, what role different serotonin receptors play in regulating brain-wide activity and, in turn, human behavior, remains unknown. Here, we developed transcriptomic-neuroimaging mapping to characterize brain-wide functional signatures associated with specific serotonin receptors: serotonin receptor networks (SRNs). Probing SRNs with optogenetics-functional magnetic resonance imaging (MRI) and pharmacology in mice, we show that activation of dorsal raphe serotonin neurons differentially modulates the amplitude and functional connectivity of different SRNs, showing that receptors' spatial distributions can confer specificity not only at the local, but also at the brain-wide, network level. In humans, using resting-state functional MRI, SRNs replicate established divisions of serotonin effects on impulsivity and negative biases. These results provide compelling evidence that heterogeneous brain-wide distributions of different serotonin receptor types may underpin behaviorally distinct modes of serotonin regulation. This suggests that serotonin neurons may regulate multiple aspects of human behavior via modulation of large-scale receptor networks.

A macroscopic link between interhemispheric tract myelination and cortico-cortical interactions during action reprogramming.

Myelination has been increasingly implicated in the function and dysfunction of the adult human brain. Although it is known that axon myelination shapes axon physiology in animal models, it is unclear whether a similar principle applies in the living human brain, and at the level of whole axon bundles in white matter tracts. Here, we hypothesised that in humans, cortico-cortical interactions between two brain areas may be shaped by the amount of myelin in the white matter tract connecting them. As a test bed for this hypothesis, we use a well-defined interhemispheric premotor-to-motor circuit. We combined TMS-derived physiological measures of cortico-cortical interactions during action reprogramming with multimodal myelin markers (MT, R1, R2* and FA), in a large cohort of healthy subjects. We found that physiological metrics of premotor-to-motor interaction are broadly associated with multiple myelin markers, suggesting interindividual differences in tract myelination may play a role in motor network physiology. Moreover, we also demonstrate that myelination metrics link indirectly to action switching by influencing local primary motor cortex dynamics. These findings suggest that myelination levels in white matter tracts may influence millisecond-level cortico-cortical interactions during tasks. They also unveil a link between the physiology of the motor network and the myelination of tracts connecting its components, and provide a putative mechanism mediating the relationship between brain myelination and human behaviour.

Hebbian activity-dependent plasticity in white matter.

Synaptic plasticity is required for learning and follows Hebb's rule, the computational principle underpinning associative learning. In recent years, a complementary type of brain plasticity has been identified in myelinated axons, which make up the majority of brain's white matter. Like synaptic plasticity, myelin plasticity is required for learning, but it is unclear whether it is Hebbian or whether it follows different rules. Here, we provide evidence that white matter plasticity operates following Hebb's rule in humans. Across two experiments, we find that co-stimulating cortical areas to induce Hebbian plasticity leads to relative increases in cortical excitability and associated increases in a myelin marker within the stimulated fiber bundle. We conclude that Hebbian plasticity extends beyond synaptic changes and can be observed in human white matter fibers.

The importance of prototype similarity for physical activity: Cross-sectional and longitudinal associations in a large sample of young adolescents.

OBJECTIVES: Physical activity declines during adolescence. The Theory of Planned Behaviour (TPB) is a useful framework for investigating activity but leaves variance unexplained. We explored the utility of a dual-process approach using the TPB and the Prototype Willingness Model (PWM) to investigate correlates of physical activity, and 1-year change in physical activity, among a large sample of adolescents. DESIGN: A cross-sectional and longitudinal analysis of baseline and follow-up data from the Fit to Study cluster-randomized trial. METHODS: A total of 9,699 secondary school pupils at baseline and 4,632 at follow-up (mean age = 12.5 years) completed measures of past week physical activity and constructs from both behaviour-change models, at time-points 1 year apart. Cross-sectional analyses used multilevel, stepwise regression models to measure the strength of associations between model constructs and physical activity, and variance in behaviour explained by PWM over and above TPB. In longitudinal analyses, change scores were calculated by subtracting follow-up from baseline scores. Models controlling for trial treatment status measured the strength of associations between change scores, and variance explained. RESULTS: At baseline, after controlling for past behaviour, physically active prototype similarity had the strongest relationship with activity after the intention to be active. Change in prototype similarity had the strongest relationship with change in activity after the change in intention and attitudes. Prototype perceptions and willingness explained additional variance in behaviour. CONCLUSION: A dual-process model incorporating prototype perceptions could more usefully predict physical activity than models based on rational expectations alone. Behaviour-change interventions promoting an active self-image could be tested for effects on physical activity.

A triple-network organization for the mouse brain.

The triple-network model of psychopathology is a framework to explain the functional and structural neuroimaging phenotypes of psychiatric and neurological disorders. It describes the interactions within and between three distributed networks: the salience, default-mode, and central executive networks. These have been associated with brain disorder traits in patients. Homologous networks have been proposed in animal models, but their integration into a triple-network organization has not yet been determined. Using resting-state datasets, we demonstrate conserved spatio-temporal properties between triple-network elements in human, macaque, and mouse. The model predictions were also shown to apply in a mouse model for depression. To validate spatial homologies, we developed a data-driven approach to convert mouse brain maps into human standard coordinates. Finally, using high-resolution viral tracers in the mouse, we refined an anatomical model for these networks and validated this using optogenetics in mice and tractography in humans. Unexpectedly, we find serotonin involvement within the salience rather than the default-mode network. Our results support the existence of a triple-network system in the mouse that shares properties with that of humans along several dimensions, including a disease condition. Finally, we demonstrate a method to humanize mouse brain networks that opens doors to fully data-driven trans-species comparisons.

Reassessing associations between white matter and behaviour with multimodal microstructural imaging.

Several studies have established specific relationships between White Matter (WM) and behaviour. However, these studies have typically focussed on fractional anisotropy (FA), a neuroimaging metric that is sensitive to multiple tissue properties, making it difficult to identify what biological aspects of WM may drive such relationships. Here, we carry out a pre-registered assessment of WM-behaviour relationships in 50 healthy individuals across multiple behavioural and anatomical domains, and complementing FA with myelin-sensitive quantitative MR modalities (MT, R1, R2∗). Surprisingly, we only find support for predicted relationships between FA and behaviour in one of three pre-registered tests. For one behavioural domain, where we failed to detect an FA-behaviour correlation, we instead find evidence for a correlation between behaviour and R1. This hints that multimodal approaches are able to identify a wider range of WM-behaviour relationships than focusing on FA alone. To test whether a common biological substrate such as myelin underlies WM-behaviour relationships, we then ran joint multimodal analyses, combining across all MRI parameters considered. No significant multimodal signatures were found and power analyses suggested that sample sizes of 40-200 may be required to detect such joint multimodal effects, depending on the task being considered. These results demonstrate that FA-behaviour relationships from the literature can be replicated, but may not be easily generalisable across domains. Instead, multimodal microstructural imaging may be best placed to detect a wider range of WM-behaviour relationships, as different MRI modalities provide distinct biological sensitivities. Our findings highlight a broad heterogeneity in WM's relationship with behaviour, suggesting that variable biological effects may be shaping their interaction.

Frequency modulation of entorhinal cortex neuronal activity drives distinct frequency-dependent states of brain-wide dynamics.

Human neuroimaging studies have shown that, during cognitive processing, the brain undergoes dynamic transitions between multiple, frequency-tuned states of activity. Although different states may emerge from distinct sources of neural activity, it remains unclear whether single-area neuronal spiking can also drive multiple dynamic states. In mice, we ask whether frequency modulation of the entorhinal cortex activity causes dynamic states to emerge and whether these states respond to distinct stimulation frequencies. Using hidden Markov modeling, we perform unsupervised detection of transient states in mouse brain-wide fMRI fluctuations induced via optogenetic frequency modulation of excitatory neurons. We unveil the existence of multiple, frequency-dependent dynamic states, invisible through standard static fMRI analyses. These states are linked to different anatomical circuits and disrupted in a frequency-dependent fashion in a transgenic model of cognitive disease directly related to entorhinal cortex dysfunction. These findings provide cross-scale insight into basic neuronal mechanisms that may underpin flexibility in brain-wide dynamics.

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.

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.

Associations between fitness, physical activity and mental health in a community sample of young British adolescents: baseline data from the Fit to Study trial.

OBJECTIVES: To examine relationships between fitness, physical activity and psychosocial problems among English secondary school pupils and to explore how components of physically active lifestyles are associated with mental health and well-being. METHODS: A total of 7385 participants aged 11-13 took a fitness test and completed self-reported measures of physical activity, attitudes to activity, psychosocial problems and self-esteem during the Fit to Study trial. Multilevel regression, which modelled school-level cluster effects, estimated relationships between activity, fitness and psychosocial problems; canonical correlation analysis (CCA) explored modes of covariation between active lifestyle and mental health variables. Models were adjusted for covariates of sex, free school meal status, age, and time and location of assessments. RESULTS: Higher fitness was linked with fewer internalising problems (ß=-0.23; 95% CI -0.26 to -0.21; p<0.001). More activity was also related to fewer internalising symptoms (ß=-0.24; 95% CI -0.27 to -0.20; p<0.001); the relationship between activity and internalising problems was significantly stronger for boys than for girls. Fitness and activity were also favourably related to externalising symptoms, with smaller effect sizes. One significant CCA mode, with a canonical correlation of 0.52 (p=0.001), was characterised high cross-loadings for positive attitudes to activity (0.46) and habitual activity (0.42) among lifestyle variables; and for physical and global self-esteem (0.47 and 0.42) among mental health variables. CONCLUSION: Model-based and data-driven analysis methods indicate fitness as well as physical activity are linked to adolescent mental health. If effect direction is established, fitness monitoring could complement physical activity measurement when tracking public health.

Language ability in preterm children is associated with arcuate fasciculi microstructure at term.

In the mature human brain, the arcuate fasciculus mediates verbal working memory, word learning, and sublexical speech repetition. However, its contribution to early language acquisition remains unclear. In this work, we aimed to evaluate the role of the direct segments of the arcuate fasciculi in the early acquisition of linguistic function. We imaged a cohort of 43 preterm born infants (median age at birth of 30 gestational weeks; median age at scan of 42 postmenstrual weeks) using high b value high-angular resolution diffusion-weighted neuroimaging and assessed their linguistic performance at 2 years of age. Using constrained spherical deconvolution tractography, we virtually dissected the arcuate fasciculi and measured fractional anisotropy (FA) as a metric of white matter development. We found that term equivalent FA of the left and right arcuate fasciculi was significantly associated with individual differences in linguistic and cognitive abilities in early childhood, independent of the degree of prematurity. These findings suggest that differences in arcuate fasciculi microstructure at the time of normal birth have a significant impact on language development and modulate the first stages of language learning. Hum Brain Mapp 38:3836-3847, 2017. © 2017 Wiley Periodicals, Inc.

Road work on memory lane--functional and structural alterations to the learning and memory circuit in adults born very preterm.

Very preterm (VPT) birth is considered a risk factor not only for neurological impairment, but also for reduced function in several cognitive domains in childhood and later in life. Individuals who were born VPT are more likely to demonstrate learning and memory difficulties compared to term-born controls. These problems contribute to more VPT-born children repeating grades and underachieving in school. This, in turn, affects their prospects in adult life. Here we aimed to 1) study how the VPT-born adult brain functionally recruited specific areas during learning, i.e. encoding and recall across four repeated blocks of verbal stimuli, and to investigate how these patterns of activation differed from term-born subjects; and 2) probe the microstructural differences of white-matter tracts connecting these areas to other parts of the learning and memory network. To investigate these functional-structural relationships we analyzed functional and diffusion-weighted MRI. Functional-MRI and a verbal paired associate learning (VPAL) task were used to extract Blood Oxygenation Level Dependent (BOLD) activity in 21 VPT-born adults (<33 weeks of gestation) (mean age: 19.68 years ± 0.85; IQ: 99.86 ± 11.20) and 10 term-born controls (mean age: 19.87 years ± 2.04; IQ: 108.9 ± 13.18). Areas in which differences in functional activation were observed between groups were used as seed regions for tractography. Fractional anisotropy (FA) of the tract-skeleton was then compared between groups on a voxel-wise basis. Results of functional MRI analysis showed a significantly different pattern of activation between groups during encoding in right anterior cingulate-caudate body, and during retrieval in left thalamus, hippocampus and parts of left posterior parahippocampal gyrus. The number of correctly recalled word pairs did not statistically differ between individuals who were born VPT and controls. The VPT-born group was found to have reduced FA in tracts passing through the thalamic/hippocampal region that was differently activated during the recall condition, with the hippocampal fornix, inferior longitudinal fasciculus and inferior fronto-occipital fasciculus particularly affected. Young adults who were born very preterm display a strikingly different pattern of activation during the process of learning in key structures of the learning and memory network, including anterior cingulate and caudate body during encoding and thalamus/parahippocampal gyrus during cued recall. Altered activation in thalamus/parahippocampal gyrus may be explained by reduced connections between these areas and the hippocampus, which may be a direct consequence of neonatal hypoxic/ischemic injury. These results could reflect the effect of adaptive plastic processes associated with high-order cognitive functions, at least when the cognitive load remains relatively low, as ex-preterm young adults displayed unimpaired performance in completing the verbal paired associate learning task.