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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  Relationships between functional and structural corticospinal tract integrity and walking post stroke 
Clinical Neurophysiology  2012;123(12):2422-2428.
Highlights
► We investigated the relationship between walking impairment after stroke and integrity of the corticospinal tract (CST). ► We used transcranial magnetic stimulation and diffusion tensor imaging to assess CST integrity. ► We demonstrate that patients with more ipsilateral connectivity between the unlesioned M1 and the affected leg had more structural damage to their CST.
Objective
Studies on upper limb recovery following stroke have highlighted the importance of the structural and functional integrity of the corticospinal tract (CST) in determining clinical outcomes. However, such relationships have not been fully explored for the lower limb. We aimed to test whether variation in walking impairment was associated with variation in the structural or functional integrity of the CST.
Methods
Transcranial magnetic stimulation was used to stimulate each motor cortex while EMG recordings were taken from the vastus lateralis (VL) bilaterally; these EMG measures were used to calculate both ipsilateral and contralateral recruitment curves for each lower limb. The slope of these recruitment curves was used to examine the strength of functional connectivity from the motor cortex in each hemisphere to the lower limbs in chronic stroke patients and to calculate a ratio between ipsilateral and contralateral outputs referred to as the functional connectivity ratio (FCR). The structural integrity of the CST was assessed using diffusion tensor MRI to measure the asymmetry in fractional anisotropy (FA) of the internal capsule. Lower limb impairment and walking speed were also measured.
Results
The FCR for the paretic leg correlated with walking impairment, such that greater relative ipsilateral connectivity was associated with slower walking speeds. Asymmetrical FA values, reflecting reduced structural integrity of the lesioned CST, were associated with greater walking impairment. FCR and FA asymmetry were strongly positively correlated with each other.
Conclusions
Patients with relatively greater ipsilateral connectivity between the contralesional motor cortex and the paretic lower limb were more behaviorally impaired and had more structural damage to their ipsilesional hemisphere CST.
Significance
Measures of structural and functional damage may be useful in the selection of therapeutic strategies, allowing for more tailored and potentially more beneficial treatments.
doi:10.1016/j.clinph.2012.04.026
PMCID: PMC3778984  PMID: 22717679
CST, corticospinal tract; DTI, diffusion tensor imaging; FA, fractional anisotropy; FCR, functional connectivity ratio; M1, primary motor cortex; TMS, transcranial magnetic stimulation; VL, vastus lateralis; Stroke; Locomotion; Motor recovery; TMS; DTI
22.  A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology 
Brain  2012;135(10):2938-2951.
Multiple sclerosis is a chronic inflammatory neurological condition characterized by focal and diffuse neurodegeneration and demyelination throughout the central nervous system. Factors influencing the progression of pathology are poorly understood. One hypothesis is that anatomical connectivity influences the spread of neurodegeneration. This predicts that measures of neurodegeneration will correlate most strongly between interconnected structures. However, such patterns have been difficult to quantify through post-mortem neuropathology or in vivo scanning alone. In this study, we used the complementary approaches of whole brain post-mortem magnetic resonance imaging and quantitative histology to assess patterns of multiple sclerosis pathology. Two thalamo-cortical projection systems were considered based on their distinct neuroanatomy and their documented involvement in multiple sclerosis: lateral geniculate nucleus to primary visual cortex and mediodorsal nucleus of the thalamus to prefrontal cortex. Within the anatomically distinct thalamo-cortical projection systems, magnetic resonance imaging derived cortical thickness was correlated significantly with both a measure of myelination in the connected tract and a measure of connected thalamic nucleus cell density. Such correlations did not exist between these markers of neurodegeneration across different thalamo-cortical systems. Magnetic resonance imaging lesion analysis depicted clearly demarcated subcortical lesions impinging on the white matter tracts of interest; however, quantitation of the extent of lesion-tract overlap failed to demonstrate any appreciable association with the severity of markers of diffuse pathology within each thalamo-cortical projection system. Diffusion-weighted magnetic resonance imaging metrics in both white matter tracts were correlated significantly with a histologically derived measure of tract myelination. These data demonstrate for the first time the relevance of functional anatomical connectivity to the spread of multiple sclerosis pathology in a ‘tract-specific’ pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted magnetic resonance imaging and histological measures from fixed tissue further validates the potential of imaging for future neuropathological studies.
doi:10.1093/brain/aws242
PMCID: PMC3470716  PMID: 23065787
multiple sclerosis; post-mortem imaging; diffusion imaging; white matter tracts; neurodegeneration
23.  The Effects of Aerobic Activity on Brain Structure 
Aerobic activity is a powerful stimulus for improving mental health and for generating structural changes in the brain. We review the literature documenting these structural changes and explore exactly where in the brain these changes occur as well as the underlying substrates of the changes including neural, glial, and vasculature components. Aerobic activity has been shown to produce different types of changes in the brain. The presence of novel experiences or learning is an especially important component in how these changes are manifest. We also discuss the distinct time courses of structural brain changes with both aerobic activity and learning as well as how these effects might differ in diseased and elderly groups.
doi:10.3389/fpsyg.2012.00086
PMCID: PMC3311131  PMID: 22470361
exercise; plasticity; hippocampus; neurogenesis; angiogenesis; learning; environmental enrichment; aging
24.  Structural correlates of skilled performance on a motor sequence task 
The brain regions functionally engaged in motor sequence performance are well-established, but the structural characteristics of these regions and the fiber pathways involved have been less well studied. In addition, relatively few studies have combined multiple magnetic resonance imaging (MRI) and behavioral performance measures in the same sample. Therefore, the current study used diffusion tensor imaging (DTI), probabilistic tractography, and voxel-based morphometry (VBM) to determine the structural correlates of skilled motor performance. Further, we compared these findings with fMRI results in the same sample. We correlated final performance and rate of improvement measures on a temporal motor sequence task (TMST) with skeletonized fractional anisotropy (FA) and whole brain gray matter (GM) volume. Final synchronization performance was negatively correlated with FA in white matter (WM) underlying bilateral sensorimotor cortex—an effect that was mediated by a positive correlation with radial diffusivity. Multi-fiber tractography indicated that this region contained crossing fibers from the corticospinal tract (CST) and superior longitudinal fasciculus (SLF). The identified SLF pathway linked parietal and auditory cortical regions that have been shown to be functionally engaged in this task. Thus, we hypothesize that enhanced synchronization performance on this task may be related to greater fiber integrity of the SLF. Rate of improvement on synchronization was positively correlated with GM volume in cerebellar lobules HVI and V—regions that showed training-related decreases in activity in the same sample. Taken together, our results link individual differences in brain structure and function to motor sequence performance on the same task. Further, our study illustrates the utility of using multiple MR measures and analysis techniques to specify the interpretation of structural findings.
doi:10.3389/fnhum.2012.00289
PMCID: PMC3486688  PMID: 23125826
superior longitudinal fasciculus; individual differences; motor sequence performance; fractional anisotropy; diffusion tensor imaging; gray matter volume
25.  Cortical activation changes underlying stimulation-induced behavioural gains in chronic stroke 
Brain  2011;135(1):276-284.
Transcranial direct current stimulation, a form of non-invasive brain stimulation, is showing increasing promise as an adjunct therapy in rehabilitation following stroke. However, although significant behavioural improvements have been reported in proof-of-principle studies, the underlying mechanisms are poorly understood. The rationale for transcranial direct current stimulation as therapy for stroke is that therapeutic stimulation paradigms increase activity in ipsilesional motor cortical areas, but this has not previously been directly tested for conventional electrode placements. This study was performed to test directly whether increases in ipsilesional cortical activation with transcranial direct current stimulation are associated with behavioural improvements in chronic stroke patients. Patients at least 6 months post-first stroke participated in a behavioural experiment (n = 13) or a functional magnetic resonance imaging experiment (n = 11), each investigating the effects of three stimulation conditions in separate sessions: anodal stimulation to the ipsilesional hemisphere; cathodal stimulation to the contralesional hemisphere; and sham stimulation. Anodal (facilitatory) stimulation to the ipsilesional hemisphere led to significant improvements (5–10%) in response times with the affected hand in both experiments. This improvement was associated with an increase in movement-related cortical activity in the stimulated primary motor cortex and functionally interconnected regions. Cathodal (inhibitory) stimulation to the contralesional hemisphere led to a functional improvement only when compared with sham stimulation. We show for the first time that the significant behavioural improvements produced by anodal stimulation to the ipsilesional hemisphere are associated with a functionally relevant increase in activity within the ipsilesional primary motor cortex in patients with a wide range of disabilities following stroke.
doi:10.1093/brain/awr313
PMCID: PMC3267983  PMID: 22155982
transcranial direct current stimulation; stroke rehabilitation; motor system

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