The medial frontal-prefrontal network for altered awareness and control of action in corticobasal syndrome

Abstract

The volitional impairments of alien limb and apraxia are a defining feature of the corticobasal syndrome, but a limited understanding of their neurocognitive aetiology has hampered progress towards effective treatments. Here we combined several key methods to investigate the mechanism of impairments in voluntary action in corticobasal syndrome. We used a quantitative measure of awareness of action that is based on well-defined processes of motor control; structural and functional anatomical information; and evaluation against the clinical volitional disorders of corticobasal syndrome. In patients and healthy adults we measured 'intentional binding', the perceived temporal attraction between voluntary actions and their sensory effects. Patients showed increased binding of the perceived time of actions towards their effects. This increase correlated with the severity of alien limb and apraxia, which we suggest share a core deficit in motor control processes, through reduced precision in voluntary action signals. Structural neuroimaging analyses showed the behavioural variability in patients was related to changes in grey matter volume in pre-supplementary motor area, and changes in its underlying white matter tracts to prefrontal cortex. Moreover, changes in functional connectivity at rest between the pre-supplementary motor area and prefrontal cortex were proportional to changes in binding. These behavioural, structural and functional results converge to reveal the frontal network for altered awareness and control of voluntary action in corticobasal syndrome, and provide candidate markers to evaluate new therapies.

Keywords: alien limb; apraxia; corticobasal syndrome; pre-supplementary motor area; volition; voluntary action.

Figure 1

Illustration of the experimental behavioural procedure. Participants attended a clock and were asked to either press a button at their own pace or listen to a tone occurring at random, and then report the time of the event in -these- baseline conditions. The means of these baseline estimation errors were subtracted from those in the corresponding operant conditions, when the button press was followed by the tone. On any given trial, participants reported either the time of action or tone.

Figure 2

Action and tone binding in controls and patients with CBS. The bar chart illustrates the differences in the perception of time of action and tone between the two hands (averaged together) in controls and (separated) in patients with CBS. Mean action (red bar) and tone (grey) binding values are displayed proportionally to their perceptual shift (error bars indicate mean standard error). Dashed lines indicate the veridical time of action and tone events. Significance level in pair-wise comparisons is indicated by ***P < 0.001 and **P < 0.01.

Figure 3

Grey matter correlates of action binding variability in patients with CBS. (A) Grey matter volume in the pre-SMA (P < 0.05, FWE small volume corrected) and medial prefrontal cortex (P = 0.05, FWE small volume corrected) correlated positively with action binding in patients (blue); overlaid on MNI 152 average brain (grey-scale). For illustration, significant voxels shown are at P < 0.001, uncorrected. (B) Change in grey matter volume plotted against action binding in the more-affected hand in patients for the peak voxel in the pre-SMA (adjusted for group differences in action binding, total intracranial volume and age).

Figure 4

White matter correlates of action binding variability in patients with CBS. White matter tracts in which mean diffusivity positively correlated with action binding in the more-affected hand in patients (red; P < 0.05, FWE corrected); overlaid on the mean fractional anisotropy skeleton (opaque green) and MNI 152 average brain (grey-scale). Slice coordinate is indicated. These tracts were adjacent to the medial frontal and medial and lateral prefrontal areas, and the anterior corpus callosum (tracts listed in Supplementary Table 3).

Figure 5

Functional connectivity of the pre-SMA associated with abnormal action binding. (A) Areas showing increased functional connectivity with the pre-SMA at rest in patients, relative to control subjects (blue; P < 0.05, FWE corrected). Slice x-coordinate is indicated. A large fronto-parietal network showed increased coactivation with the pre-SMA, including the cerebellum, intraparietal sulcus, dorsal anterior cingulate cortex and lateral prefrontal cortex. (B) Voxels showing positive correlation between coactivation with the pre-SMA and action binding measures in patients (red; P < 0.05, FWE corrected). Slices as in A. These correlations indicate a predominantly frontal cortical network associated with agency and the disorders of voluntary action, including alien limb phenomena and apraxia.