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1.  Changes in white matter microstructure in the developing brain—A longitudinal diffusion tensor imaging study of children from 4 to 11 years of age 
Neuroimage  2016;124(Pt A):473-486.
The purpose of the present study was to detail the childhood developmental course of different white matter (WM) characteristics. In a longitudinal diffusion tensor imaging (DTI) study of 159 healthy children between 4 and 11 years scanned twice, we used tract-based spatial statistics as well as delineation of 15 major WM tracts to characterize the regional pattern of change in fractional anisotropy (FA), mean (MD), radial (RD) and axial diffusivity (AD). We tested whether there were decelerations of change with increasing age globally and tract-wise, and also illustrated change along medial-to-lateral, posterior-to-anterior and inferior-to-superior gradients. We found a significant linear increase in global FA, and decrease in MD and RD over time. For mean AD, a weak decrease was observed. The developmental changes in specific WM tracts showed regional differences. Eight WM tracts showed non-linear development patterns for one or several DTI metrics, with a deceleration in change with age. Sex did not affect change in any DTI metric. Overall, greater rate of change was found in the left hemisphere. Spatially, there was a posterior-to-anterior gradient of change with greater change in frontal regions for all metrics. The current study provides a comprehensive characterization of the regional patters of change in WM microstructure across pre-adolescence childhood.
Highlights
•We explore longitudinal change in white matter (WM) microstructure in children.•Using TBSS to delineate 15 WM tracts and several gradients in the brain•Global WM change show linear developmental patterns from age 4 to 11 years.•Greater WM change in the anterior compared to the posterior brain region.•The developmental patterns for WM tracts show regional differences.
doi:10.1016/j.neuroimage.2015.09.017
PMCID: PMC4655940  PMID: 26375208
WM, White matter; DTI, Diffusion tensor imaging; FA, fractional anisotropy; MD, Mean diffusivity; RD, Radial diffusivity; AD, Axial diffusivity; LCBC, Research Group for Lifespan Changes in Brain and Cognition; MoBa, Norwegian Mother and Child Cohort Study; tp1, Time point one; tp2, Time point two; MRI, Magnetic resonance imaging; CNS, Central nervous system; TR, Repetition time; TE, Echo time; GRAPPA, GeneRalized Autocalibrating Partially Parallel Acquisition; FMRIB, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain; TBSS, Tract-Based Spatial Statistics; GLM, General linear model; SDR, Studentized Deleted Residuals; GAMM, General additive mixed model; JHU, Johns Hopkins University; ATR, Anterior thalamic radiation; CCG, Cingulum-cingulate gyrus; CHG, Cingulum-hippocampus gyrus; CC, corpus callosum; IFOF, Inferior fronto-occipital fasciculus; ILF, Inferior longitudinal fasciculus; SLF, Superior fronto-occipital fasciculus; SFOF, Superior fronto-occipital fasciculus; UF, Uncinate fasciculus; Development; White matter maturation; MRI; DTI; Longitudinal; Children
2.  An Ultra-High Field Magnetic Resonance Spectroscopy Study of Post Exercise Lactate, Glutamate and Glutamine Change in the Human Brain 
During strenuous exercise there is a progressive increase in lactate uptake and metabolism into the brain as workload and plasma lactate levels increase. Although it is now widely accepted that the brain can metabolize lactate, few studies have directly measured brain lactate following vigorous exercise. Here, we used ultra-high field magnetic resonance spectroscopy of the brain to obtain static measures of brain lactate, as well as brain glutamate and glutamine after vigorous exercise. The aims of our experiment were to (a) track the changes in brain lactate following recovery from exercise, and (b) to simultaneously measure the signals from brain glutamate and glutamine. The results of our experiment showed that vigorous exercise resulted in a significant increase in brain lactate. Furthermore, both glutamate and glutamine were successfully resolved, and as expected, although contrary to some previous reports, we did not observe any significant change in either amino acid after exercise. We did however observe a negative correlation between glutamate and a measure of fitness. These results support the hypothesis that peripherally derived lactate is taken up by the brain when available. Our data additionally highlight the potential of ultra-high field MRS as a non-invasive way of measuring multiple brain metabolite changes with exercise.
doi:10.3389/fphys.2015.00351
PMCID: PMC4681779  PMID: 26732236
brain; lactate; glutamate; magnetic resonance spectroscopy; exercise
3.  Sleep and Motor Learning: Implications for Physical Rehabilitation After Stroke 
Sleep is essential for healthy brain function and plasticity underlying learning and memory. In the context of physical impairment such as following a stroke, sleep may be particularly important for supporting critical recovery of motor function through similar processes of reorganization in the brain. Despite a link between stroke and poor sleep, current approaches to rehabilitative care often neglect the importance of sleep in clinical assessment and treatment. This review assimilates current evidence on the role of sleep in motor learning, with a focus on the implications for physical rehabilitation after stroke. We further outline practical considerations for integrating sleep assessment as a vital part of clinical care.
doi:10.3389/fneur.2015.00241
PMCID: PMC4656813  PMID: 26635718
sleep; motor memory; consolidation; plasticity and learning; rehabilitation; motor recovery; stroke; aging
4.  Modulation of GABA and resting state functional connectivity by transcranial direct current stimulation 
eLife  null;4:e08789.
We previously demonstrated that network level functional connectivity in the human brain could be related to levels of inhibition in a major network node at baseline (Stagg et al., 2014). In this study, we build upon this finding to directly investigate the effects of perturbing M1 GABA and resting state functional connectivity using transcranial direct current stimulation (tDCS), a neuromodulatory approach that has previously been demonstrated to modulate both metrics. FMRI data and GABA levels, as assessed by Magnetic Resonance Spectroscopy, were measured before and after 20 min of 1 mA anodal or sham tDCS. In line with previous studies, baseline GABA levels were negatively correlated with the strength of functional connectivity within the resting motor network. However, although we confirm the previously reported findings that anodal tDCS reduces GABA concentration and increases functional connectivity in the stimulated motor cortex; these changes are not correlated, suggesting they may be driven by distinct underlying mechanisms.
DOI: http://dx.doi.org/10.7554/eLife.08789.001
doi:10.7554/eLife.08789
PMCID: PMC4654253  PMID: 26381352
brain stimulation; GABA; tDCS; resting state networks; functional connectivity; plasticity; human
5.  Imaging Surrogates of Disease Activity in Neuromyelitis Optica Allow Distinction from Multiple Sclerosis 
PLoS ONE  2015;10(9):e0137715.
Inflammatory demyelinating lesions of the central nervous system are a common feature of both neuromyelitis optica and multiple sclerosis. Despite this similarity, it is evident clinically that the accumulation of disability in patients with neuromyelitis optica is relapse related and that a progressive phase is very uncommon. This poses the question whether there is any pathological evidence of disease activity or neurodegeneration in neuromyelitis optica between relapses. To investigate this we conducted a longitudinal advanced MRI study of the brain and spinal cord in neuromyelitis optica patients, comparing to patients with multiple sclerosis and controls. We found both cross-sectional and longitudinal evidence of diffusely distributed neurodegenerative surrogates in the multiple sclerosis group (including thalamic atrophy, cervical cord atrophy and progressive widespread diffusion and myelin water imaging abnormalities in the normal appearing white matter) but not in those with neuromyelitis optica, where localised abnormalities in the optic radiations of those with severe visual impairment were noted. In addition, between relapses, there were no new silent brain lesions in the neuromyelitis optica group. These findings indicate that global central nervous system neurodegeneration is not a feature of neuromyelitis optica. The work also questions the theory that neurodegeneration in multiple sclerosis is a chronic sequela to prior inflammatory and demyelinating pathology, as this has not been found to be the case in neuromyelitis optica where the lesions are often more destructive.
doi:10.1371/journal.pone.0137715
PMCID: PMC4575169  PMID: 26381510
6.  Network-level reorganisation of functional connectivity following arm amputation 
Neuroimage  2015;114:217-225.
One of the most striking demonstrations of plasticity in the adult human brain follows peripheral injury, such as amputation. In the primary sensorimotor cortex, arm amputation results in massive local remapping of the missing hands' cortical territory. However, little is known about the consequences of sensorimotor deprivation on global brain organisation. Here, we used resting-state fMRI to identify large-scale reorganisation beyond the primary sensorimotor cortex in arm amputees, compared with two-handed controls. Specifically, we characterised changes in functional connectivity between the cortical territory of the missing hand in the primary sensorimotor cortex (‘missing hand cortex’) and two networks of interest: the sensorimotor network, which is typically strongly associated with the hand cortex, and the default mode network (DMN), which is normally dissociated from it. Functional connectivity values between the missing hand cortex and the sensorimotor network were reduced in amputees, and connectivity was weaker in individuals amputated for longer periods. Lower levels of functional coupling between the missing hand cortex and the sensorimotor network were also associated with emerged coupling of this cortex with the DMN. Our results demonstrate that plasticity following arm amputation is not restricted to local remapping occurring within the sensorimotor homunculus of the missing hand but rather produces a cascade of cortical reorganisation at a network-level scale. These findings may provide a new framework for understanding how local deprivation following amputation could elicit complex perceptual experiences of phantom sensations, such as phantom pain.
doi:10.1016/j.neuroimage.2015.02.067
PMCID: PMC4461307  PMID: 25776216
Neuroimaging; Deprivation; Plasticity; Resting state networks; Somatosensory; Motor
7.  Reassessing cortical reorganization in the primary sensorimotor cortex following arm amputation 
Brain  2015;138(8):2140-2146.
The brain’s ability to reorganise itself is key to our recovery from injuries, but the subsequent mismatch between old and new organisation may lead to pain. Makin et al. argue against this ‘maladaptive plasticity’ theory by showing that phantom pain in upper limb amputees is independent of cortical remapping.
The brain’s ability to reorganise itself is key to our recovery from injuries, but the subsequent mismatch between old and new organisation may lead to pain. Makin et al. argue against this ‘maladaptive plasticity’ theory by showing that phantom pain in upper limb amputees is independent of cortical remapping.
The role of cortical activity in generating and abolishing chronic pain is increasingly emphasized in the clinical community. Perhaps the most striking example of this is the maladaptive plasticity theory, according to which phantom pain arises from remapping of cortically neighbouring representations (lower face) into the territory of the missing hand following amputation. This theory has been extended to a wide range of chronic pain conditions, such as complex regional pain syndrome. Yet, despite its growing popularity, the evidence to support the maladaptive plasticity theory is largely based on correlations between pain ratings and oftentimes crude measurements of cortical reorganization, with little consideration of potential contributions of other clinical factors, such as adaptive behaviour, in driving the identified brain plasticity. Here, we used a physiologically meaningful measurement of cortical reorganization to reassess its relationship to phantom pain in upper limb amputees. We identified small yet consistent shifts in lip representation contralateral to the missing hand towards, but not invading, the hand area. However, we were unable to identify any statistical relationship between cortical reorganization and phantom sensations or pain either with this measurement or with the traditional Euclidian distance measurement. Instead, we demonstrate that other factors may contribute to the observed remapping. Further research that reassesses more broadly the relationship between cortical reorganization and chronic pain is warranted.
doi:10.1093/brain/awv161
PMCID: PMC4511862  PMID: 26072517
pain; plasticity; amputees; functional MRI; phantom pain
8.  Ventral Striatum/Nucleus Accumbens Activation to Smoking-Related Pictorial Cues in Smokers and Nonsmokers: A Functional Magnetic Resonance Imaging Study 
Biological psychiatry  2005;58(6):488-494.
Background
Converging evidence from several theories of the development of incentive-sensitization to smoking-related environmental stimuli suggests that the ventral striatum plays an important role in the processing of smoking-related cue reactivity.
Methods
Twenty-six healthy right-handed volunteers (14 smokers and 12 nonsmoking controls) underwent functional magnetic resonance imaging (fMRI) during which neutral and smoking-related images were presented. Region of interest analyses were performed within the ventral striatum/nucleus accumbens (VS/NAc) for the contrast between smoking-related (SR) and nonsmoking related neutral (N) cues.
Results
Group activation for SR versus N cues was observed in smokers but not in nonsmokers in medial orbitofrontal cortex, superior frontal gyrus, anterior cingulate cortex, and posterior fusiform gyrus using whole-brain corrected Z thresholds and in the ventral VS/NAc using uncorrected Z-statistics (smokers Z = 3.2). Region of interest analysis of signal change within ventral VS/NAc demonstrated significantly greater activation to SR versus N cues in smokers than controls.
Conclusions
This is the first demonstration of greater VS/NAc activation in addicted smokers than nonsmokers presented with smoking-related cues using fMRI. Smokers, but not controls, demonstrated activation to SR versus N cues in a distributed reward signaling network consistent with cue reactivity studies of other drugs of abuse.
doi:10.1016/j.biopsych.2005.04.028
PMCID: PMC4439461  PMID: 16023086
Nucleus accumbens; smoking; nicotine; tobacco; cue reactivity; fMRI
9.  Accelerated Changes in White Matter Microstructure during Aging: A Longitudinal Diffusion Tensor Imaging Study 
The Journal of Neuroscience  2014;34(46):15425-15436.
It is well established that human brain white matter structure changes with aging, but the timescale and spatial distribution of this change remain uncertain. Cross-sectional diffusion tensor imaging (DTI) studies indicate that, after a period of relative stability during adulthood, there is an accelerated decline in anisotropy and increase in diffusivity values during senescence; and, spatially, results have been discussed within the context of several anatomical frameworks. However, inferring trajectories of change from cross-sectional data can be challenging; and, as yet, there have been no longitudinal reports of the timescale and spatial distribution of age-related white matter change in healthy adults across the adult lifespan. In a longitudinal DTI study of 203 adults between 20 and 84 years of age, we used tract-based spatial statistics to characterize the pattern of annual change in fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity and examined whether there was an acceleration of change with age. We found extensive and overlapping significant annual decreases in fractional anisotropy, and increases in axial diffusivity, radial diffusivity, and mean diffusivity. Spatially, results were consistent with inferior-to-superior gradients of lesser-to-greater vulnerability. Annual change increased with age, particularly within superior regions, with age-related decline estimated to begin in the fifth decade. Charting white matter microstructural changes in healthy aging provides essential context to clinical studies, and future studies should compare age trajectories between healthy participants and at-risk populations and also explore the relationship between DTI rates of change and cognitive decline.
doi:10.1523/JNEUROSCI.0203-14.2014
PMCID: PMC4228140  PMID: 25392509
aging; DTI; lifespan; longitudinal; white matter
10.  A Tractography Analysis of Two Deep Brain Stimulation White Matter Targets for Depression 
Biological psychiatry  2008;65(4):276-282.
Background
Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCwm) or anterior limb of the internal capsule (ALIC) may be effective in treating depression. Connectivity patterns of these regions may inform on mechanisms of action for DBS of these targets.
Methods
Diffusion tensor imaging (DTI) and probabilistic tractography were performed in 13 nondepressed subjects to determine connectivity patterns of SCCwm and ALIC. Tract maps were generated for each target in each subject, and tract voxels were coded as being unique to either target or shared. Group level tract maps were generated by including only those voxels common to at least 10 of 13 (>75%) subjects.
Results
The two targets have distinct patterns of connectivity with regions of overlap. The SCCwm showed consistent ipsilateral connections to the medial frontal cortex, the full extent of the anterior and posterior cingulate, medial temporal lobe, dorsal medial thalamus, hypothalamus, nucleus accumbens, and the dorsal brainstem. The ALIC seed, in contrast, demonstrated widespread projections to frontal pole, medial temporal lobe, cerebellum, nucleus accumbens, thalamus, hypothalamus, and brainstem. Common to both targets, albeit through distinct white matter bundles, were connections to frontal pole, medial temporal lobe, nucleus accumbens, dorsal thalamus, and hypothalamus.
Conclusions
Connectivity patterns of these two DBS white matter targets suggest distinct neural networks with areas of overlap in regions implicated in depression and antidepressant response.
doi:10.1016/j.biopsych.2008.09.021
PMCID: PMC4423548  PMID: 19013554
DBS; deep brain stimulation; depression; diffusion tensor imaging; DTI; internal capsule; subgenual cingulate; tractography
11.  Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults 
Neurology  2014;83(11):967-973.
Objective:
To examine the relationship between sleep quality and cortical and hippocampal volume and atrophy within a community-based sample, explore the influence of age on results, and assess the possible confounding effects of physical activity levels, body mass index (BMI), and blood pressure.
Methods:
In 147 community-dwelling adults (92 female; age 53.9 ± 15.5 years), sleep quality was measured using the Pittsburgh Sleep Quality Index and correlated with cross-sectional measures of volume and longitudinal measures of atrophy derived from MRI scans separated by an average of 3.5 years. Exploratory post hoc analysis compared correlations between different age groups and included physical activity, BMI, and blood pressure as additional covariates.
Results:
Poor sleep quality was associated with reduced volume within the right superior frontal cortex in cross-sectional analyses, and an increased rate of atrophy within widespread frontal, temporal, and parietal regions in longitudinal analyses. Results were largely driven by correlations within adults over the age of 60, and could not be explained by variation in physical activity, BMI, or blood pressure. Sleep quality was not associated with hippocampal volume or atrophy.
Conclusions:
We found that longitudinal measures of cortical atrophy were widely correlated with sleep quality. Poor sleep quality may be a cause or a consequence of brain atrophy, and future studies examining the effect of interventions that improve sleep quality on rates of atrophy may hold key insights into the direction of this relationship.
doi:10.1212/WNL.0000000000000774
PMCID: PMC4162301  PMID: 25186857
12.  Sleep-dependent motor memory consolidation in older adults depends on task demands 
Neurobiology of Aging  2015;36(3):1409-1416.
It is often suggested that sleep-dependent consolidation of motor learning is impaired in older adults. The current study challenges this view and suggests that the degree of motor consolidation seen with sleep in older age groups depends on the kinematic demands of the task. We show that, when tested with a classic sequence learning task, requiring individuated finger movements, older adults did not show sleep-dependent consolidation. By contrast, when tested with an adapted sequence learning task, in which movements were performed with the whole hand, sleep-dependent motor improvement was observed in older adults. We suggest that age-related decline in fine motor dexterity may in part be responsible for the previously described deficit in sleep-dependent motor consolidation with aging.
doi:10.1016/j.neurobiolaging.2014.12.014
PMCID: PMC4353561  PMID: 25618616
Sleep; Motor memory; Consolidation; Aging; Fine motor skill; Sequence learning
13.  Changes in functional connectivity and GABA levels with long-term motor learning 
Neuroimage  2015;106:15-20.
Learning novel motor skills alters local inhibitory circuits within primary motor cortex (M1) (Floyer-Lea et al., 2006) and changes long-range functional connectivity (Albert et al., 2009). Whether such effects occur with long-term training is less well established. In addition, the relationship between learning-related changes in functional connectivity and local inhibition, and their modulation by practice, has not previously been tested.
Here, we used resting-state functional magnetic resonance imaging (rs-fMRI) to assess functional connectivity and MR spectroscopy to quantify GABA in primary motor cortex (M1) before and after a 6 week regime of juggling practice. Participants practiced for either 30 min (high intensity group) or 15 min (low intensity group) per day. We hypothesized that different training regimes would be reflected in distinct changes in brain connectivity and local inhibition, and that correlations would be found between learning-induced changes in GABA and functional connectivity.
Performance improved significantly with practice in both groups and we found no evidence for differences in performance outcomes between the low intensity and high intensity groups. Despite the absence of behavioral differences, we found distinct patterns of brain change in the two groups: the low intensity group showed increases in functional connectivity in the motor network and decreases in GABA, whereas the high intensity group showed decreases in functional connectivity and no significant change in GABA. Changes in functional connectivity correlated with performance outcome. Learning-related changes in functional connectivity correlated with changes in GABA.
The results suggest that different training regimes are associated with distinct patterns of brain change, even when performance outcomes are comparable between practice schedules. Our results further indicate that learning-related changes in resting-state network strength in part reflect GABAergic plastic processes.
Highlights
•Long-term learning modulated functional connectivity.•Changes in functional connectivity correlated with performance outcome.•Long-term learning decreased GABA levels.•Learning-related changes in functional connectivity correlated with changes in GABA.
doi:10.1016/j.neuroimage.2014.11.032
PMCID: PMC4405007  PMID: 25463472
Plasticity; Functional connectivity; GABA; Motor learning
14.  Normalisation of brain connectivity through compensatory behaviour, despite congenital hand absence 
eLife  null;4:e04605.
Previously we showed, using task-evoked fMRI, that compensatory intact hand usage after amputation facilitates remapping of limb representations in the cortical territory of the missing hand (Makin et al., 2013a). Here we show that compensatory arm usage in individuals born without a hand (one-handers) reflects functional connectivity of spontaneous brain activity in the cortical hand region. Compared with two-handed controls, one-handers showed reduced symmetry of hand region inter-hemispheric resting-state functional connectivity and corticospinal white matter microstructure. Nevertheless, those one-handers who more frequently use their residual (handless) arm for typically bimanual daily tasks also showed more symmetrical functional connectivity of the hand region, demonstrating that adaptive behaviour drives long-range brain organisation. We therefore suggest that compensatory arm usage maintains symmetrical sensorimotor functional connectivity in one-handers. Since variability in spontaneous functional connectivity in our study reflects ecological behaviour, we propose that inter-hemispheric symmetry, typically observed in resting sensorimotor networks, depends on coordinated motor behaviour in daily life.
DOI: http://dx.doi.org/10.7554/eLife.04605.001
doi:10.7554/eLife.04605
PMCID: PMC4281879  PMID: 25562885
neuroimaging; rehabilitation; plasticity; human
15.  FAST INdiCATE Trial protocol. Clinical efficacy of functional strength training for upper limb motor recovery early after stroke: Neural correlates and prognostic indicators 
International Journal of Stroke  2013;9(2):240-245.
Rationale
Functional strength training in addition to conventional physical therapy could enhance upper limb recovery early after stroke more than movement performance therapy plus conventional physical therapy.
Aims
To determine (a) the relative clinical efficacy of conventional physical therapy combined with functional strength training and conventional physical therapy combined with movement performance therapy for upper limb recovery; (b) the neural correlates of response to conventional physical therapy combined with functional strength training and conventional physical therapy combined with movement performance therapy; (c) whether any one or combination of baseline measures predict motor improvement in response to conventional physical therapy combined with functional strength training or conventional physical therapy combined with movement performance therapy.
Design
Randomized, controlled, observer-blind trial.
Study
The sample will consist of 288 participants with upper limb paresis resulting from a stroke that occurred within the previous 60 days. All will be allocated to conventional physical therapy combined with functional strength training or conventional physical therapy combined with movement performance therapy. Functional strength training and movement performance therapy will be undertaken for up to 1·5 h/day, five-days/week for six-weeks.
Outcomes and Analysis
Measurements will be undertaken before randomization, six-weeks thereafter, and six-months after stroke. Primary efficacy outcome will be the Action Research Arm Test. Explanatory measurements will include voxel-wise estimates of brain activity during hand movement, brain white matter integrity (fractional anisotropy), and brain–muscle connectivity (e.g. latency of motor evoked potentials). The primary clinical efficacy analysis will compare treatment groups using a multilevel normal linear model adjusting for stratification variables and for which therapist administered the treatment. Effect of conventional physical therapy combined with functional strength training versus conventional physical therapy combined with movement performance therapy will be summarized using the adjusted mean difference and 95% confidence interval. To identify the neural correlates of improvement in both groups, we will investigate associations between change from baseline in clinical outcomes and each explanatory measure. To identify baseline measurements that independently predict motor improvement, we will develop a multiple regression model.
doi:10.1111/ijs.12179
PMCID: PMC4228758  PMID: 24025033
functional strength training; movement performance therapy; neuroimaging; physical therapy; rehabilitation; stroke; upper limb
16.  Function in the Human Connectome: Task-fMRI and Individual Differences in Behavior 
NeuroImage  2013;80:169-189.
The primary goal of the Human Connectome Project (HCP) is to delineate the typical patterns of structural and functional connectivity in the healthy adult human brain. However, we know that there are important individual differences in such patterns of connectivity, with evidence that this variability is associated with alterations in important cognitive and behavioral variables that affect real world function. The HCP data will be a critical stepping-off point for future studies that will examine how variation in human structural and functional connectivity play a role in adult and pediatric neurological and psychiatric disorders that account for a huge amount of public health resources. Thus, the HCP is collecting behavioral measures of a range of motor, sensory, cognitive and emotional processes that will delineate a core set of functions relevant to understanding the relationship between brain connectivity and human behavior. In addition, the HCP is using task-fMRI (tfMRI) to help delineate the relationships between individual differences in the neurobiological substrates of mental processing and both functional and structural connectivity, as well as to help characterize and validate the connectivity analyses to be conducted on the structural and functional connectivity data. This paper describes the logic and rationale behind the development of the behavioral, individual difference, and tfMRI batteries and provides preliminary data on the patterns of activation associated with each of the fMRI tasks, at both a group and individual level.
doi:10.1016/j.neuroimage.2013.05.033
PMCID: PMC4011498  PMID: 23684877
Cognitive; Emotion; Sensory and Motor Function; Individual Differences; Task-fMRI; Personality; Connectivity
17.  Glial Biology in Learning and Cognition 
Neurons are exquisitely specialized for rapid electrical transmission of signals, but some properties of glial cells, which do not communicate with electrical impulses, are well suited for participating in complex cognitive functions requiring broad spatial integration and long-term temporal regulation. Astrocytes, microglia, and oligodendrocytes all have biological properties that could influence learning and cognition. Myelination by oligodendrocytes increases conduction velocity, affecting spike timing and oscillations in neuronal activity. Astrocytes can modulate synaptic transmission and may couple multiple neurons and synapses into functional assemblies. Microglia can remove synapses in an activity-dependent manner altering neural networks. Incorporating glia into a bicellular mechanism of nervous system function may help answer long-standing questions concerning the cellular mechanisms of learning and cognition.
doi:10.1177/1073858413504465
PMCID: PMC4161624  PMID: 24122821
memory; astrocyte; microglia; oligodendrocyte; myelin; synaptic plasticity; neuron–glia interactions
18.  Gray matter volume is associated with rate of subsequent skill learning after a long term training intervention 
Neuroimage  2014;96(100):158-166.
The ability to predict learning performance from brain imaging data has implications for selecting individuals for training or rehabilitation interventions. Here, we used structural MRI to test whether baseline variations in gray matter (GM) volume correlated with subsequent performance after a long-term training of a complex whole-body task. 44 naïve participants were scanned before undertaking daily juggling practice for 6 weeks, following either a high intensity or a low intensity training regime. To assess performance across the training period participants' practice sessions were filmed. Greater GM volume in medial occipito-parietal areas at baseline correlated with steeper learning slopes. We also tested whether practice time or performance outcomes modulated the degree of structural brain change detected between the baseline scan and additional scans performed immediately after training and following a further 4 weeks without training. Participants with better performance had higher increases in GM volume during the period following training (i.e., between scans 2 and 3) in dorsal parietal cortex and M1. When contrasting brain changes between the practice intensity groups, we did not find any straightforward effects of practice time though practice modulated the relationship between performance and GM volume change in dorsolateral prefrontal cortex. These results suggest that practice time and performance modulate the degree of structural brain change evoked by long-term training regimes.
Highlights
•Inter-individual differences in brain structure correlate with subsequent performance outcome.•Performance outcome plays an important role in positive structural brain change.•Performance outcome and amount of practice modulate structural brain change.
doi:10.1016/j.neuroimage.2014.03.056
PMCID: PMC4075341  PMID: 24680712
Structural plasticity; Skill learning; MRI
19.  Local GABA concentration is related to network-level resting functional connectivity 
eLife  2014;3:e01465.
Anatomically plausible networks of functionally inter-connected regions have been reliably demonstrated at rest, although the neurochemical basis of these ‘resting state networks’ is not well understood. In this study, we combined magnetic resonance spectroscopy (MRS) and resting state fMRI and demonstrated an inverse relationship between levels of the inhibitory neurotransmitter GABA within the primary motor cortex (M1) and the strength of functional connectivity across the resting motor network. This relationship was both neurochemically and anatomically specific. We then went on to show that anodal transcranial direct current stimulation (tDCS), an intervention previously shown to decrease GABA levels within M1, increased resting motor network connectivity. We therefore suggest that network-level functional connectivity within the motor system is related to the degree of inhibition in M1, a major node within the motor network, a finding in line with converging evidence from both simulation and empirical studies.
DOI: http://dx.doi.org/10.7554/eLife.01465.001
eLife digest
Even when your body is at rest, your brain remains active. Subjects lying in brain scanners without any specific task to perform show coordinated and reproducible patterns of brain activity. Areas of the brain with similar functions, such as those involved in vision or in movement, tend to increase or decrease their activity in sync, and these coordinated patterns are referred to as resting state networks.
The functions of these networks are unclear—they may support introspection, memory recall or planning for the future, or they may help to strengthen newly acquired skills by enabling the brain to replay previous learning episodes. There is evidence that resting state networks are altered in disorders such as Alzheimer’s disease, autism and schizophrenia, but little is known about how these changes arise or what they might mean.
Now, Stagg et al. have used a type of brain scan called magnetic resonance spectroscopy to gain insights into the mechanisms by which one particular network—the resting motor network—is generated. This network consists of areas involved in planning, monitoring and executing movements, and includes the primary motor cortex, which initiates movements by sending instructions to the spinal cord.
The levels of a chemical called GABA—a neurotransmitter molecule that tends to inhibit the activity of nerve cells—were measured in the primary motor cortex of young healthy volunteers as they lay idle in a scanner. GABA levels were negatively correlated with the amount of coordinated activity within the resting motor network. By contrast, no relation was seen between coordinated activity and the levels of the neurotransmitter glutamate, which tends to increase the activity of nerve cells. Furthermore, when a weak electric current was applied through the subjects’ scalp to their primary motor cortex—a technique previously shown to lower levels of GABA in the region—the resting motor network became stronger.
In addition to providing new information on how the rhythmic patterns of activity seen in the resting brain arise, the work of Stagg et al. contributes to the more general effort to understand the complex patterns of connections within the human brain.
DOI: http://dx.doi.org/10.7554/eLife.01465.002
doi:10.7554/eLife.01465
PMCID: PMC3964822  PMID: 24668166
magnetic resonance spectroscopy; GABA; resting state fMRI; human
20.  Neuroplasticity and functional recovery in multiple sclerosis 
Nature reviews. Neurology  2012;8(11):635-646.
The development of therapeutic strategies that promote functional recovery is a major goal of multiple sclerosis (MS) research. Neuroscientific and methodological advances have improved our understanding of the brain’s recovery from damage, generating novel hypotheses for potential targets or modes of intervention and laying the foundation for the development of scientifically informed strategies promoting recovery in interventional studies. This Review aims to encourage the transition from characterization of recovery mechanisms to the development of strategies that promote recovery in MS. We discuss current evidence for functional reorganization that underlies recovery and its implications for development of new recovery-oriented strategies in MS. Promotion of functional recovery requires an improved understanding of recovery mechanisms modulated by interventions and the development of reliable measures of therapeutic effects. As imaging methods can be used to measure functional and structural alterations associated with recovery, this Review discusses their use as reliable markers to measure the effects of interventions.
doi:10.1038/nrneurol.2012.179
PMCID: PMC3770511  PMID: 22986429
21.  Polarity-specific effects of motor transcranial direct current stimulation on fMRI resting state networks☆ 
Neuroimage  2014;88(100):155-161.
Transcranial direct current stimulation (tDCS) has been used to modify motor performance in healthy and patient populations. However, our understanding of the large-scale neuroplastic changes that support such behavioural effects is limited. Here, we used both seed-based and independent component analyses (ICA) approaches to probe tDCS-induced modifications in resting state activity with the aim of establishing the effects of tDCS applied to the primary motor cortex (M1) on both motor and non-motor networks within the brain. Subjects participated in three separate sessions, during which resting fMRI scans were acquired before and after 10 min of 1 mA anodal, cathodal, or sham tDCS. Cathodal tDCS increased the inter-hemispheric coherence of resting fMRI signal between the left and right supplementary motor area (SMA), and between the left and right hand areas of M1. A similar trend was documented for the premotor cortex (PMC). Increased functional connectivity following cathodal tDCS was apparent within the ICA-generated motor and default mode networks. Additionally, the overall strength of the default mode network was increased. Neither anodal nor sham tDCS produced significant changes in resting state connectivity. This work indicates that cathodal tDCS to M1 affects the motor network at rest. In addition, the effects of cathodal tDCS on the default mode network support the hypothesis that diminished top-down control may contribute to the impaired motor performance induced by cathodal tDCS.
Highlights
•Resting state BOLD fMRI data was acquired before and after tDCS applied to M1.•Cathodal tDCS increased inter-hemispheric correlations between the M1 hand areas.•Cathodal tDCS increased connectivity in ICA-generated motor and default networks.•Cathodal tDCS increased the overall strength of the default network.
doi:10.1016/j.neuroimage.2013.11.037
PMCID: PMC3991849  PMID: 24287440
Transcranial direct current stimulation; Resting state connectivity; Functional MRI; Independent component analysis; Motor; Default mode
22.  Predicting behavioural response to TDCS in chronic motor stroke☆ 
Neuroimage  2014;85(Pt 3):924-933.
Transcranial direct current stimulation (TDCS) of primary motor cortex (M1) can transiently improve paretic hand function in chronic stroke. However, responses are variable so there is incentive to try to improve efficacy and or to predict response in individual patients. Both excitatory (Anodal) stimulation of ipsilesional M1 and inhibitory (Cathodal) stimulation of contralesional M1 can speed simple reaction time. Here we tested whether combining these two effects simultaneously, by using a bilateral M1–M1 electrode montage, would improve efficacy. We tested the physiological efficacy of Bilateral, Anodal or Cathodal TDCS in changing motor evoked potentials (MEPs) in the healthy brain and their behavioural efficacy in changing reaction times with the paretic hand in chronic stroke. In addition, we aimed to identify clinical or neurochemical predictors of patients' behavioural response to TDCS. There were three main findings: 1) unlike Anodal and Cathodal TDCS, Bilateral M1–M1 TDCS (1 mA, 20 min) had no significant effect on MEPs in the healthy brain or on reaction time with the paretic hand in chronic stroke patients; 2) GABA levels in ipsilesional M1 predicted patients' behavioural gains from Anodal TDCS; and 3) although patients were in the chronic phase, time since stroke (and its combination with Fugl–Meyer score) was a positive predictor of behavioural gain from Cathodal TDCS. These findings indicate the superiority of Anodal or Cathodal over Bilateral TDCS in changing motor cortico-spinal excitability in the healthy brain and in speeding reaction time in chronic stroke. The identified clinical and neurochemical markers of behavioural response should help to inform the optimization of TDCS delivery and to predict patient outcome variability in future TDCS intervention studies in chronic motor stroke.
Highlights
•Ipsilesional M1 GABA levels predict motor gains from Anodal TDCS in chronic stroke.•Time since stroke and Fugl–Meyer score jointly predict response to Cathodal TDCS.•Bilateral motor cortex TDCS did not reliably change motor evoked potentials.•Bilateral motor cortex TDCS did not reliably change manual reaction time.
doi:10.1016/j.neuroimage.2013.05.096
PMCID: PMC3899017  PMID: 23727528
Motor stroke; Plasticity; TDCS; Brain stimulation; Magnetic resonance spectroscopy; GABA
23.  Motor Skill Learning Induces Changes in White Matter Microstructure and Myelination 
The Journal of Neuroscience  2013;33(50):19499-19503.
Learning a novel motor skill is associated with well characterized structural and functional plasticity in the rodent motor cortex. Furthermore, neuroimaging studies of visuomotor learning in humans have suggested that structural plasticity can occur in white matter (WM), but the biological basis for such changes is unclear. We assessed the influence of motor skill learning on WM structure within sensorimotor cortex using both diffusion MRI fractional anisotropy (FA) and quantitative immunohistochemistry. Seventy-two adult (male) rats were randomly assigned to one of three conditions (skilled reaching, unskilled reaching, and caged control). After 11 d of training, postmortem diffusion MRI revealed significantly higher FA in the skilled reaching group compared with the control groups, specifically in the WM subjacent to the sensorimotor cortex contralateral to the trained limb. In addition, within the skilled reaching group, FA across widespread regions of WM in the contralateral hemisphere correlated significantly with learning rate. Immunohistological analysis conducted on a subset of 24 animals (eight per group) revealed significantly increased myelin staining in the WM underlying motor cortex in the hemisphere contralateral (but not ipsilateral) to the trained limb for the skilled learning group versus the control groups. Within the trained hemisphere (but not the untrained hemisphere), myelin staining density correlated significantly with learning rate. Our results suggest that learning a novel motor skill induces structural change in task-relevant WM pathways and that these changes may in part reflect learning-related increases in myelination.
doi:10.1523/JNEUROSCI.3048-13.2013
PMCID: PMC3858622  PMID: 24336716
24.  Deprivation-related and use-dependent plasticity go hand in hand 
eLife  2013;2:e01273.
Arm-amputation involves two powerful drivers for brain plasticity—sensory deprivation and altered use. However, research has largely focused on sensory deprivation and maladaptive change. Here we show that adaptive patterns of limb usage after amputation drive cortical plasticity. We report that individuals with congenital or acquired limb-absence vary in whether they preferentially use their intact hand or residual arm in daily activities. Using fMRI, we show that the deprived sensorimotor cortex is employed by whichever limb individuals are over-using. Individuals from either group that rely more on their intact hands (and report less frequent residual arm usage) showed increased intact hand representation in the deprived cortex, and increased white matter fractional anisotropy underlying the deprived cortex, irrespective of the age at which deprivation occurred. Our results demonstrate how experience-driven plasticity in the human brain can transcend boundaries that have been thought to limit reorganisation after sensory deprivation in adults.
DOI: http://dx.doi.org/10.7554/eLife.01273.001
eLife digest
The loss of a limb will have a profound impact on an individual’s daily life. Nevertheless, individuals can employ a variety of behavioural strategies to adapt to the loss of, say, a hand. Some become skilled at using the residual part of their arm, while others prefer to rely on their other hand. Their brain, too, will undergo major changes. Many studies have shown that the region of the brain that controlled a given limb can be “taken over” by another part of the body if that limb is lost. This process has been previously considered to be harmful, as it has been linked to experiences of pain arising from the missing limb.
Now, Makin et al. have explored the links between changes in the behaviour of individuals missing a hand and changes in their brains. People who had been born without a hand or who had lost a hand in later life were asked to wear a device that recorded their movements as they went about their daily lives. The data revealed that people who had been born without a hand made relatively more use of their residual limb, while those who had lost their hand made relatively more use of their remaining hand.
Moreover, these differences were reflected in patterns of brain activity. In the subjects born without a hand (who were making relatively extensive use of their residual limb), the area of the brain that would otherwise control the ‘missing’ hand was activated when the subjects moved their residual limb. And in the subjects who had lost their hand, this brain region was activated when they moved their remaining hand. However, in individual subjects, the size of the effect depended on the usage preferences of the subject: for example, the minority of people who were born without a hand but nevertheless make extensive use of their intact hand showed a pattern of activation that resembled the average pattern seen in those who had lost a hand in later life.
By providing new insights into the plasticity of brain and behaviour following the loss of a hand, the work of Makin et al. may aid the development of rehabilitation techniques to help patients to optimise the use of both their residual and their intact limbs.
DOI: http://dx.doi.org/10.7554/eLife.01273.002
doi:10.7554/eLife.01273
PMCID: PMC3823186  PMID: 24220510
plasticity; neuroimaging; deprivation; Human
25.  Visualization of altered neurovascular coupling in chronic stroke patients using multimodal functional MRI 
Evaluation of cortical reorganization in chronic stroke patients requires methods to accurately localize regions of neuronal activity. Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is frequently employed; however, BOLD contrast depends on specific coupling relationships between the cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF), and volume (CBV), which may not exist following stroke. The aim of this study was to understand whether CBF-weighted (CBFw) and CBV-weighted (CBVw) fMRI could be used in sequence with BOLD to characterize neurovascular coupling mechanisms poststroke. Chronic stroke patients (n=11) with motor impairment and age-matched controls (n=11) performed four sets of unilateral motor tasks (60 seconds/30 seconds off/on) during CBFw, CBVw, and BOLD fMRI acquisition. While control participants elicited mean BOLD, CBFw, and CBVw responses in motor cortex (P<0.01), patients showed only mean changes in CBF (P<0.01) and CBV (P<0.01), but absent mean BOLD responses (P=0.20). BOLD intersubject variability was consistent with differing coupling indices between CBF, CBV, and CMRO2. Thus, CBFw and/or CBVw fMRI may provide crucial information not apparent from BOLD in these patients. A table is provided outlining distinct vascular and metabolic uncoupling possibilities that elicit different BOLD responses, and the strengths and limitations of the multimodal protocol are summarized.
doi:10.1038/jcbfm.2012.105
PMCID: PMC3493993  PMID: 22828998
arterial spin labeling; BOLD; cerebral blood flow; cerebral blood volume; cerebrovascular disease; neurovascular coupling

Results 1-25 (61)