Magnetization transfer saturation reveals subclinical optic nerve injury in pediatric-onset multiple sclerosis.

BACKGROUND: The presence of subclinical optic nerve (ON) injury in youth living with pediatric-onset MS has not been fully elucidated. Magnetization transfer saturation (MTsat) is an advanced magnetic resonance imaging (MRI) parameter sensitive to myelin density and microstructural integrity, which can be applied to the study of the ON. OBJECTIVE: The objective of this study was to investigate the presence of subclinical ON abnormalities in pediatric-onset MS by means of magnetization transfer saturation and evaluate their association with other structural and functional parameters of visual pathway integrity. METHODS: Eleven youth living with pediatric-onset MS (ylPOMS) and no previous history of optic neuritis and 18 controls underwent standardized brain MRI, optical coherence tomography (OCT), Magnetoencephalography (MEG)-Visual Evoked Potentials (VEPs), and visual battery. Data were analyzed with mixed effect models. RESULTS: While ON volume, OCT parameters, occipital MEG-VEPs outcomes, and visual function did not differ significantly between ylPOMS and controls, ylPOMS had lower MTsat in the supratentorial normal appearing white matter (-0.26 nU, p = 0.0023), and in both in the ON (-0.62 nU, p < 0.001) and in the normal appearing white matter of the optic radiation (-0.56 nU, p = 0.00071), with these being positively correlated (+0.57 nU, p = 0.00037). CONCLUSIONS: Subclinical microstructural injury affects the ON of ylPOMS. This may appear as MTsat changes before being detectable by other currently available testing.

Neural and cognitive function in a pediatric brain injury model: The impact of task complexity.

Acquired brain injury (ABI) in childhood/adolescence results in dysfunctional neural and attentional resources during minimal and higher task load. Impact of injury on these resources during increasing load, when task design (e.g., stimuli, timing) is held constant, is not yet well understood. We examined neural communication, processing speed and controlled attention in pediatric brain tumor survivors (PBTS; Mtime since treatment = 6.78 years) and typically developing children (TDC; n = 57). Participants performed simple-go and choice reaction time (RxnT) tasks during magnetoencephalography. The weighted phase lag index estimated seed-based and whole-brain functional connectivity. Group differences were assessed using tmax and network based statistics. Mean RxnT and response accuracy measured performance. Linear models assessed group differences. Tasks were analyzed individually to account for a difference in trial numbers. During both tasks, PBTS demonstrated decreased seed-based connectivity in the high gamma frequency (60-100 Hz; p < .01) relative to TDC. During the choice task alone, PBTS also demonstrated decreased theta (4-7 Hz) and alpha (8-12 Hz) seed-based connectivity (p < .01), and increased RxnT in adolescence (p < .05). ABI in childhood/adolescence may predominantly disrupt recruitment of neural and attentional resources necessary for higher load tasks. These findings advance understanding of the impact of task load on brain function and cognition during development, and effects of injury.

Memory retrieval brain-behavior disconnection in mild traumatic brain injury: A magnetoencephalography and diffusion tensor imaging study.

Mild traumatic brain (mTBI) injury is often associated with long-term cognitive and behavioral complications, including an increased risk of memory impairment. Current research challenges include a lack of cross-modal convergence regarding the underlying neural-behavioral mechanisms of mTBI, which hinders therapeutics and outcome management for this frequently under-treated and vulnerable population. We used multi-modality imaging methods including magnetoencephalography (MEG) and diffusion tensor imaging (DTI) to investigate brain-behavior impairment in mTBI related to working memory. A total of 41 participants were recruited, including 23 patients with a first-time mTBI imaged within 3 months of injury (all male, age = 29.9, SD = 6.9), and 18 control participants (all male, age = 27.3, SD = 5.3). Whole-brain statistics revealed spatially concomitant functional-structural disruptions in brain-behavior interactions in working memory in the mTBI group compared with the control group. These disruptions are located in the hippocampal-prefrontal region and, additionally, in the amygdala (measured by MEG neural activation and DTI measures of fractional anisotropy in relation to working memory performance; p < .05, two-way ANCOVA, nonparametric permutations, corrected). Impaired brain-behavior connections found in the hippocampal-prefrontal and amygdala circuits indicate brain dysregulation of memory, which may leave mTBI patients vulnerable to increased environmental demands exerting memory resources, leading to related cognitive and emotional psychopathologies. The findings yield clinical implications and highlight a need for early rehabilitation after mTBI, including attention- and sensory-based behavioral exercises.

Patterns of white and gray structural abnormality associated with paediatric demyelinating disorders.

The impact of multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) - associated disorders (MOGAD) on brain structure in youth remains poorly understood. Reductions in cortical mantle thickness on structural MRI and abnormal diffusion-based white matter metrics (e.g., diffusion tensor parameters) have been well documented in MS but not in MOGAD. Characterizing structural abnormalities found in children with these disorders can help clarify the differences and similarities in their impact on neuroanatomy. Importantly, while MS and MOGAD affect the entire CNS, the visual pathway is of particular interest in both groups, as most patients have evidence for clinical or subclinical involvement of the anterior visual pathway. Thus, the visual pathway is of key interest in analyses of structural abnormalities in these disorders and may distinguish MOGAD from MS patients. In this study we collected MRI data on 18 MS patients, 14 MOGAD patients and 26 age- and sex-matched typically developing children (TDC). Full-brain group differences in fixel diffusion measures (fibre-bundle populations) and cortical thickness measures were tested using age and sex as covariates. Visual pathway analysis was performed by extracting mean diffusion measures within lesion free optic radiations, cortical thickness within the visual cortex, and retinal nerve fibre layer (RNFL) and ganglion cell layer thickness measures from optical coherence tomography (OCT). Fixel based analysis (FBA) revealed MS patients have widespread abnormal white matter within the corticospinal tract, inferior longitudinal fasciculus, and optic radiations, while within MOGAD patients, non-lesional impact on white matter was found primarily in the right optic radiation. Cortical thickness measures were reduced predominately in the temporal and parietal lobes in MS patients and in frontal, cingulate and visual cortices in MOGAD patients. Additionally, our findings of associations between reduced RNFLT and axonal density in MOGAD and TORT in MS patients in the optic radiations imply widespread axonal and myelin damage in the visual pathway, respectively. Overall, our approach of combining FBA, cortical thickness and OCT measures has helped evaluate similarities and differences in brain structure in MS and MOGAD patients in comparison to TDC.

Drumming Motor Sequence Training Induces Apparent Myelin Remodelling in Huntington's Disease: A Longitudinal Diffusion MRI and Quantitative Magnetization Transfer Study.

BACKGROUND: Impaired myelination may contribute to Huntington's disease (HD) pathogenesis. OBJECTIVE: This study assessed differences in white matter (WM) microstructure between HD patients and controls, and tested whether drumming training stimulates WM remodelling in HD. Furthermore, it examined whether training-induced microstructural changes are related to improvements in motor and cognitive function. METHODS: Participants undertook two months of drumming exercises. Working memory and executive function were assessed before and post-training. Changes in WM microstructure were investigated with diffusion tensor magnetic resonance imaging (DT-MRI)-based metrics, the restricted diffusion signal fraction (Fr) from the composite hindered and restricted model of diffusion (CHARMED) and the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) imaging. WM pathways linking putamen and supplementary motor areas (SMA-Putamen), and three segments of the corpus callosum (CCI, CCII, CCIII) were studied using deterministic tractography. Baseline MPF differences between patients and controls were assessed with tract-based spatial statistics. RESULTS: MPF was reduced in the mid-section of the CC in HD subjects at baseline, while a significantly greater change in MPF was detected in HD patients relative to controls in the CCII, CCIII, and the right SMA-putamen post-training. Further, although patients improved their drumming and executive function performance, such improvements did not correlate with microstructural changes. Increased MPF suggests training-induced myelin changes in HD. CONCLUSION: Though only preliminary and based on a small sample size, these results suggest that tailored behavioural stimulation may lead to neural benefits in early HD, that could be exploited for delaying disease progression.

Activity-dependent myelination: A glial mechanism of oscillatory self-organization in large-scale brain networks.

Communication and oscillatory synchrony between distributed neural populations are believed to play a key role in multiple cognitive and neural functions. These interactions are mediated by long-range myelinated axonal fiber bundles, collectively termed as white matter. While traditionally considered to be static after development, white matter properties have been shown to change in an activity-dependent way through learning and behavior-a phenomenon known as white matter plasticity. In the central nervous system, this plasticity stems from oligodendroglia, which form myelin sheaths to regulate the conduction of nerve impulses across the brain, hence critically impacting neural communication. We here shift the focus from neural to glial contribution to brain synchronization and examine the impact of adaptive, activity-dependent changes in conduction velocity on the large-scale phase synchronization of neural oscillators. Using a network model based on primate large-scale white matter neuroanatomy, our computational and mathematical results show that such plasticity endows white matter with self-organizing properties, where conduction delay statistics are autonomously adjusted to ensure efficient neural communication. Our analysis shows that this mechanism stabilizes oscillatory neural activity across a wide range of connectivity gain and frequency bands, making phase-locked states more resilient to damage as reflected by diffuse decreases in connectivity. Critically, our work suggests that adaptive myelination may be a mechanism that enables brain networks with a means of temporal self-organization, resilience, and homeostasis.

A controlled clinical crossover trial of exercise training to improve cognition and neural communication in pediatric brain tumor survivors.

OBJECTIVE: To assess the efficacy of aerobic exercise training to improve controlled attention, information processing speed and neural communication during increasing task load and rest in pediatric brain tumor survivors (PBTS) treated with cranial radiation. METHODS: Participants completed visual-motor Go and Go/No-Go tasks during magnetoencephalography recording prior to and following the completion of 12-weeks of exercise training. Exercise-related changes in response accuracy and visual-motor latency were evaluated with Linear Mixed models. The Phase Lag Index (PLI) was used to estimate functional connectivity during task performance and rest. Changes in PLI values after exercise training were assessed using Partial Least Squares analysis. RESULTS: Exercise training predicted sustained (12-weeks) improvement in response accuracy (p<0.05) during No-Go trials. Altered functional connectivity was detected in theta (4-7Hz) alpha (8-12Hz) and high gamma (60-100Hz) frequency bands (p<0.001) during Go and Go/No-Go trials. Significant changes in response latency and resting state connectivity were not detected. CONCLUSION: These findings support the efficacy of aerobic exercise to improve controlled attention and enhance functional mechanisms under increasing task load in participants. SIGNIFICANCE: It may be possible to harness the beneficial effects of exercise as therapy to promote cognitive recovery and enhance brain function in PBTS.

Mapping neural dynamics underlying saccade preparation and execution and their relation to reaction time and direction errors.

Our ability to control and inhibit automatic behaviors is crucial for negotiating complex environments, all of which require rapid communication between sensory, motor, and cognitive networks. Here, we measured neuromagnetic brain activity to investigate the neural timing of cortical areas needed for inhibitory control, while 14 healthy young adults performed an interleaved prosaccade (look at a peripheral visual stimulus) and antisaccade (look away from stimulus) task. Analysis of how neural activity relates to saccade reaction time (SRT) and occurrence of direction errors (look at stimulus on antisaccade trials) provides insight into inhibitory control. Neuromagnetic source activity was used to extract stimulus-aligned and saccade-aligned activity to examine temporal differences between prosaccade and antisaccade trials in brain regions associated with saccade control. For stimulus-aligned antisaccade trials, a longer SRT was associated with delayed onset of neural activity within the ipsilateral parietal eye field (PEF) and bilateral frontal eye field (FEF). Saccade-aligned activity demonstrated peak activation 10ms before saccade-onset within the contralateral PEF for prosaccade trials and within the bilateral FEF for antisaccade trials. In addition, failure to inhibit prosaccades on anti-saccade trials was associated with increased activity prior to saccade onset within the FEF contralateral to the peripheral stimulus. This work on dynamic activity adds to our knowledge that direction errors were due, at least in part, to a failure to inhibit automatic prosaccades. These findings provide novel evidence in humans regarding the temporal dynamics within oculomotor areas needed for saccade programming and the role frontal brain regions have on top-down inhibitory control.

White matter plasticity and maturation in human cognition.

White matter plasticity likely plays a critical role in supporting cognitive development. However, few studies have used the imaging methods specific to white matter tissue structure or experimental designs sensitive to change in white matter necessary to elucidate these relations. Here we briefly review novel imaging approaches that provide more specific information regarding white matter microstructure. Furthermore, we highlight recent studies that provide greater clarity regarding the relations between changes in white matter and cognition maturation in both healthy children and adolescents and those with white matter insult. Finally, we examine the hypothesis that white matter is linked to cognitive function via its impact on neural synchronization. We test this hypothesis in a population of children and adolescents with recurrent demyelinating syndromes. Specifically, we evaluate group differences in white matter microstructure within the optic radiation; and neural phase synchrony in visual cortex during a visual task between 25 patients and 28 typically developing age-matched controls. Children and adolescents with demyelinating syndromes show evidence of myelin and axonal compromise and this compromise predicts reduced phase synchrony during a visual task compared to typically developing controls. We investigate one plausible mechanism at play in this relationship using a computational model of gamma generation in early visual cortical areas. Overall, our findings show a fundamental connection between white matter microstructure and neural synchronization that may be critical for cognitive processing. In the future, longitudinal or interventional studies can build upon our knowledge of these exciting relations between white matter, neural communication, and cognition.

Disrupted network connectivity in pediatric brain tumor survivors is a signature of injury.

Cognition is compromised in pediatric brain tumor survivors but the neurophysiological basis of this compromise remains unclear. We hypothesized that reduced neural synchronization across brain networks is involved. To test this, we evaluated group differences using a retrospective cohort comparison design between 24 pediatric brain tumor survivors [11.81 ± 3.27)] and 24 age matched healthy children [12.04 ± 3.28)] in functional connectivity within a cerebellar network to examine local effects of the tumor, a whole brain network to examine diffuse effects of treatment (i.e., chemotherapy and radiation), and across multiple intrinsic connectivity networks. Neural activity was recorded during magnetoencephalography scanning while participants were at rest and functional connectivity within networks was measured using the phase lag index. We corroborated our findings using a computational model representing the local tumor effects on neural synchrony. Compared to healthy children, pediatric brain tumor survivors show increased functional connectivity for theta and beta frequency bands within the cerebellar network and increased functional connectivity for the theta band within the whole brain network that again localized to the cerebellum. Computational modeling showed that increased synchrony in the theta bad is observed following local clustering as well as sparse interarea brain connectivity. We also observed increased functional connectivity for the alpha frequency band in the ventral attention network and decreased functional connectivity within the gamma frequency band in the motor network within paedatric brain tumor survivors versus healthy children. Notably, increased gamma functional connectivity within the motor network predicted decreased reaction time on behavioral tasks in pediatric brain tumor survivors. Disrupted network synchrony may be a signature of neurological injury and disease.

Comparing MRI metrics to quantify white matter microstructural damage in multiple sclerosis.

Quantifying white matter damage in vivo is becoming increasingly important for investigating the effects of neuroprotective and repair strategies in multiple sclerosis (MS). While various approaches are available, the relationship between MRI-based metrics of white matter microstructure in the disease, that is, to what extent the metrics provide complementary versus redundant information, remains largely unexplored. We obtained four microstructural metrics from 123 MS patients: fractional anisotropy (FA), radial diffusivity (RD), myelin water fraction (MWF), and magnetisation transfer ratio (MTR). Coregistration of maps of these four indices allowed quantification of microstructural damage through voxel-wise damage scores relative to healthy tissue, as assessed in a group of 27 controls. We considered three white matter tissue-states, which were expected to vary in microstructural damage: normal appearing white matter (NAWM), T2-weighted hyperintense lesional tissue without T1-weighted hypointensity (T2L), and T1-weighted hypointense lesional tissue with corresponding T2-weighted hyperintensity (T1L). All MRI indices suggested significant damage in all three tissue-states, the greatest damage being in T1L. The correlations between indices ranged from r = 0.18 to r = 0.87. MWF was most sensitive when differentiating T2L from NAWM, while MTR was most sensitive when differentiating T1L from NAWM and from T2L. Combining the four metrics into one, through a principal component analysis, did not yield a measure more sensitive to damage than any single measure. Our findings suggest that the metrics are (at least partially) correlated with each other, but sensitive to the different aspects of pathology. Leveraging these differences could be beneficial in clinical trials testing the effects of therapeutic interventions.

Myelin Breakdown in Human Huntington's Disease: Multi-Modal Evidence from Diffusion MRI and Quantitative Magnetization Transfer.

Huntington's disease (HD) leads to white matter (WM) degeneration that may be due to an early breakdown in axon myelination but in vivo imaging correlates of demyelination remain relatively unexplored in HD compared to other neurodegenerative diseases. This study investigated HD-related effects on a putative marker of myelin, the macromolecular proton fraction (MMPF) from quantitative magnetization transfer and on fractional anisotropy, axial and radial diffusivity from diffusion tensor MR-imaging. Microstructural differences were studied in WM pathways of the basal ganglia and motor systems known to be impaired in HD: the corpus callosum, the cortico-spinal tract, the anterior thalamic radiation, fibers between prefrontal cortex and caudate and between supplementary motor area and putamen. Principal component analysis was employed for dimensionality reduction. Patients showed reductions in a component with high loadings on MMPF in all WM pathways and a trend for increases in a component loading on axial and radial diffusivities but no differences in a component loading on fractional anisotropy. While patients' performance in executive functioning was impaired, their working memory span was preserved. Inter-individual differences in the diffusivity component correlated with patients' performance in clinical measures of the United Huntington Disease Rating Scale. In summary, HD-related reductions in MMPF suggest that myelin breakdown contributes to WM impairment in human HD and emphasize the potential of quantitative MRI metrics to inform about disease pathogenesis. Disease severity in manifest HD, however, was best captured by non-specific diffusivity metrics sensitive to multiple disease and age-related changes.

Changes in White Matter Microstructure Impact Cognition by Disrupting the Ability of Neural Assemblies to Synchronize.

Cognition is compromised by white matter (WM) injury but the neurophysiological alterations linking them remain unclear. We hypothesized that reduced neural synchronization caused by disruption of neural signal propagation is involved. To test this, we evaluated group differences in: diffusion tensor WM microstructure measures within the optic radiations, primary visual area (V1), and cuneus; neural phase synchrony to a visual attention cue during visual-motor task; and reaction time to a response cue during the same task between 26 pediatric patients (17/9: male/female) treated with cranial radiation treatment for a brain tumor (12.67 ± 2.76 years), and 26 healthy children (16/10: male/female; 12.01 ± 3.9 years). We corroborated our findings using a corticocortical computational model representing perturbed signal conduction from myelin. Patients show delayed reaction time, WM compromise, and reduced phase synchrony during visual attention compared with healthy children. Notably, using partial least-squares-path modeling we found that WM insult within the optic radiations, V1, and cuneus is a strong predictor of the slower reaction times via disruption of neural synchrony in visual cortex. Observed changes in synchronization were reproduced in a computational model of WM injury. These findings provide new evidence linking cognition with WM via the reliance of neural synchronization on propagation of neural signals.SIGNIFICANCE STATEMENT By comparing brain tumor patients to healthy children, we establish that changes in the microstructure of the optic radiations and neural synchrony during visual attention predict reaction time. Furthermore, by testing the directionality of these links through statistical modeling and verifying our findings with computational modeling, we infer a causal relationship, namely that changes in white matter microstructure impact cognition in part by disturbing the ability of neural assemblies to synchronize. Together, our human imaging data and computer simulations show a fundamental connection between WM microstructure and neural synchronization that is critical for cognitive processing.

Improving the Reliability of Network Metrics in Structural Brain Networks by Integrating Different Network Weighting Strategies into a Single Graph.

Structural brain networks estimated from diffusion MRI (dMRI) via tractography have been widely studied in healthy controls and patients with neurological and psychiatric diseases. However, few studies have addressed the reliability of derived network metrics both node-specific and network-wide. Different network weighting strategies (NWS) can be adopted to weight the strength of connection between two nodes yielding structural brain networks that are almost fully-weighted. Here, we scanned five healthy participants five times each, using a diffusion-weighted MRI protocol and computed edges between 90 regions of interest (ROI) from the Automated Anatomical Labeling (AAL) template. The edges were weighted according to nine different methods. We propose a linear combination of these nine NWS into a single graph using an appropriate diffusion distance metric. We refer to the resulting weighted graph as an Integrated Weighted Structural Brain Network (ISWBN). Additionally, we consider a topological filtering scheme that maximizes the information flow in the brain network under the constraint of the overall cost of the surviving connections. We compared each of the nine NWS and the ISWBN based on the improvement of: (a) intra-class correlation coefficient (ICC) of well-known network metrics, both node-wise and per network level; and (b) the recognition accuracy of each subject compared to the remainder of the cohort, as an attempt to access the uniqueness of the structural brain network for each subject, after first applying our proposed topological filtering scheme. Based on a threshold where the network level ICC should be >0.90, our findings revealed that six out of nine NWS lead to unreliable results at the network level, while all nine NWS were unreliable at the node level. In comparison, our proposed ISWBN performed as well as the best performing individual NWS at the network level, and the ICC was higher compared to all individual NWS at the node level. Importantly, both network and node-wise ICCs of network metrics derived from the topologically filtered ISBWN (ISWBNTF), were further improved compared to the non-filtered ISWBN. Finally, in the recognition accuracy tests, we assigned each single ISWBNTF to the correct subject. We also applied our methodology to a second dataset of diffusion-weighted MRI in healthy controls and individuals with psychotic experience. Following a binary classification scheme, the classification performance based on ISWBNTF outperformed the nine different weighting strategies and the ISWBN. Overall, these findings suggest that the proposed methodology results in improved characterization of genuine between-subject differences in connectivity leading to the possibility of network-based structural phenotyping.

Myelination of the right parahippocampal cingulum is associated with physical activity in young healthy adults.

Recent evidence suggests that individual differences in physical activity (PA) may be associated with individual differences in white matter microstructure and with grey matter volume of the hippocampus. Therefore, this study investigated the association between PA and white matter microstructure of pathways connecting to the hippocampus. A total of 33 young, healthy adults underwent magnetic resonance imaging (MRI). High angular resolution diffusion-weighted imaging and multi-component relaxometry MRI scans (multi-component driven equilibrium pulse observation of T1 and T2) were acquired for each participant. Activity levels (AL) of participants were calculated from 72-h actigraphy recordings. Tractography using the damped Richardson Lucy algorithm was used to reconstruct the fornix and bilateral parahippocampal cinguli (PHC). The mean fractional anisotropy (FA) and the myelin water fraction (MWF), a putative marker of myelination, were determined for each pathway. A positive correlation between both AL and FA and between AL and MWF were hypothesized for the three pathways. There was a selective positive correlation between AL and MWF in the right PHC (r = 0.482, p = 0.007). Thus, our results provide initial in vivo evidence for an association between myelination of the right PHC and PA in young healthy adults. Our results suggest that MWF may not only be more specific, but also more sensitive than FA to detect white matter microstructural alterations. If PA was to induce structural plasticity of the right PHC this may contribute to reverse structural alterations of the right PHC in neuropsychiatric disorder with hippocampal pathologies.

Why diffusion tensor MRI does well only some of the time: variance and covariance of white matter tissue microstructure attributes in the living human brain.

Fundamental to increasing our understanding of the role of white matter microstructure in normal/abnormal function in the living human is the development of MR-based metrics that provide increased specificity to distinct attributes of the white matter (e.g., local fibre architecture, axon morphology, and myelin content). In recent years, different approaches have been developed to enhance this specificity, and the Tractometry framework was introduced to combine the resulting multi-parametric data for a comprehensive assessment of white matter properties. The present work exploits that framework to characterise the statistical properties, specifically the variance and covariance, of these advanced microstructural indices across the major white matter pathways, with the aim of giving clear indications on the preferred metric(s) given the specific research question. A cohort of healthy subjects was scanned with a protocol that combined multi-component relaxometry with conventional and advanced diffusion MRI acquisitions to build the first comprehensive MRI atlas of white matter microstructure. The mean and standard deviation of the different metrics were analysed in order to understand how they vary across different brain regions/individuals and the correlation between them. Characterising the fibre architectural complexity (in terms of number of fibre populations in a voxel) provides clear insights into correlation/lack of correlation between the different metrics and explains why DT-MRI is a good model for white matter only some of the time. The study also identifies the metrics that account for the largest inter-subject variability and reports the minimal sample size required to detect differences in means, showing that, on the other hand, conventional DT-MRI indices might still be the safest choice in many contexts.

How and how not to correct for CSF-contamination in diffusion MRI.

Diffusion MRI is used extensively to investigate changes in white matter microstructure related to brain development and pathology. Ageing, however, is also associated with significant white and grey matter loss which in turn can lead to cerebrospinal fluid (CSF) based partial volume artefacts in diffusion MRI metrics. This is especially problematic in regions prone to CSF contamination, such as the fornix and the genu of corpus callosum, structures that pass through or close to the ventricles respectively. The aim of this study was to model the effects of CSF contamination on diffusion MRI metrics, and to evaluate different post-acquisition strategies to correct for CSF-contamination: Controlling for whole brain volume and correcting on a voxel-wise basis using the Free Water Elimination (FWE) approach. Using the fornix as an exemplar of a structure prone to CSF-contamination, corrections were applied to tract-specific and voxel-based [tract based spatial statistics (TBSS)] analyses of empirical DT-MRI data from 39 older adults (53-93 years of age). In addition to significant age-related decreases in whole brain volume and fornix tissue volume fraction, age was also associated with a reduction in mean fractional anisotropy and increase in diffusivity metrics in the fornix. The experimental data agreed with the simulations in that diffusivity metrics (mean diffusivity, axial and radial diffusivity) were more prone to partial volume CSF-contamination errors than fractional anisotropy. After FWE-based voxel-by-voxel partial volume corrections, the significant positive correlations between age and diffusivity metrics, in particular with axial diffusivity, disappeared whereas the correlation with anisotropy remained. In contrast, correcting for whole brain volume had little effect in removing these spurious correlations. Our study highlights the importance of correcting for CSF-contamination partial volume effects in the structures of interest on a voxel-by-voxel basis prior to drawing inferences about underlying changes in white matter structures and have implications for the interpretation of many recent diffusion MRI results in ageing and disease.

Subcortical alterations in tissue microstructure adjacent to focal cortical dysplasia: detection at diffusion-tensor MR imaging by using magnetoencephalographic dipole cluster localization.

PURPOSE: To determine whether changes at diffusion-tensor magnetic resonance (MR) imaging were present in children with intractable epilepsy and focal cortical dysplasia (FCD) in (a) subcortical white matter subjacent to MR imaging-visible areas of FCD, (b) subcortical white matter beyond the MR imaging-visible abnormality but subjacent to a magnetoencephalographic (MEG) dipole cluster, and (c) deep white matter tracts. MATERIALS AND METHODS: The study protocol had institutional research ethics board approval, and written informed consent was obtained. Fifteen children with FCD and intractable epilepsy (mean age, 11.6 years; range, 3.6-18.3 years) underwent diffusion-tensor MR imaging and MEG. Regions of interest were placed in (a) the subcortical white matter subjacent to the MR imaging-visible abnormality, as well as the contralateral side; (b) the subcortical white matter beyond the MR imaging-visible abnormality but subjacent to a MEG dipole cluster, as well as the contralateral side; and (c) deep white matter tracts projecting to or from the MR imaging-visible FCD, as well as the contralateral side. Fractional anisotropy (FA), mean diffusivity, and eigenvalues (lambda(1), lambda(2), lambda(3)) were evaluated. RESULTS: Eleven of 15 children had MEG dipole clusters, and four children had MEG scatter. There were significant differences in FA, mean diffusivity, lambda(2), and lambda(3) of the subcortical white matter subjacent to the MR imaging-visible FCD (P < .001 for all), as well as that beyond the MR imaging-visible FCD but subjacent to a MEG dipole cluster (P = .001, P = .036, P < .001, and P = .002, respectively), compared with the contralateral side. There were also significant differences in FA (P < .001), mean diffusivity (P = .008), lambda(2) (P < .001), and lambda(3) (P = .001) of the deep white matter tracts projecting to or from the MR imaging-visible FCD compared with the contralateral side. CONCLUSION: With use of MEG dipole clusters to localize the epileptogenic zone, diffusion-tensor imaging can help identify alterations in tissue microstructure beyond the MR imaging-visible FCD.

Self-paced movements induce high-frequency gamma oscillations in primary motor cortex.

There has been increasing interest in the functional role of high-frequency (>30 Hz) cortical oscillations accompanying various sensorimotor and cognitive tasks in humans. Similar "high gamma" activity has been observed in the motor cortex, although the role of this activity in motor control is unknown. Using whole-head MEG recordings combined with advanced source localization methods, we identified high-frequency (65 to 80 Hz) gamma oscillations in the primary motor cortex during self-paced movements of the upper and lower limbs. Brief bursts of gamma activity were localized to the contralateral precentral gyrus (MI) during self-paced index finger abductions, elbow flexions and foot dorsiflexions. In comparison to lower frequency (10-30 Hz) sensorimotor rhythms that are bilaterally suppressed prior to and during movement (Jurkiewicz et al., 2006), high gamma activity increased only during movement, reaching maximal increase 100 to 250 ms following EMG onset, and was lateralized to contralateral MI, similar to findings from intracranial EEG studies. Peak frequency of gamma activity was significantly lower during foot dorsiflexion (67.4+/-5.2 Hz) than during finger abduction (75.3+/-4.4 Hz) and elbow flexion (73.9+/-3.7 Hz) although markedly similar for left and right movements of the same body part within subjects, suggesting activation of a common underlying network for gamma oscillations in the left and right motor cortex. These findings demonstrate that voluntary movements elicit high-frequency gamma oscillations in the primary motor cortex that are effector specific, and possibly reflect the activation of cortico-subcortical networks involved in the feedback control of discrete movements.