Abnormal subcortical activity in congenital mirror movement disorder with RAD51 mutation

Abstract

Purpose: Congenital mirror movement disorder (CMMD) is characterized by unintended, nonsuppressible, homologous mirroring activity contralateral to the movement on the intended side of the body. In healthy controls, unilateral movements are accompanied with predominantly contralateral cortical activity, whereas in CMMD, in line with the abnormal behavior, bilateral cortical activity is observed for unilateral motor tasks. However, task-related activities in subcortical structures, which are known to play critical roles in motor actions, have not been investigated in CMMD previously.

Methods: We investigated the functional activation patterns of the motor components in CMMD patients. By using linkage analysis and exome sequencing, common mutations were revealed in seven affected individuals from the same family. Next, using functional magnetic resonance imaging (fMRI) we investigated cortical and subcortical activity during manual motor actions in two right-handed affected brothers and sex, age, education, and socioeconomically matched healthy individuals.

Results: Genetic analyses revealed heterozygous RAD51 c.401C>T mutation which cosegregated with the phenotype in two affected members of the family. Consistent with previous literature, our fMRI results on these two affected individuals showed that mirror movements were closely related to abnormal cortical activity in M1 and SMA during unimanual movements. Furthermore, we have found previously unknown abnormal task-related activity in subcortical structures. Specifically, we have found increased and bilateral activity during unimanual movements in thalamus, striatum, and globus pallidus in CMMD patients.

Conclusion: These findings reveal further neural correlates of CMMD, and may guide our understanding of the critical roles of subcortical structures for unimanual movements in healthy individuals.

Figure 1. a–c

Comparison of fMRI responses in patients and controls in primary motor cortex hand area (M1) and supplementary motor area (SMA). Panels indicate right hand (a), left hand (b), and both hand (c) movements. Top row: Statistical parametric maps for a representative control and a patient during finger tapping. Bar plots: fMRI responses in predefined regions of interest (ROIs). Abnormal lateralization in M1 in patients is clearly seen in the statistical parametric maps. Abnormal activity pattern was also observed in SMA in patients: in controls, left SMA activity was always larger than right SMA activity, but not in patients. Error bars show ±1 standard deviation. Color bar for the statistical parametric map indicates the t-score ranging from −8 (blue) to 2.98 (yellow). Maps are thresholded at an α level of 0.05.

Figure 2. a–c

Comparison of fMRI responses in patients and controls in thalamus (THA), globus pallidus (GP), and striatum (STR, consisting of caudate nucleus [CAU] and putamen [PUT]) shows abnormal activity in patients. Panels indicate right hand (a), left hand (b), and both hand (c) movements. Top row: Statistical parametric maps for a representative control and a patient during finger tapping. Bar plots: fMRI responses in pre-defined regions of interest (ROIs). Error bars show ±1 standard deviation. Color bar for the statistical parametric map indicates the t-score ranging from −8 (blue) to 2.98 (yellow). Maps are thresholded at an α level of 0.05.