Increased sensorimotor network activity in DYT1 dystonia: a functional imaging study

Abstract

Neurophysiological studies have provided evidence of primary motor cortex hyperexcitability in primary dystonia, but several functional imaging studies suggest otherwise. To address this issue, we measured sensorimotor activation at both the regional and network levels in carriers of the DYT1 dystonia mutation and in control subjects. We used (15)Oxygen-labelled water and positron emission tomography to scan nine manifesting DYT1 carriers, 10 non-manifesting DYT1 carriers and 12 age-matched controls while they performed a kinematically controlled motor task; they were also scanned in a non-motor audio-visual control condition. Within- and between-group contrasts were analysed with statistical parametric mapping. For network analysis, we first identified a normal motor-related activation pattern in a set of 39 motor and audio-visual scans acquired in an independent cohort of 18 healthy volunteer subjects. The expression of this pattern was prospectively quantified in the motor and control scans acquired in each of the gene carriers and controls. Network values for the three groups were compared with ANOVA and post hoc contrasts. Voxel-wise comparison of DYT1 carriers and controls revealed abnormally increased motor activation responses in the former group (P < 0.05, corrected; statistical parametric mapping), localized to the sensorimotor cortex, dorsal premotor cortex, supplementary motor area and the inferior parietal cortex. Network analysis of the normative derivation cohort revealed a significant normal motor-related activation pattern topography (P < 0.0001) characterized by covarying neural activity in the sensorimotor cortex, dorsal premotor cortex, supplementary motor area and cerebellum. In the study cohort, normal motor-related activation pattern expression measured during movement was abnormally elevated in the manifesting gene carriers (P < 0.001) but not in their non-manifesting counterparts. In contrast, in the non-motor control condition, abnormal increases in network activity were present in both groups of gene carriers (P < 0.001). In this condition, normal motor-related activation pattern expression in non-manifesting carriers was greater than in controls, but lower than in affected carriers. In the latter group, measures of normal motor-related activation pattern expression in the audio-visual condition correlated with independent dystonia clinical ratings (r = 0.70, P = 0.04). These findings confirm that overexcitability of the sensorimotor system is a robust feature of dystonia. The presence of elevated normal motor-related activation pattern expression in the non-motor condition suggests that abnormal integration of audio-visual input with sensorimotor network activity is an important trait feature of this disorder. Lastly, quantification of normal motor-related activation pattern expression in individual cases may have utility as an objective descriptor of therapeutic response in trials of new treatments for dystonia and related disorders.

Figure 1

Brain regions with abnormal activation in manifesting DYT1 carriers (Table 2, see text). SPM{t} maps (left) were superimposed on a single-subject MRI T₁ template (x, y, z coordinates in MNI space indicate the position of the slice). The colour scale represents t-values thresholded at 3.5 corresponding to P < 0.05 false discovery rate corrected. Bar diagrams (right) of adjusted rCBF measured during performance of the motor task (CCW) or in the non-motor audio-visual control condition (AV) (see text). For each volume-of-interest, rCBF values (mean ± SE) were displayed for manifesting (MAN) DYT1 (dark grey), non-manifesting (NM) DYT1 (light grey), and control subjects (white). Increased motor activation was present in affected carriers in the left sensorimotor cortex (SMC, A), supplementary motor area (SMA, B), and in the dorsal premotor cortex (dPMC, C). Loss of task-related deactivation was evident in the inferior parietal lobule (PARi, D). The activation abnormalities in the sensorimotor cortex and supplementary motor area were specific for clinically affected DYT1 carriers. In dorsal premotor cortex and PARi, abnormal activation was also present in non-manifesting gene carriers. In the non-motor AV condition, rCBF was elevated in the right cerebellum (E), with significant rCBF elevations in both manifesting and non-manifesting DYT1 carriers. In contrast, in the left sensorimotor cortex (F), rCBF was elevated only in the affected mutation carriers. (Significant P-values of post hoc tests are denoted by asterisks).

Figure 2

The normal motor-related activation pattern. (A) Normal motor-related activation pattern (NMRP) identified by ordinal trends canonical variates analysis (OrT/CVA) of 78 PET scans (39 CCW- and 39 AV) acquired in 18 healthy volunteer subjects (see text). This spatial covariance pattern was characterized by activation of the left sensorimotor cortex (SMC), premotor cortex (dPMC) and inferior parietal cortex (Table 3). Additional regional contributions to network activity were found bilaterally in the cerebellar vermis and hemispheres. [The colour scale represents positive voxel weights thresholded at Z = 3.09, corresponding to regions that contributed significantly (P < 0.001) to network activity and which were also reliable (P < 0.001) on bootstrap estimation.] (B) Normal motor-related activation pattern expression in the subjects comprising the original derivation sample. For all subjects and runs, the expression of this pattern increased during the performance of the motor task (P < 0.0001; see text).

Figure 3

Normal motor-related activation pattern expression in DYT1 mutation carriers. (A) Box-whisker plots of normal motor-related activation pattern expression recorded in the AV reference condition (AV, left) and during movement (right). In the AV condition, pattern expression was elevated in both the manifesting and non-manifesting DYT1 groups, with the latter positioned between the affected carriers and the controls. In the motor condition, significant increases in normal motor-related activation pattern expression were evident only for the affected carriers. [Significant post hoc comparisons with controls (P < 0.05) are denoted by asterisks; see text.] (B) Normal motor-related activation pattern expression in manifesting DYT1 carriers measured in the AV condition correlated with clinical severity ratings according to the BFMDRS. (Black diamonds: subjects without contractions at rest; grey diamonds: subjects with constant or with occasional contractions at rest. The normal mean and range are indicated by the shaded area).