A total of 15 MIS patients with no history of neurological or psychiatric disorder were recruited. All patients were selected through a detailed questionnaire including any symptoms of eye-strain or visual perceptual distortion and other associated symptoms to determine if the described reading difficulties were due to MIS. A complete ophthalmologic evaluation including visual acuity, refractive errors, slit lamp examination, tear break-up time, strabismus, and retinal findings was performed prior to inclusion in the study. Exclusion criteria were the following: 1) any ophthalmologic disorder other than MIS, 2) history of proven neurological or psychiatric disorder, 3) history of significant head injury, 4) patients who were younger than nine years of age, and 5) patients who were linguistically, intellectually, or mentally challenged. All participants gave written informed consent prior to study inclusion and the local ethics committee approved the study protocol of the institutional review board at Korea University Medical Center.

We conducted a thorough examination for dyslexia via the Reading Writing Speed Meter, which was developed in Korea to evaluate both reading and writing abilities [8,9,10]. Patients were asked to read paragraphs aloud written in different font sizes, with letter spacing and vocabulary level that was dependent on the age group. The number of words read in one minute were determined and recorded. Different paragraphs were provided for those in grades 4 to 6, middle school, and high school. To eliminate the possibility of guessing words based on the context, the wording was randomized so that the presented sentences were meaningless. Statistical analysis of the reading speed before and after use of tinted lenses was conducted using the Wilcoxon signed-rank test. Statistical significance was set at p < 0.05 (SPSS ver. 13.0; SPSS Inc., Chicago, IL, USA).

MISViS filters consist of a variety of lens colors. Each color provides four to five lenses with differences in the degree of darkness (Fig. 1). Patients first wore the lightest lens of each color group to be sure they were comfortable with the color group. Within the selected color group, subjects with a reading speed that improved more than 20% compared to their base line speed without selected lenses or those with marked alleviation of subjective visual symptoms with color-tinted lenses were considered to have MIS (Table 1) [8,9,10].

fMRI acquisition was performed using a Trio 3T scanner (Siemens, Erlangen, Germany) equipped with a 12-channel phased array head coil. We acquired gradient echo T2-weighted echo-planar images with blood-oxygenation-level-dependent (BOLD) contrast as an index of brain activity [11]. A functional image volume consisted of 38 continuous axial slices of 3 mm thickness (repetition time, 2,000 ms; echo time, 21 ms; field-of-view, 220 × 220; matrix, 64 × 64; in-plane resolution, 3.4 mm × 3.4 mm). A total of 400 functional volumes were acquired for each participant (200 in each session, as described below). To co-register echo-planar images and facilitate the anatomical localization of statistically significant activations, a high-resolution 3D MP-RAGE sequence was acquired with the following parameters: repetition time, 1,780 ms; echo time, 2.34 ms; number of excitation, 1; matrix, 256 × 256; FOV, 256 × 256 mm; voxel size, 1 mm. Axial T2-weighted images (3-mm-thickness) were also acquired to identify structural abnormalities. Structural magnetic resonance images of all participants were reviewed by a board-certified neuroradiologist to identify any structural abnormalities and were reported as normal.

Each participant wore eyeglasses without metal frames that were specifically designed for the fMRI study. The fMRI paradigm used a block design comprised of alterations of 20-s rest epochs of passive viewing of an onscreen black cross with 20-s activation epochs during which patients were previously instructed to make their best effort to soundlessly read sentences on the magnetic resonance imaging-compatible LCD screen. This rest-activation procedure was repeated for a total of ten cycles for each session. Each patient underwent two sessions of fMRI experimentation, before and after application of color-tinted lenses.

Pre-processing and analysis of f MRI data were performed using SPM8 (Wellcome Department of Cognitive Neurology, http://www.fil.ion.ucl.ac.uk/spm). Functional images were realigned to correct for head movements and co-registered with the high-resolution structural image from each participant. The structural image was then segmented into grey matter, white matter, and cerebrospinal fluid partitions and normalized to the Montreal Neurological Institute standard brain. The resulting transformation matrix was then applied to all functional volumes, which were resampled to a voxel size of 3.0 mm × 3.0 mm × 3.0 mm. Finally, the functional images were smoothed with an 8-mm full-width at half-maximum isotropic Gaussian kernel.

Changes in BOLD contrast associated with the performance of the sentence reading task were assessed on a pixel-by-pixel basis using the general linear model and the theory of Gaussian fields [12]. Each boxcar stimulus function was convolved with a canonical hemodynamic response function, and data were high-pass filtered with a cutoff period of 128 seconds. For two sessions in each subject, a first-level design matrix was built, in which motion parameters were used as regressors. Specific effects to identify areas of brain activation were then tested by defining the contrast of sentence reading versus resting conditions. Significant hemodynamic changes for this contrast (1, 0) were assessed, and resulting contrast images were submitted to a second-level random-effect analysis. A within-group paired t-test was then used to identify brain activations of sentence reading with application of a color-tinted lens condition compared to those without the application of a color-tinted lens. We report activations with a threshold of p < 0.05, corrected for multiple comparisons for the whole brain using family-wise error (FWE).