Corticospinal tract abnormalities are associated with weakness in multiple sclerosis.

BACKGROUND AND PURPOSE: The association of MR imaging abnormalities with clinical disability in multiple sclerosis (MS) has been disappointing. This association might be improved by imaging specific functional systems in the central nervous system-for example, the motor system in a patient with weakness. Our aim was to assess the relationship between muscle strength in MS and corticospinal tract (CST) abnormalities detected with multimodality MR imaging of the brain. MATERIALS AND METHODS: In 47 individuals with MS, diffusion tensor imaging (DTI) at 3T was used to reconstruct the intracranial CSTs. Tract profiles depicted the variation in T2 relaxation time, magnetization transfer ratio (MTR), and DTI-derived indices (fractional anisotropy and diffusivity) as a function of normalized position along the tract. Brain parenchymal fraction was calculated as a normalized measure of brain volume. Stepwise linear regression modeling was used to determine the MR imaging indices most closely related to ankle dorsiflexion and hip flexion strength assessed with quantitative dynamometry. RESULTS: Individuals with MS were significantly weak: Average ankle strength fell 1.7 SDs below the age-, handedness-, and sex-corrected healthy mean. Brain parenchymal fraction was not associated with weakness. A parsimonious model that includes MTR in the brain stem and MS clinical subtype explained 30%-45% of the variance in ankle and hip strength. The model was successfully applied to scans and strength data from the same individuals at an earlier time point. CONCLUSION: MR imaging abnormalities specific to the motor tract are associated with clinical dysfunction related to that tract. The relevant abnormalities are found in the brain stem, distant from the periventricular inflammatory lesions that are common in MS. This suggests that neurodegeneration, rather than primary inflammation, at least partially explains the findings.

Quantitative characterization of the corticospinal tract at 3T.

BACKGROUND AND PURPOSE: White matter tract-specific imaging will probably become a major component of clinical neuroradiology. Fiber tracking with diffusion tensor imaging (DTI) is widely used, but variability is substantial. This article reports the ranges of MR imaging appearance and right-left asymmetry of healthy corticospinal tracts (CST) reconstructed with DTI. METHODS: For 20 healthy volunteers, whole-brain DTI data were coregistered with maps of absolute T1 and T2 relaxation times and magnetization transfer ratio (MTR), all acquired at 3T. For each individual, the 2 reconstructed CSTs and their asymmetry were analyzed with respect to the number of fibers reconstructed; tract volume; and individual MR imaging parameters restricted to the tracts. Interscan variability was estimated by repeat imaging of 8 individuals. RESULTS: Reconstructed fiber number and tract volume are highly variable, rendering them insensitive to abnormalities in disease. Individual tract-restricted MR imaging parameters are more constrained, and their population averages and normal ranges are reported. The average population asymmetry is generally zero; therefore, normal ranges for an index of asymmetry are reported. By way of example, CST-restricted MR imaging parameters and their asymmetries are shown to be abnormal in an individual with multiple sclerosis who had a lesion affecting the CST. CONCLUSIONS: The results constitute a normative dataset for the following imaging parameters of the CST: T1, T2, MTR, fractional anisotropy, mean diffusivity, transverse diffusivity, and the 3 diffusion tensor eigenvalues. These data can be used to identify, characterize, and establish the significance of changes in diseases that affect the CST.

Magnetization transfer MRI demonstrates spinal cord abnormalities in adrenomyeloneuropathy.

BACKGROUND: In adrenomyeloneuropathy (AMN) conventional MRI detects only spinal cord atrophy in the late stages. OBJECTIVE: To apply a magnetization transfer-weighted (MTw) imaging to patients with AMN and AMN-like syndrome in order to visualize and quantitatively assess the pathology of white matter tracts in the cervical spinal cord. METHODS: MTw studies were conducted in nine men with AMN, eight symptomatic heterozygous women, and 10 age- and sex-matched controls and compared to the Expanded Disability Status Scale (EDSS) and quantitative tests of vibratory sense and postural sway. MTw data sets were obtained at the level of C1 to C3 using a three-dimensional gradient echo acquisition technique, these images were then standardized between subjects by using the in-slice CSF signal as a normalization reference, allowing a quantitative assessment of the MTw signal. RESULTS: In contrast to conventional MRI, MTw images showed signal hyperintensities in the lateral and dorsal columns of all patients. The MT signal quantified in the dorsal column showed significant differences between patients with AMN, X-linked adrenoleukodystrophy heterozygotes, and controls. MT hyperintensity in the dorsal column correlated with EDSS, vibratory sense, and postural sway. CONCLUSION: Magnetization transfer-weighted imaging is a sensitive modality for the visual and quantitative assessment of spinal cord pathology in adrenomyeloneuropathy, and is a potential tool for evaluation of new therapies.

Spectroscopic evidence of cerebral axonopathy in patients with "pure" adrenomyeloneuropathy.

BACKGROUND: Adrenomyeloneuropathy (AMN) is the adult variant of X-linked adrenoleukodystrophy. The disease pathology is usually limited to spinal cord and peripheral nerves, and when this is the case, it is referred to as "pure" AMN. Histopathology shows cerebral involvement even in pure AMN; however, not much is known about the nature, extent, and clinical relevance of these findings. OBJECTIVE: To investigate brain involvement in AMN patients with normal MRI, employing multislice MR spectroscopic imaging. METHODS: Twelve men with pure AMN were compared with 19 age-matched healthy volunteers. Metabolite ratios (N-acetylaspartate [NAA]/choline [Cho], NAA/creatine [Cr], and Cho/Cr) were measured from seven brain regions. Global metabolite ratios were generated as an average of these seven regional ratios. The Expanded Disability Status Scale (EDSS) was used for neurologic evaluation. RESULTS: The patients with AMN showed reduced global NAA/Cho (AMN 1.40 +/- 0.16 vs controls 1.75 +/- 0.34; p = 0.003)) and global NAA/Cr (AMN 2.32 +/- 0.13 vs controls 2.62 +/- 0.43; p = 0.03). Regionally, NAA/Cho was lowered in the internal capsule (AMN 1.30 +/- 0.20 vs controls 1.69 +/- 0.37; p = 0.002) and in parieto-occipital white matter (AMN 1.45 +/- 0.19 vs controls 1.78 +/- 0.55; p = 0.04). NAA/Cr was lowered in parieto-occipital white matter (AMN 2.34 +/- 0.31 vs controls 2.83 +/- 0.71; p = 0.04). EDSS demonstrated an inverse association with global NAA/Cr (r = -0.65, p = 0.02) and NAA/Cr in centrum semiovale (r = -0.73, p = 0.006) and in parieto-occipital white matter (r = -0.64, p = 0.02). Cho/Cr was not significantly elevated. CONCLUSIONS: (1)H-MR spectroscopic imaging is able to detect biochemical abnormalities suggestive of axonal damage even in the brains of patients with pure adrenomyeloneuropathy. The axonopathy is most prominent in internal capsule and parieto-occipital white matter and may contribute to clinical disability.

How do strength, sensation, spasticity and joint individuation relate to the reaching deficits of people with chronic hemiparesis?

Hemiparetic subjects present with movement deficits including weakness, spasticity and an inability to isolate movement to one or a few joints. Voluntary attempts to move a single joint often result in excessive motion at adjacent joints. We investigated whether the inability to individuate joint movements is associated with deficits in functional reaching. Controls and hemiparetic subjects performed two different reaching movements and three individuated arm movements, all in the parasagittal plane. The reaching movements were a sagittal 'reach up' (shoulder flexion and elbow flexion) and 'reach out' (shoulder flexion and elbow extension). Joint individuation was assessed by getting each subject to perform an isolated flexion-extension movement at each of the shoulder, elbow and wrist joints. In addition, we measured strength, muscle tone and sensation using standard clinical instruments. Hemiparetic subjects showed varying degrees of impairment when performing reaching movements and individuated joint movements. Reaching impairments (hand path curvature, velocity) were worse in the reach out versus the reach up condition. Typical joint individuation abnormalities were excessive flexion of joints that should have been held fixed during movement of the instructed joint. Hemiparetic subjects tended to produce concurrent flexion motions of shoulder and elbow joints when attempting any movement, one explanation for why they were better at the 'reach up' than the 'reach out' task. Hierarchical regression analysis showed that impaired joint individuation explained most of the variance in the reach path curvature and end point error; strength explained most of the variance in reaching velocity. Sensation also contributed significantly, but spasticity and strength were not significant in the model. We conclude that the deficit in joint individuation reflects a fundamental motor control problem that largely explains some aspects of voluntary reaching deficits of hemiparetic subjects.

Cerebellar subjects show impaired coupling of reach and grasp movements.

We examined how cerebellar deficits in isolated reaching or grasping movements contribute to abnormalities in a combined reach and grasp movement, and whether people with cerebellar damage show abnormalities in the spatiotemporal relationships of reach and grasp movements. We studied subjects with cerebellar damage and matched controls as they performed a combined reach and grasp, an isolated reach, and an isolated grasp. These movements were performed under slow-accurate and fast speed conditions. Subjects were also tested for their ability to correctly estimate the target size based on visual information. We measured the three-dimensional position of the index finger, thumb and wrist joint during all tasks. Results showed that cerebellar subjects overestimated the target size to a greater extent than did controls. During movement testing, cerebellar subjects were impaired on isolated reach and isolated grasp. However, they did not worsen parameters of reach or grasp movements during the combined reach and grasp. Instead there were distinct deficits in the coupling of the reach and grasp movement. Compared with controls, cerebellar subjects showed abnormalities in the sequence of the reach and grasp movement and highly variable timing of peak grip aperture. In the slow-accurate condition, cerebellar subjects decomposed the reach and grasp movement into separate reach then grasp components, and produced multiple peaks in grip aperture. In the fast condition, cerebellar subjects did not decompose, produced a single peak grip aperture, and dropped the target more often. These results indicate that cerebellar damage can cause a specific breakdown in the coupling of reach and grasp movements. The cerebellum may be involved in combining reach and grasp movements into a single motor program.

Blood flow responses to deep brain stimulation of thalamus.

BACKGROUND AND OBJECTIVE: Deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus (VIM) provides remarkable relief of tremor in the limbs contralateral to the side of the brain stimulated. The benefits have been sufficiently dramatic that this is now an accepted clinical treatment of essential as well as other forms of tremor. Despite this clinical benefit, the mechanism of action of DBS remains unknown. In this investigation, we sought to determine the effects of VIM DBS on neuronal function. METHODS: The authors used PET measurements of qualitative regional cerebral blood flow in patients with essential tremor to determine the effects of DBS in the left VIM. Each subject had four to six scans with the arms at rest and DBS turned either on or off during alternate scans. Continuous physiologic monitoring revealed no tremor during any of the scans. The PET images from each subject were aligned, averaged, and coregistered to a standard image oriented in stereotactic space. RESULTS: The authors used subtraction image analysis with statistical parametric mapping methods and a restricted volume search to identify a significantly increased flow response at the site of stimulation in thalamus. An exploratory analysis revealed increased flow in ipsilateral supplementary motor area, a region that receives afferents from VIM. CONCLUSIONS: The increased blood flow at terminal fields of thalamocortical projections suggests that DBS stimulates and does not inactivate projection neurons in VIM thalamus.

Thalamic stimulation reduces essential tremor but not the delayed antagonist muscle timing.

BACKGROUND: Electrical stimulation of the thalamus dramatically reduces essential tremor (ET). It has been hypothesized that the cerebellum and inferior olive are involved in the generation of ET, and thalamic stimulation is presumed to dampen ET through interactions with cerebellar output to the thalamus. Evidence suggests that abnormal timing of agonist and antagonist muscle responses contribute to cerebellar tremor (CbT); however, this relationship has not been investigated for ET. The mechanisms of the tremor and improvement are unknown. OBJECTIVE: To measure the effect of ventral intermediate thalamic stimulation in controlling the ET response to sudden stretch of an agonist muscle and to determine whether, in ET, the timing relationships between the initial agonist and antagonist electromyography (EMG) responses show abnormalities similar to those seen in CbT. METHODS: The authors studied ET subjects (with implanted thalamic stimulators turned off and on) and normal controls as they responded to mechanical torque pulses given at the wrist joint. The wrist joint angle, wrist agonist, and antagonist EMG were recorded. RESULTS: Like CbT, patients with ET showed delayed onsets of antagonist EMG and excessive rebound. Thalamic stimulation reduced the tremor but did not alter the antagonist delay or the rebound. CONCLUSIONS: In ET, antagonist muscle responses to a torque pulse are similar to that in CbT. However, benefit from thalamic stimulation did not alter these EMG responses; therefore, suppression of tremor must be caused by mechanisms other than the re-establishment of normal agonist-antagonist timing.

Cerebellar ataxia: torque deficiency or torque mismatch between joints?

Prior work has shown that cerebellar subjects have difficulty adjusting for interaction torques that occur during multi-jointed movements. The purpose of this study was to determine whether this deficit is due to a general inability to generate sufficient levels of phasic torque inability or due to an inability to generate muscle torques that predict and compensate for interaction torques. A second purpose was to determine whether reducing the number of moving joints by external mechanical fixation could improve cerebellar subjects' targeted limb movements. We studied control and cerebellar subjects making elbow flexion movements to touch a target under two conditions: 1) a shoulder free condition, which required only elbow flexion, although the shoulder joint was unconstrained and 2) a shoulder fixed condition, where the shoulder joint was mechanically stabilized so it could not move. We measured joint positions of the arm in the sagittal plane and electromyograms (EMGs) of shoulder and elbow muscles. Elbow and shoulder torques were estimated using inverse dynamics equations. In the shoulder free condition, cerebellar subjects made greater endpoint errors (primarily overshoots) than did controls. Cerebellar subjects' overshoot errors were largely due to unwanted flexion at the shoulder. The excessive shoulder flexion resulted from a torque mismatch, where larger shoulder muscle torques were produced at higher rates than would be appropriate for a given elbow movement. In the shoulder fixed condition, endpoint errors of cerebellar subjects and controls were comparable. The improved accuracy of cerebellar subjects was accompanied by reduced shoulder flexor muscle activity. Most of the correct cerebellar trials in the shoulder fixed condition were movements made using only muscles that flex the elbow. Our findings suggest that cerebellar subjects' poor shoulder control is due to an inability to generate muscle torques that predict and compensate for interaction torques, and not due to a general inability to generate sufficient levels of phasic torque. In addition, reducing the number of muscles to be controlled improved cerebellar ataxia.

Impairment of neuromuscular propagation during human fatiguing contractions at submaximal forces.

1. The purpose of the study was to examine the dependence of neuromuscular propagation impairment on the level of isometric force sustained to the endurance limit. The task involved human volunteers sustaining a submaximal abduction force with the index finger by activating the first dorsal interosseous muscle as long as possible. 2. The submaximal force was sustained at one of three levels (20, 35 or 65% of maximum) by increasing motor unit activity, as indicated by the electromyogram (EMG), during the fatiguing contraction. Although the EMG increased during the fatiguing contraction, the EMG was significantly less than maximum at the endurance limit for all subjects (deficit of 19-55% of maximum). This deficit was inversely related to the level of the sustained submaximal force. 3. The maximum voluntary contraction and twitch forces were significantly reduced following the fatiguing contraction. As with the EMG, the degree of force reduction was greatest for the subjects who sustained the low target forces. 4. The fatiguing contraction caused a 12-23% decline in M wave amplitude, a 33-51% increase in M wave duration, and no change in M wave area. The decline in M wave amplitude, which is an index of neuromuscular propagation impairment, was greatest among the subjects who sustained the low target forces. 5. The mean power frequency of the EMG decreased by a similar amount (50-57%) during the fatiguing contraction for all three groups of subjects. 6. A model representing the interaction of processes that enhance and impair force was developed to explain the recovery of twitch force following the sustained contractions at different target forces. 7. We conclude that the fatigue experienced by a subject when force is sustained at a submaximal value does involve an impairment of neuromuscular propagation. This impairment is one factor that limits muscle excitation during a submaximal, fatiguing contraction and contributes to the diminished force capability by the end of the fatigue task.