Kathleen M. Zackowski

Blood flow responses to deep brain stimulation of thalamus

Background and ObjectiveDeep 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. MethodsThe 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. ResultsThe 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. ConclusionsThe increased blood flow at terminal fields of thalamocortical projections suggests that DBS stimulates and does not inactivate projection neurons in VIM thalamus.

Sensorimotor dysfunction in multiple sclerosis and column-specific magnetization transfer-imaging abnormalities in the spinal cord

The human spinal cord contains segregated sensory and motor pathways that have been difficult to quantify using conventional magnetic resonance imaging (MRI) techniques. Multiple sclerosis is characterized by both focal and spatially diffuse spinal cord lesions with heterogeneous pathologies that have limited attempts at linking MRI and behaviour. We used a novel magnetization-transfer-weighted imaging approach to quantify damage to spinal white matter columns and tested its association with sensorimotor impairment. We studied 42 participants with multiple sclerosis who each underwent MRI at 3 Tesla and quantitative tests of sensorimotor function. We measured cerebrospinal-fluid-normalized magnetization-transfer signals in the dorsal and lateral columns and grey matter of the cervical cord. We also measured brain lesion volume, cervical spinal cord lesion number and cross-sectional area, vibration sensation, strength, walking velocity and standing balance. We used linear regression to assess the relationship between sensorimotor impairment and MRI abnormalities. We found that the dorsal column cerebrospinal-fluid-normalized magnetization-transfer signal specifically correlated with vibration sensation (R = 0.58, P < 0.001) and the lateral column signal with strength (R = -0.45, P = 0.003). Spinal cord signal measures also correlated with walking and balance dysfunction. A stepwise multiple regression showed that the dorsal column signal and diagnosis subtype alone explained a significant portion of the variance in sensation (R(2) = 0.54, P < 0.001), whereas the lateral column signal and diagnosis subtype explained a significant portion of the variance in strength (R(2) = 0.30, P < 0.001). These results help to understand the anatomic basis of sensorimotor disability in multiple sclerosis and have implications for testing the effects of neuroprotective and reparative interventions.

Revisiting Brain Atrophy and Its Relationship to Disability in Multiple Sclerosis

Background Brain atrophy is a well-accepted imaging biomarker of multiple sclerosis (MS) that partially correlates with both physical disability and cognitive impairment. Methodology/Principal Findings Based on MRI scans of 60 MS cases and 37 healthy volunteers, we measured the volumes of white matter (WM) lesions, cortical gray matter (GM), cerebral WM, caudate nucleus, putamen, thalamus, ventricles, and brainstem using a validated and completely automated segmentation method. We correlated these volumes with the Expanded Disability Status Scale (EDSS), MS Severity Scale (MSSS), MS Functional Composite (MSFC), and quantitative measures of ankle strength and toe sensation. Normalized volumes of both cortical and subcortical GM structures were abnormally low in the MS group, whereas no abnormality was found in the volume of the cerebral WM. High physical disability was associated with low cerebral WM, thalamus, and brainstem volumes (partial correlation coefficients ∼0.3–0.4) but not with low cortical GM volume. Thalamus volumes were inversely correlated with lesion load (r = −0.36, p<0.005). Conclusion The GM is atrophic in MS. Although lower WM volume is associated with greater disability, as might be expected, WM volume was on average in the normal range. This paradoxical result might be explained by the presence of coexisting pathological processes, such as tissue damage and repair, that cause both atrophy and hypertrophy and that underlie the observed disability.

Multiparametric magnetic resonance imaging analysis of the corticospinal tract in multiple sclerosis

BACKGROUND/PURPOSE Muscle weakness is an important feature of multiple sclerosis and is responsible for much of the disability associated with that condition. Here, we describe the quantitative magnetic resonance imaging (MRI) attributes of the major intracerebral motor pathway--the corticospinal tract--in multiple sclerosis. To do so, we develop an intuitive method for creating and displaying spatially normalized tract-specific imaging data. METHODS In 75 individuals with multiple sclerosis and 29 healthy controls, the corticospinal tracts were reconstructed from diffusion tensor imaging at 3 T. Multiple MRI indices--T2 relaxation time; fractional anisotropy; mean, longitudinal, and transverse diffusivity; and magnetization transfer ratio--were examined within the reconstructed tracts. Spatially normalized tract profiles were created to compare, across subjects, the variation in MRI index as a function of tract position. RESULTS Each indexs tract profile had a characteristic shape. Individual subjects had markedly abnormal tract profiles, particularly at lesion sites. On average, tract profiles were different between patients and controls, particularly in the subcortical white matter and corona radiata, for all indices examined except for fractional anisotropy. Magnetization transfer ratio was further decreased in subjects with secondary progressive disease. Tract asymmetry was increased in multiple sclerosis compared to controls. CONCLUSION Multiparametric MRI allows rapid detection, localization, and characterization of tract-specific abnormalities in multiple sclerosis. Tract profiles bridge the gap between whole-brain imaging of neurological disease and the interrogation of individual, functionally relevant subsystems.

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.

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.

Multiparametric MRI correlates of sensorimotor function in the spinal cord in multiple sclerosis

Background: Spinal cord (SC) pathology is a major contributor to clinical disability in multiple sclerosis (MS). Conventional magnetic resonance imaging (MRI), specifically SC-MRI lesion load measures that include lesion count and volume, demonstrate only a modest relationship with the clinical status of MS patients. Although SC cross-sectional area (CSA) correlates better with clinical dysfunction than MRI lesion count, SC atrophy likely signifies irreversible tissue loss. Using quantitative MRI indices sensitive to early and late microstructural changes in the spinal cord, we searched for the presence of better correlations between MRI measures and clinical status in MS. Objectives: We investigated whether diffusion-tensor imaging indices and the magnetization-transfer ratio (MTR) were better associated with the clinical status of MS patients than conventional SC-MRI measures. Methods: A total of 129 MS patients underwent 3-tesla cervical SC-MRI and quantitative sensorimotor function testing, using the Vibratron-II and dynamometer. Regions-of-interest circumscribed the SC on axial slices between C3-C4. We calculated SC-CSA, fractional anisotropy (FA), mean diffusivity (MD), perpendicular diffusivity (λ⊥), parallel diffusivity (λ||) and MTR. We used multivariable linear regression to determine if there were any associations between MRI indices and clinical measures of dysfunction. Results: All MRI indices were significantly different in subjects with MS versus healthy controls, and between the progressive versus relapsing MS subtypes, with the exception of λ||. In multivariable regression models that were adjusted for age, sex, brain parenchymal fraction, and SC-CSA, the MRI indices independently explained variability in hip flexion strength (p-values: MD, λ⊥, λ|| < 0.001; FA = 0.07), vibration sensation threshold (p-values: FA = 0.04; MTR = 0.05; λ⊥ = 0.06), and Expanded Disability Status Scale scores (p-values: FA = 0.003; MD = 0.03; λ⊥ = 0.005; MTR = 0.02). Conclusions: In a large, heterogeneous MS sample, quantitative SC-MRI indices demonstrated independent associations with system-specific and global clinical dysfunction. Our findings suggest that the indices studied may provide important information about microstructural SC changes and the substrates of limb disability in MS. The identified structure-function relationships underpin the potential utility of these measures in assessments of therapeutic efficacy.

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: 1H-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.

Adrenoleukodystrophy in female heterozygotes: Underrecognized and undertreated

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease resulting from mutations in the gene ABCD1 and alterations in peroxisomal beta-oxidation of long chain fatty acids. As it has been frequently discussed, it manifests a wide range of phenotypes in male, with progressive myelopathy being the most common. Even though the gene is localized to the X-chromosome and a region subject to X-inactivation, female carriers still are affected significantly by this condition. It has been stated that between 20 and 50% of women who are carriers may manifest some symptoms and recent evidence has suggested the differences in disease manifestations and relative rates of progression between men and women. However there have been only limited studies specifically addressing this and to date there has been no comprehensive review discussing the different phenotypes in female carriers, as well as the differences in disease onset, progression, disability, nervous system pathology and neuroimaging patterns compared to affected males. This is of key importance as similarities and differences between genders will assist in determining how best to target therapies in all affected individuals as opportunities for treatment present themselves. As will be further addressed in this review, we need to improve our understanding of the associations of emergent neuroimaging techniques to physical disability in this population. We reviewed the clinical presentations in the carrier population, the distinct disability profile and neuroimaging findings in order to put together pieces of this neglected segment in X-ALD and give direction to further studies.