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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  Ventral Premotor Cortex May Be Required for Dynamic Changes in the Feeling of Limb Ownership: A Lesion Study 
The feeling of “body ownership” may be experimentally investigated by perceptual illusions. The “rubber hand illusion” (RHI) leads human subjects to experience an artificial hand as their own. According to functional imaging, the ventral premotor cortex (PMv) plays a key role in the integration of multisensory inputs allowing the “incorporation” of the rubber hand into body representation. However, causal structure–function relationships can only be obtained by lesion studies.
Here, we tested the RHI in 70 stroke patients and in 40 age-matched healthy controls. Additionally, asomatognosia, the unawareness of one’s own body parts, was assessed in a subgroup of 64 stroke patients. Ischemic lesions were delineated on diffusion-weighted magnetic resonance images and normalized. Right-hemispheric lesions were mirrored across the midline. Voxels that might be essential for RHI and/or somatognosia were defined by voxel-based lesion-symptom mapping. Probabilistic diffusion tractography was used to identify tracts passing through these voxels.
Contralesional rubber hand illusion failure (RHIF) was observed in 18 (26%) of 70 stroke patients, an additional ipsilesional RHIF in seven of these patients. RHIF-associated lesion voxels were located subcortically adjacent to the insula, basal ganglia, and within the periventricular white matter. Tractography revealed fiber tract connections of these voxels with premotor, parietal, and prefrontal cortex. Contralesional asomatognosia was found in 18 (28%) of 64 stroke patients. In contrast to RHIF, asomatognosia-associated lesion voxels showed no connection with PMv.
The results point to a role of PMv and its connections in mediating changes in the sense of limb ownership driven by multisensory stimulation.
doi:10.1523/JNEUROSCI.5154-10.2011
PMCID: PMC3119817  PMID: 21451023
8.  DIFFUSION-WEIGHTED IMAGING TRACTOGRAPHY-BASED PARCELLATION OF THE HUMAN PARIETAL CORTEX AND COMPARISON WITH HUMAN AND MACAQUE RESTING STATE FUNCTIONAL CONNECTIVITY 
Despite the prominence of parietal activity in human neuromaging investigations of sensorimotor and cognitive processes there remains uncertainty about basic aspects of parietal cortical anatomical organization. Descriptions of human parietal cortex draw heavily on anatomical schemes developed in other primate species but the validity of such comparisons has been questioned by claims that there are fundamental differences between the parietal cortex in humans and other primates. A scheme is presented for parcellation of human lateral parietal cortex into component regions on the basis of anatomical connectivity and the functional interactions of the resulting clusters with other brain regions. Anatomical connectivity was estimated using diffusion-weighted magnetic resonance image (MRI) based tractography and functional interactions were assessed by correlations in activity measured with functional MRI (fMRI) at rest. Resting state functional connectivity was also assessed directly in the rhesus macaque lateral parietal cortex in an additional experiment and the patterns found reflected known neuroanatomical connections. Cross-correlation in the tractography-based connectivity patterns of parietal voxels reliably parcellated human lateral parietal cortex into ten component clusters. The resting state functional connectivity of human superior parietal and intraparietal clusters with frontal and extrastriate cortex suggested correspondences with areas in macaque superior and intraparietal sulcus. Functional connectivity patterns with parahippocampal cortex and premotor cortex again suggested fundamental correspondences between inferior parietal cortex in humans and macaques. In contrast, the human parietal cortex differs in the strength of its interactions between the central inferior parietal lobule region and the anterior prefrontal cortex.
doi:10.1523/JNEUROSCI.5102-10.2011
PMCID: PMC3091022  PMID: 21411650
AIP; MIP; LIP; VIP; IPL; SPL
9.  What are we measuring with GABA magnetic resonance spectroscopy? 
A number of recent papers1–3 have demonstrated a relationship between in vivo concentration of GABA, as assessed using Magnetic Resonance Spectroscopy (MRS), and an individual's task performance, giving a unique insight into the relationship between physiology and behavior. However, interpretation of the functional significance of the MRS GABA measure is not straightforward. Here we discuss some of the outstanding questions as to how total concentration of GABA within a cortical region relates to phasic and tonic GABA activity within the cortical volume studied.
doi:10.4161/cib.4.5.16213
PMCID: PMC3204132  PMID: 22046466
gamma-amino butyric acid (GABA); motor cortex; magnetic resonance spectroscopy; human; inter-individual differences
10.  Diffusion imaging of whole, post-mortem human brains on a clinical MRI scanner 
Neuroimage  2011;57(1-4):167-181.
Diffusion imaging of post mortem brains has great potential both as a reference for brain specimens that undergo sectioning, and as a link between in vivo diffusion studies and “gold standard” histology/dissection. While there is a relatively mature literature on post mortem diffusion imaging of animals, human brains have proven more challenging due to their incompatibility with high-performance scanners. This study presents a method for post mortem diffusion imaging of whole, human brains using a clinical 3-Tesla scanner with a 3D segmented EPI spin-echo sequence. Results in eleven brains at 0.94 × 0.94 × 0.94 mm resolution are presented, and in a single brain at 0.73 × 0.73 × 0.73 mm resolution. Region-of-interest analysis of diffusion tensor parameters indicate that these properties are altered compared to in vivo (reduced diffusivity and anisotropy), with significant dependence on post mortem interval (time from death to fixation). Despite these alterations, diffusion tractography of several major tracts is successfully demonstrated at both resolutions. We also report novel findings of cortical anisotropy and partial volume effects.
Research highlights
► Acquisition and processing protocols for diffusion MRI of post-mortem human brains. ► Effect of post-mortem and scan intervals on diffusion indices. ► Tractography in post-mortem human brains. ► Radial diffusion anisotropy in cortical gray matter.
doi:10.1016/j.neuroimage.2011.03.070
PMCID: PMC3115068  PMID: 21473920
Diffusion tensor imaging; Tractography; Post mortem; Human; Brain
11.  The Role of GABA in Human Motor Learning 
Current Biology  2011;21(6):480-484.
Summary
GABA modification plays an important role in motor cortical plasticity [1–4]. We therefore hypothesized that interindividual variation in the responsiveness of the GABA system to modification influences learning capacity in healthy adults. We assessed GABA responsiveness by transcranial direct current stimulation (tDCS), an intervention known to decrease GABA [5, 6]. The magnitude of M1 GABA decrease induced by anodal tDCS correlated positively with both the degree of motor learning and the degree of fMRI signal change within the left M1 during learning. This study therefore suggests that the responsiveness of the GABAergic system to modification may be relevant to short-term motor learning behavior and learning-related brain activity.
Highlights
► Change in GABA due to transcranial stimulation correlates with motor learning behavior ► GABA change also correlates with localized fMRI responses during short-term learning ► No correlations are found for these measures with GABA levels in visual cortex
doi:10.1016/j.cub.2011.01.069
PMCID: PMC3063350  PMID: 21376596

Results 1-11 (11)