Anatomical Characteristics of Benign Essential Blepharospasm: A Diffusion Tensor Imaging Investigation Using Group Fractional Anisotropy Comparisons and Probabilistic Tractography

Benign Essential Blepharosmasm (BEB) is a form of cranial and focal dystonia characterized by involuntary closure of the eyelids. Although first case of BEB was documented in the 1600s, the underlying cause of this disease has yet to be discovered. Newly developed imaging techniques, such as diffusion weighted imaging (DWI), have the potential to reveal peculiarities of the neural organization in BEB. DWI is the fist non-invasive imaging method that allows assessment of white matter integrity of the living tissues. It measures the distance traveled by water molecules set in motion by the magnetic gradients. If the water molecules do not encounter any constraints along their paths, then the distances traveled will be large and equidistant in all directions, or isotropic. This type of motion of the water molecules occurs in the ventricles, large atriums in the brain filled with cerebrospinal fluid. The water molecules located in highly organized white matter bundles, such as the corpus callosum, can only move along the longitudinal axis of the axons comprising the fiber bundles. In this case the diffusion of the molecules is called anisotropic, motion preferred in a particular direction.

The DWI measurements that characterize the diffusion properties on voxel basis are the fractional anisotropy (FA) and mean diffusivity (MD). FA values range from 0 to 1, where the values close to 0 indicate isotropic diffusion and values close to 1 describe voxels with highly anisotropic diffusion. The mean diffusivity values describe the average rate of diffusion of the water molecules in the voxel.

Another useful application of the DWI is white matter fiber tractography where white matter bundles of interest can be traced in vivo. Tractography algorithms can be categorized as either streamline or probabilistic. The streamline technique traces the fibers along the principal direction of motion of the water molecules in a voxel. While this approach produces consistent results in large fiber bundles, it fails to accurately represent fiber crossings, where no single principle direction of diffusion exists. In contrast, probabilistic approaches extract a large number of samples from the data and trace multiple diffusion directions per voxel.

The purpose of my summer project at the NIH was to perform a group voxelwise analysis on the FA values in a group of BEB patients and healthy volunteers (HV) in order to examine structural integrity of white matter in the BEB patients compared to controls. The areas that show differences between the two groups were used in further analysis using probabilistic tractography, which map the deviation in fiber bundles between two groups.

We obtained DWI data on 19 BEB patients and 19 controls. The FA maps for each participant were computed (1) and registered to a common template (FMRIB_FA_58, MNI152) using non-linear registration (2). A mean skeleton, which represents the major white matter tracts common to all subjects was created. This skeleton was used as a template onto which each individual subjects' FA values from the nearest tract center were projected (3). The areas that showed higher FA values in the healthy volunteers were the anterior cingulum, the fornix, the anterior limb of the internal capsule, the thalamus, the cerebellum, the brainstem, superior temporal gyrus, middle temporal gyrus, as well as medial frontal areas. The region of particular interest in this patient population is the cingulum, due to its involvement in voluntary blinking (4). Thus, the voxels in the anterior cingulum that were shown to have lower FA values in the patients vs the controls were projected back to the original FA space for each subject. These voxels were used as seeds for the fiber tracing using probabilistic tractography (5). The tractography analysis showed that the BEB patients have less extensive projections from the anterior cingulate to the mediofrontal regions. The medial frontal cortex performs a wide array of executive control functions. Thus lower connectivity between these regions and the anterior cingulum might be responsible for BEB patients' inability to control the muscles of the eyelids.

The statistical analysis of the FA values in the BEB patients compared to age matched healthy volunteers revealed a number of regions with lower FA values in the patient group. The lower FA values indicate lower degree of structural organization in the white matter of the patients. Of particular interest is the region of anterior cingulate. This region has been implicated to play a role in voluntary blinking. Lower FA values in this region together with decreased connectivity between anterior cingulate and medial frontal cortex could explain involuntary blinking in the BEB patients.

References:

1. K. Simonyan, F. Tovar-Moll, J. Ostuni, M. Hallett, V.F. Kalasinsky, M.R. Lewin-Smith, E.J. Rushing, A.O. Vortmeyer and L. Christy, Focal white matter changes in spasmodic dysphonia: a combined diffusion tensor imaging and neuropathological study, Brain 131 (2008), pp. 447-459.

2.T.E.J. Behrens, M.W. Woolrich, M. Jenkinson, H. Johansen-Berg, R.G. Nunes, S. Clare, P.M. Matthews, J.M. Brady, and S.M. Smith, Characterization and propagation of uncertainty in diffusion-weighted MR imaging, Magn. Reson. Med. 50 (2003), pp. 1077-1088.

3. D. Rueckert, L. Sonoda, C. Hayes, D. Hill, M. Leach and D. Hawkes, Nonrigid registration using free-form deformations: application to breast MR images, IEEE Trans. Med. Imag. 18 (1999) pp. 712-721.

4.S.M. Smith, M. Jenkinson, H. Johansen-Berg, D. Rueckert, T.E. Nichols, C.E. Mackay, K.E. Watkins, O. Ciccarelli, M.Z. Cader, P.M. Matthews and T.E.J. Behrens, Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data, NeuroImage 31 (2006), pp. 1487-1505.

5. T. Hanakawa, M.A. Dimyan and M. Hallett, The representation of blinking movement in cingulate motor areas: A functional magnetic resonance imaging study, Cerebral Cortex 18 (2008), pp. 930-937.