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1.  Effects of motor skill learning on reciprocal inhibition 
Learning a skilled movement is associated with more efficient use of subcortical motor circuits which can coordinate features of the movements such as the timing and patterns of activation of different muscles. Learning a motor skill could strengthen spinal interneuron circuits that facilitate the movement. We hypothesized that learning a simple, alternating movement would produce changes in spinal circuits that mediate reciprocal inhibition between antagonist muscles.
Sixteen healthy adult subjects were trained to perform a wrist flexion and extension task to control the movement of a cursor between targets appearing on a computer display. The goal of the task was to hit the targets. Subjects practiced for 15 minutes daily until reaching the acquisition criterion. Surface EMG recordings from wrist flexor and extensor muscles showed reduced co-contraction during acquisition of the task.
Compared to the initial session, in the final session short-latency reciprocal inhibition was enhanced during the late-extension phase in the final session. This phase-dependent increase in short-latency reciprocal inhibition is likely to facilitate switching activation between wrist antagonistic muscles.
Learning a motor skill can produce alterations in spinal reflex circuits that facilitate the desired movement.
PMCID: PMC4279717  PMID: 23142814
Motor skill learning; reciprocal inhibition; electromyography; dual task; spinal plasticity
2.  Reliability of Fiber Tracking Measurements in Diffusion Tensor Imaging for Longitudinal Study 
NeuroImage  2009;49(2):1572-1580.
The statistical reliability of diffusion property measurements was evaluated in ten healthy subjects using deterministic fiber tracking to localize tracts affected in motor neuron disease: corticospinal tract (CST), uncinate fasciculus (UNC), and the corpus callosum in its entirety (CC), and its genu (GE), motor (CCM), and splenium (SP) fibers separately. Measurements of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ1), transverse diffusivity (λ⊥), and volume of voxels containing fibers (VV) were obtained within each tract. To assess intra-rater and inter-rater reliability, two raters carried out fiber tracking five times on each scan. Scan-rescan and longitudinal reliability were assessed in a subset of four subjects who had six scans, with two sets of three scans separated by one year. The statistical reliability of repeated measurements was evaluated using intra-class correlation coefficients (ICC) and coefficients of variation (CV). Spatial agreement of tract shape was assessed using the kappa (κ) statistic.
Repeated same-scan fiber tracking evaluations showed good geometric alignment (intra-rater κ > 0.90, inter-rater κ > 0.76) and reliable diffusion property measurements (intra-rater ICC > 0.92, inter-rater ICC > 0.77). FA, MD, and λ⊥ were highly reliable with repeated scans on different days, up to a year apart (ICC > 0.8). VV also exhibited good reliability, but with higher CVs. We were unable to demonstrate reproducibility of λ1. Longitudinal reliability after one year was improved by averaging measurements from multiple scans at each timepoint. Fiber tracking provides a reliable tool for the longitudinal evaluation of white matter diffusion properties.
PMCID: PMC2789889  PMID: 19744567
diffusion tensor imaging; tractography; fiber tracking; corticospinal tract; corpus callosum; test-retest reliability
3.  Imaging Findings Associated with Cognitive Performance in Primary Lateral Sclerosis and Amyotrophic Lateral Sclerosis 
Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS), but it has not been well studied in primary lateral sclerosis (PLS). The aims of this study were to (1) compare cognitive function in PLS to that in ALS patients, (2) explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI) metrics of white matter tracts and gray matter volumes, and (3) compare DTI metrics in patients with and without cognitive and behavioral changes.
The Delis-Kaplan Executive Function System (D-KEFS), the Mattis Dementia Rating Scale (DRS-2), and other behavior and mood scales were administered to 25 ALS patients and 25 PLS patients. Seventeen of the PLS patients, 13 of the ALS patients, and 17 healthy controls underwent structural magnetic resonance imaging (MRI) and DTI. Atlas-based analysis using MRI Studio software was used to measure fractional anisotropy, and axial and radial diffusivity of selected white matter tracts. Voxel-based morphometry was used to assess gray matter volumes. The relationship between diffusion properties of selected association and commissural white matter and performance on executive function and memory tests was explored using a linear regression model.
More ALS than PLS patients had abnormal scores on the DRS-2. DRS-2 and D-KEFS scores were related to DTI metrics in several long association tracts and the callosum. Reduced gray matter volumes in motor and perirolandic areas were not associated with cognitive scores.
The changes in diffusion metrics of white matter long association tracts suggest that the loss of integrity of the networks connecting fronto-temporal areas to parietal and occipital areas contributes to cognitive impairment.
PMCID: PMC3776403  PMID: 24052798
Motor neuron disease; Executive function; Diffusion tensor imaging
4.  Structural imaging differences and longitudinal changes in primary lateral sclerosis and amyotrophic lateral sclerosis☆ 
NeuroImage : Clinical  2012;2:151-160.
Magnetic resonance imaging measures have been proposed as objective markers to study upper motor neuron loss in motor neuron disorders. Cross-sectional studies have identified imaging differences between groups of healthy controls and patients with amyotrophic lateral sclerosis (ALS) or primary lateral sclerosis (PLS) that correlate with disease severity, but it is not known whether imaging measures change as disease progresses. Additionally, whether imaging measures change in a similar fashion with disease progression in PLS and ALS is unclear. To address these questions, clinical and imaging evaluations were first carried out in a prospective cross-sectional study of 23 ALS and 22 PLS patients with similar motor impairment and 19 age-matched healthy controls. Clinical evaluations consisted of a neurological examination, the ALS Functional rating scale-revised, and measures of finger tapping, gait, and timed speech. Age and ALSFRS score were not different, but PLS patients had longer duration of symptoms. Imaging measures examined were cortical thickness, regional brain volumes, and diffusion tensor imaging of the corticospinal tract and callosum. Imaging measures that differed from controls in a cross-sectional vertex-wise analysis were used as regions of interest for longitudinal analysis, which was carried out in 9 of the ALS patients (interval 1.26 ± 0.72 years) and 12 PLS patients (interval 2.08 ± 0.93 years). In the cross-sectional study both groups had areas of cortical thinning, which was more extensive in motor regions in PLS patients. At follow-up, clinical measures declined more in ALS than PLS patients. Cortical thinning and grey matter volume loss of the precentral gyri progressed over the follow-up interval. Fractional anisotropy of the corticospinal tracts remained stable, but the cross-sectional area declined in ALS patients. Changes in clinical measures correlated with changes in precentral cortical thickness and grey matter volume. The rate of cortical thinning was greater in ALS patients with shorter disease durations, suggesting that thickness decreases in a non-linear fashion. Thus, cortical thickness changes are a potential imaging marker for disease progression in individual patients, but the magnitude of change likely depends on disease duration and progression rate. Differences between PLS and ALS patients in the magnitude of thinning in cross-sectional studies are likely to reflect longer disease duration. We conclude that there is an evolution of structural imaging changes with disease progression in motor neuron disorders. Some changes, such as diffusion properties of the corticospinal tract, occur early while cortical thinning and volume loss occur later.
► In a cross-sectional study, ALS and PLS patients had thinning of the motor cortex compared to age-matched controls ► Progressive thinning and atrophy of the precentral gyrus were correlated with clinical progression over a 1- or 2-year longitudinal follow-up ► The rate of cortical thinning was faster in ALS patients with a shorter disease duration ► Fractional anisotropy of corticospinal tracts, though reduced at baseline in ALS and PLS patients remained stable over longitudinal follow-up ► Imaging changes evolve with disease progression in motor neuron disorders ► Changes in white matter diffusion properties occur early, while cortical thinning and atrophy occur later and over a longer time frame
PMCID: PMC3778247  PMID: 24179768
ALS, amyotrophic lateral sclerosis; ALSFRS-R, ALS functional rating scale, revised; CC, corpus callosum; CST, corticospinal tract; DTI, diffusion tensor imaging; FA, fractional anisotropy; MD, mean diffusivity; MRI, magnetic resonance imaging; PLS, primary lateral sclerosis; UMN, upper motor neuron; Cortical thickness; Longitudinal studies; Motor neuron disease; Diffusion tensor imaging; FreeSurfer
5.  White matter alterations differ in primary lateral sclerosis and amyotrophic lateral sclerosis 
Brain  2011;134(9):2642-2655.
Primary lateral sclerosis is a sporadic disorder characterized by slowly progressive corticospinal dysfunction. Primary lateral sclerosis differs from amyotrophic lateral sclerosis by its lack of lower motor neuron signs and long survival. Few pathological studies have been carried out on patients with primary lateral sclerosis, and the relationship between primary lateral sclerosis and amyotrophic lateral sclerosis remains uncertain. To detect in vivo structural differences between the two disorders, diffusion tensor imaging of white matter tracts was carried out in 19 patients with primary lateral sclerosis, 18 patients with amyotrophic lateral sclerosis and 19 age-matched controls. Fibre tracking was used to reconstruct the intracranial portion of the corticospinal tract and three regions of the corpus callosum: the genu, splenium and callosal fibres connecting the motor cortices. Both patient groups had reduced fractional anisotropy, a measure associated with axonal organization, and increased mean diffusivity of the reconstructed corticospinal and callosal motor fibres compared with controls, without changes in the genu or splenium. Voxelwise comparison of the whole brain white matter using tract-based spatial statistics confirmed the differences between patients and controls in the diffusion properties of the corticospinal tracts and motor fibres of the callosum. This analysis further revealed differences in the regional distribution of white matter alterations between the patient groups. In patients with amyotrophic lateral sclerosis, the greatest reduction in fractional anisotropy occurred in the distal portions of the intracranial corticospinal tract, consistent with a distal axonal degeneration. In patients with primary lateral sclerosis, the greatest loss of fractional anisotropy and mean diffusivity occurred in the subcortical white matter underlying the motor cortex, with reduced volume, suggesting tissue loss. Clinical measures of upper motor neuron dysfunction correlated with reductions in fractional anisotropy in the corticospinal tract in patients with amyotrophic lateral sclerosis and increased mean diffusivity and volume loss of the corticospinal tract in patients with primary lateral sclerosis. Changes in the diffusion properties of the motor fibres of the corpus callosum were strongly correlated with changes in corticospinal fibres in patients, but not in controls. These findings indicate that degeneration is not selective for corticospinal neurons, but affects callosal neurons within the motor cortex in motor neuron disorders.
PMCID: PMC3170531  PMID: 21798965
diffusion tensor imaging; diffusion tensor tractography; motor neuron disorders; primary lateral sclerosis; corpus callosum
6.  Iron Accumulation in Deep Cortical Layers Accounts for MRI Signal Abnormalities in ALS: Correlating 7 Tesla MRI and Pathology 
PLoS ONE  2012;7(4):e35241.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by cortical and spinal motor neuron dysfunction. Routine magnetic resonance imaging (MRI) studies have previously shown hypointense signal in the motor cortex on T2-weighted images in some ALS patients, however, the cause of this finding is unknown. To investigate the utility of this MR signal change as a marker of cortical motor neuron degeneration, signal abnormalities on 3T and 7T MR images of the brain were compared, and pathology was obtained in two ALS patients to determine the origin of the motor cortex hypointensity. Nineteen patients with clinically probable or definite ALS by El Escorial criteria and 19 healthy controls underwent 3T MRI. A 7T MRI scan was carried out on five ALS patients who had motor cortex hypointensity on the 3T FLAIR sequence and on three healthy controls. Postmortem 7T MRI of the brain was performed in one ALS patient and histological studies of the brains and spinal cords were obtained post-mortem in two patients. The motor cortex hypointensity on 3T FLAIR images was present in greater frequency in ALS patients. Increased hypointensity correlated with greater severity of upper motor neuron impairment. Analysis of 7T T2*-weighted gradient echo imaging localized the signal alteration to the deeper layers of the motor cortex in both ALS patients. Pathological studies showed increased iron accumulation in microglial cells in areas corresponding to the location of the signal changes on the 3T and 7T MRI of the motor cortex. These findings indicate that the motor cortex hypointensity on 3T MRI FLAIR images in ALS is due to increased iron accumulation by microglia.
PMCID: PMC3328441  PMID: 22529995

Results 1-6 (6)