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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  Distinction of seropositive NMO spectrum disorder and MS brain lesion distribution 
Neurology  2013;80(14):1330-1337.
Objective:
Neuromyelitis optica and its spectrum disorder (NMOSD) can present similarly to relapsing-remitting multiple sclerosis (RRMS). Using a quantitative lesion mapping approach, this research aimed to identify differences in MRI brain lesion distribution between aquaporin-4 antibody–positive NMOSD and RRMS, and to test their diagnostic potential.
Methods:
Clinical brain MRI sequences for 44 patients with aquaporin-4 antibody–positive NMOSD and 50 patients with RRMS were examined for the distribution and morphology of brain lesions. T2 lesion maps were created for each subject allowing the quantitative comparison of the 2 conditions with lesion probability and voxel-wise analysis.
Results:
Sixty-three percent of patients with NMOSD had brain lesions and of these 27% were diagnostic of multiple sclerosis. Patients with RRMS were significantly more likely to have lesions adjacent to the body of the lateral ventricle than patients with NMOSD. Direct comparison of the probability distributions and the morphologic attributes of the lesions in each group identified criteria of “at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or the presence of a subcortical U-fiber lesion; or a Dawson's finger-type lesion,” which could distinguish patients with multiple sclerosis from those with NMOSD with 92% sensitivity, 96% specificity, 98% positive predictive value, and 86% negative predictive value.
Conclusion:
Careful inspection of the distribution and morphology of MRI brain lesions can distinguish RRMS and NMOSD.
doi:10.1212/WNL.0b013e3182887957
PMCID: PMC3656462  PMID: 23486868
15.  Diffusion MRI at 25: Exploring brain tissue structure and function 
NeuroImage  2011;61(2):324-341.
Diffusion MRI (or dMRI) came into existence in the mid-1980s. During the last 25 years, diffusion MRI has been extraordinarily successful (with more than 300,000 entries on Google Scholar for diffusion MRI). Its main clinical domain of application has been neurological disorders, especially for the management of patients with acute stroke. It is also rapidly becoming a standard for white matter disorders, as diffusion tensor imaging (DTI) can reveal abnormalities in white matter fiber structure and provide outstanding maps of brain connectivity. The ability to visualize anatomical connections between different parts of the brain, non-invasively and on an individual basis, has emerged as a major breakthrough for neurosciences. The driving force of dMRI is to monitor microscopic, natural displacements of water molecules that occur in brain tissues as part of the physical diffusion process. Water molecules are thus used as a probe that can reveal microscopic details about tissue architecture, either normal or in a diseased state.
doi:10.1016/j.neuroimage.2011.11.006
PMCID: PMC3683822  PMID: 22120012
Diffusion MRI; fMRI; Tractography; Connectivity; Human brain connectome; White matter; Stroke
16.  White matter abnormalities in Methcathinone abusers with an extrapyramidal syndrome 
Brain : a journal of neurology  2010;133(0 12):3676-3684.
Summary
We examined white matter abnormalities in patients with a distinctive extrapyramidal syndrome due to intravenous methcathinone (ephedrone) abuse. We performed diffusion tensor imaging in ten patients and fifteen age-matched controls to assess white matter structure across the whole brain. Diffuse significant decreases in white matter fractional anisotropy, a diffusion tensor imaging metric which reflects microstructural integrity, occurred in the patients compared with controls. In addition, we identified two foci of severe white matter abnormality underlying the right ventral premotor cortex and the medial frontal cortex, two cortical regions involved in higher-level executive control of motor function. Paths connecting different cortical regions with the globus pallidus, the nucleus previously shown to be abnormal on structural imaging in these patients, were generated using probabilistic tractography. The fractional anisotropy within all these tracts was lower in the patient group than controls. Finally, we tested for a relationship between white matter integrity and clinical outcome. We identified a region within the left corticospinal tract in which lower fractional anisotropy was associated with greater functional deficit but this region did not show reduced fractional anisotropy in the overall patient group compared to controls. These patients have widespread white matter damage with greatest severity of damage underlying executive motor areas.
doi:10.1093/brain/awq281
PMCID: PMC3677802  PMID: 21036949
Extrapyramidal syndrome; Methcathinone; Manganese toxicity; diffusion imaging; white matter tracts
17.  The future of functionally-related structural change assessment 
NeuroImage  2011;62(2):1293-1298.
The brain is continually changing its function and structure in response to changing environmental demands. Magnetic resonance imaging (MRI) methods can be used to repeatedly scan the same individuals over time and in this way have provided powerful tools for assessing such brain change. Functional MRI has provided important insights into changes that occur with learning or recovery but this review will focus on the complementary information that can be provided by structural MRI methods. Structural methods have been powerful in indicating when and where changes occur in both gray and white matter with learning and recovery. However, the measures that we derive from structural MRI are typically ambiguous in biological terms. An important future challenge is to develop methods that will allow us to determine precisely what has changed.
doi:10.1016/j.neuroimage.2011.10.073
PMCID: PMC3677804  PMID: 22056531
Plasticity; learning; recovery; MRI; fMRI; diffusion MRI
18.  Tractography - where do we go from here? 
Brain connectivity  2011;1(3):169-183.
Diffusion tractography offers enormous potential for the study of human brain anatomy. However, as a method to study brain connectivity, tractography suffers from limitations, as it is indirect, inaccurate, and difficult to quantify. Despite these limitations, appropriate use of tractography can be a powerful means to address certain questions. In addition, while some of tractography’s limitations are fundamental, others could be alleviated by methodological and technological advances. This article provides an overview of diffusion MR tractography methods with a focus on how future advances might address challenges in measuring brain connectivity. Parts of this review are somewhat provocative, in the hope that they may trigger discussions possibly lacking in a field where the apparent simplicity of the methods (compared to their FMRI counterparts) can hide some fundamental issues that ultimately hinder the interpretation of findings, and cast doubt as to what tractography can really teach us about human brain anatomy.
doi:10.1089/brain.2011.0033
PMCID: PMC3677805  PMID: 22433046
19.  Relating Brain Damage to Brain Plasticity in Patients With Multiple Sclerosis 
Background
Failure of adaptive plasticity with increasing pathology is suggested to contribute to progression of disability in multiple sclerosis (MS). However, functional impairments can be reduced with practice, suggesting that brain plasticity is preserved even in patients with substantial damage.
Objective
Here, functional magnetic resonance imaging (fMRI) was used to probe systems-level mechanisms of brain plasticity associated with improvements in visuomotor performance in MS patients and related to measures of microstructural damage.
Methods
23 MS patients and 12 healthy controls underwent brain fMRI during the first practice session of a visuomotor task (short-term practice) and after 2 weeks of daily practice with the same task (longer-term practice). Participants also underwent a structural brain MRI scan.
Results
Patients performed more poorly than controls at baseline. Nonetheless, with practice, patients showed performance improvements similar to controls and independent of the extent of MRI measures of brain pathology. Different relationships between performance improvements and activations were found between groups: greater short-term improvements were associated with lower activation in the sensorimotor, posterior cingulate, and parahippocampal cortices for patients, whereas greater long-term improvements correlated with smaller activation reductions in the visual cortex of controls.
Conclusions
Brain plasticity for visuomotor practice is preserved in MS patients despite a high burden of cerebral pathology. Cognitive systems different from those acting in controls contribute to this plasticity in patients. These findings challenge the notion that increasing pathology is accompanied by an outright failure of adaptive plasticity, supporting a neuroscientific rationale for recovery-oriented strategies even in chronically disabled patients.
doi:10.1177/1545968311433208
PMCID: PMC3674542  PMID: 22328685
20.  Structural and Functional Bases for Individual Differences in Motor Learning 
Human brain mapping  2011;32(3):494-508.
People vary in their ability to learn new motor skills. We hypothesize that between-subject variability in brain structure and function can explain differences in learning. We use brain functional and structural MRI methods to characterize such neural correlates of individual variations in motor learning. Healthy subjects applied isometric grip force of varying magnitudes with their right hands cued visually to generate smoothly-varying pressures following a regular pattern. We tested whether individual variations in motor learning were associated with anatomically colocalized variations in magnitude of functional MRI (fMRI) signal or in MRI differences related to white and grey matter microstructure. We found that individual motor learning was correlated with greater functional activation in the prefrontal, premotor, and parietal cortices, as well as in the basal ganglia and cerebellum.
Structural MRI correlates were found in the premotor cortex [for fractional anisotropy (FA)] and in the cerebellum [for both grey matter density and FA]. The cerebellar microstructural differences were anatomically colocalized with fMRI correlates of learning. This study thus suggests that variations across the population in the function and structure of specific brain regions for motor control explain some of the individual differences in skill learning. This strengthens the notion that brain structure determines some limits to cognitive function even in a healthy population. Along with evidence from pathology suggesting a role for these regions in spontaneous motor recovery, our results also highlight potential targets for therapeutic interventions designed to maximize plasticity for recovery of similar visuomotor skills after brain injury.
doi:10.1002/hbm.21037
PMCID: PMC3674543  PMID: 20533562
21.  Myelin Water Imaging Reflects Clinical Variability in Multiple Sclerosis 
NeuroImage  2011;60(1):263-270.
Whilst MRI is routinely used for the assessment and diagnosis of multiple sclerosis, there is poor correspondence between clinical disability in primary progressive multiple sclerosis (PPMS) patients and conventional MRI markers of disease activity (e.g., number of enhancing lesions). As PPMS patients show diffuse and global myelin loss, the aim of this study was to evaluate the efficacy of whole-brain myelin water fraction (MWF) imaging in PPMS. Specifically, we sought to use full-brain analysis techniques to: 1) determine the reproducibility of MWF estimates in PPMS brain; 2) compare MWF values in PPMS brain to healthy controls; and 3) establish the relationship between MWF and clinical disability, regionally and globally throughout the brain. Seventeen PPMS patients and seventeen age-matched controls were imaged using a whole-brain multi-component relaxation imaging technique to measure MWF. Analysis of MWF reduction was performed on three spatial levels: 1) histogram; 2) white matter skeleton; and 3) voxel-wise at the single-subject level. From histogram analysis, PPMS patients had significantly reduced global normal appearing white matter MWF (6%, p=0.04) compared to controls. Focal lesions showed lower MWF values than white matter in controls (61%, p<0.001) and patients (59%, p<0.001). Along the white matter skeleton, MWF was diffusely reduced throughout the PPMS brain, with significant correlations between reduced MWF and increased clinical disability (more severe symptoms), as measured by the Expanded Disability Status Scale, within the corpus callosum and frontal, temporal, parietal and occipital white matter. Correlations with the more specific mental and sensory functional system scores were localized to clinically eloquent locations: reduced MWF was significantly associated with increased mental scores in anterior regions (i.e., frontal lobes and genu of the corpus callosum), and increased sensory scores in more posterior regions closer to the sensory cortex. Individual patient MWF maps were also compared to a normative population atlas, which highlighted areas of statistical difference between the individual patient and the population mean. A significant correlation was found between the volume of significantly reduced MWF and clinical disability (p=0.008, R = 0.58). Our results show that clinical disability is reflected in particular regions of cerebral white matter that are consistent between subjects, and illustrates a method to examine tissue alteration throughout the brain of individual patients. These results strongly support the use of MWF imaging to evaluate disease activity in PPMS.
doi:10.1016/j.neuroimage.2011.11.070
PMCID: PMC3671155  PMID: 22155325
multiple sclerosis (MS); magnetic resonance imaging (MRI); brain; myelin water imaging; multi-component relaxation
22.  Preservation of motor skill learning in patients with multiple sclerosis 
Background
Several studies have demonstrated benefits of rehabilitation in multiple sclerosis (MS). However, the neuroscientific foundations for rehabilitation in MS are poorly established.
Objectives
As rehabilitation and motor learning share similar mechanisms of brain plasticity, we test whether the dynamics of skill learning are preserved in MS patients relative to controls.
Methods
MS patients and controls learned a repeating sequence of hand movements and were assessed for short-term learning. Long-term learning was tested in another cohort of patients and controls practising the same sequence daily for two weeks.
Results
Despite differences in baseline performance, the dynamics and extent of improvements were comparable between MS and control groups for both the short- and long-term learning. Even the most severely damaged patients were capable of performance improvements of similar magnitude to that seen in controls. After one week of training patients performed as well as the controls at baseline.
Conclusions
Mechanisms for short- and long-term plasticity may compensate for impaired functional connectivity in MS to mediate behavioural improvements. Future studies are needed to define the neurobiological substrates of this plasticity and the extent to which mechanisms of plasticity in patients may be distinct from those used for motor learning in controls.
doi:10.1177/1352458510381257
PMCID: PMC3671324  PMID: 20834040
23.  Tools of the trade: psychophysiological interactions and functional connectivity 
Psychophysiological interactions (PPIs) analysis is a method for investigating task-specific changes in the relationship between activity in different brain areas, using functional magnetic resonance imaging (fMRI) data. Specifically, PPI analyses identify voxels in which activity is more related to activity in a seed region of interest (seed ROI) in a given psychological context, such as during attention or in the presence of emotive stimuli. In this tutorial, we aim to give a simple conceptual explanation of how PPI analysis works, in order to assist readers in planning and interpreting their own PPI experiments.
doi:10.1093/scan/nss055
PMCID: PMC3375893  PMID: 22569188
psychophysiological interactions; PPI; functional connectivity; resting state
24.  Human Structural Plasticity at Record Speed 
Neuron  2012;73(6):1058-1060.
How rapidly does learning shape our brains? A new study using diffusion magnetic resonance imaging in both humans and rats suggests that just two hours of spatial learning is sufficient to change brain structure.
doi:10.1016/j.neuron.2012.03.001
PMCID: PMC3353540  PMID: 22445333
25.  Studying the Effects of Transcranial Direct-Current Stimulation in Stroke Recovery Using Magnetic Resonance Imaging 
Transcranial direct-current stimulation (tDCS) is showing increasing promise as an adjunct therapy in stroke rehabilitation. However questions still remain concerning its mechanisms of action, which currently limit its potential. Magnetic resonance (MR) techniques are increasingly being applied to understand the neural effects of tDCS. Here, we review the MR evidence supporting the use of tDCS to aid recovery after stroke and discuss the important open questions that remain.
doi:10.3389/fnhum.2013.00857
PMCID: PMC3859898  PMID: 24376413
transcranial direct-current stimulation; stroke recovery; MRI; humans; MRS spectroscopy

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