Dystonia is increasingly considered a network disorder extending beyond the basal ganglia system and even the motor system.14 Studies have shown that abnormal high-order motor processing in dystonia might occur upstream from the motor cortex. A TMS study showed that functional coupling between the posterior parietal cortex and motor cortex is abnormal in dystonic patients.15 Somatosensory impairment in dystonia is also demonstrated by an abnormal temporal discrimination threshold.16 fMRI studies have shown more widespread network abnormalities with pronounced reduced connectivity within the sensorimotor and frontoparietal network.14 Abnormal high-order sensorimotor integration was again highlighted in an fMRI study that showed increased intrinsic connectivity within the left parietal lobe at rest and decreased functional connectivity between the parietal and pre/post central gyrus.17 Clinical observation of sensory tricks in CD also suggests a role for sensorimotor integration in the pathophysiology of CD, although its mechanism has not been clearly understood. Our study is one of the first to demonstrate a central role of SMA in sensory tricks of CD. Our results showed that SMA connectivity with brain regions of sensory integration was different at rest between HC and patients. Furthermore, the SMA modulated the process of sensorimotor integration during sensory trick performance and imagination.
The SMA is associated with motor preparation as well as execution or suppression of intended movements.18,19 The SMA has been implicated in the pathophysiology of dystonia, evidenced by fMRI studies that showed reduced SMA connectivity in patients with dystonia.14,20 Our group previously performed an electroencephalogram experiment to record brain potentials during motor preparation and execution of sensory tricks using a CNV paradigm of warning and imperative signal. The late CNV was significantly larger during motor preparation of sensory tricks than during voluntary neck movements. This demonstrated that anticipatory activities in the premotor/motor area are modulated before executing the trick.6 When we examined different cortical areas including motor (C3 or C4), somatosensory (P3 or P4), and SMA/premotor (FCz, FC5, or FC6) before and during sensory tricks, the corticocortical coherence increased between premotor and motor/sensory regions during the late preparatory phase and it increased between sensory and premotor/motor regions during the execution phase when compared to that of voluntary neck movement.8 Our current study used fMRI to provide better spatial localization and showed direct evidence that SMA plays a crucial role during sensory tricks in CD.
The most compelling finding from our study is how connectivity changes between the SMA and posterior parietal cortex during sensory tricks. CD patients had decreased connectivity between the SMA and IPS region and precuneus at rest, but the connectivity increased with sensory trick performance and imagination. Given the clinical benefit associated with sensory trick, this change implies normalization of SMA-posterior parietal cortex connectivity. The posterior parietal cortex integrates multimodal sensory information to localize the body and external objects in space, and its output goes to the motor system to execute planned movements.21 The IPS divides posterior parietal cortex into dorsal superior parietal lobule and ventral inferior parietal lobule, and it is involved in selection between competing stimuli.22,23 The precuneus also serves an important function in the process of sensorimotor integration.24 Both the IPS and precuneus are activated in multimodal sensorimotor tasks.25 Our result indicates that SMA may play a key role in sensory tricks in CD by partially correcting aberrant sensorimotor processing.
A similar trend was found for the right cerebellar lobule VI– SMA connectivity with sensory trick performance and imagination. It increased for both sensory trick performance and imagination in CD patients, although its change with trick performance did not survive the statistical correction for multiple comparisons. The difference between SMA-cerebellar connectivity in CD patients with sensory tricks compared to HC adds to the growing evidence supporting cerebellar involvement in the pathophysiology of dystonia as an active component of sensorimotor integration.26 Additionally, fMRI studies have shown independent prefronto-cerebellar circuits in human brain.27,28 Our study indicated that the prefronto-cerebellar circuit might work differently in CD patients compared to HC in response to motor, imaginary, and light touch. The middle cerebellar peduncle receives afferent input via pons from prefrontal and parietal pathways as well as anterior cingulate.29 It is important to note that patients showed decreased SMA-pons connectivity with trick imagination but showed increased SMA-cerebellum connectivity, which may be because they had to suppress the actual motor output.
Another notable result from our rs-fMRI was increased connectivity between the SMA and hippocampus/parahippocampal region in CD patients compared to HC. The medial temporal lobe is associated with encoding spatial- and self- motion relative to environment to monitor inertial navigation.30 CD patients may exert extra effort for inertial navigation at rest due to abnormal head and neck position.
Overall, our results clearly showed the differences in SMA connectivity in HC and CD patients during sensory trick performance and imagination. HC had higher connectivity with the SMA in the regions of visual processing (left occipital and middle temporal) with sensory trick imagination, whereas patients showed more changes in areas of sensorimotor integration (left IPS and right cerebellum) for both tasks. Our results align with a previous study that explained sensory tricks as the presence of a cortical adaptive mechanism involving the posterior parietal cortex evidenced by better performance in temporal sensory discrimination in CD patients with effective sensory tricks compared to patients without sensory tricks.31 Our study adds evidence that the SMA and cerebellum also play an important role in effective sensorimotor integration as a cortical adaptive mechanism.
Our study has a few limitations. We did not measure the objective degree of clinical benefit from sensory tricks apart from one questionnaire on TWSTRS. Therefore, we could not draw conclusions as to whether SMA connectivity change was correlated with the effectiveness of the sensory trick. The small number of patients made the clinical correlation difficult as well. Finally, our study did not include patients without sensory trick.
Our study has potential implications for a therapeutic intervention. One could consider augmenting or enhancing functional connectivity between the SMA and posterior parietal cortex to mimic the changes associated with an effective sensory trick. The IPS is a hub to process tactile stimulation for motor control.23 The IPS could be a potential novel target for neuromodulation for CD, and the temporal discrimination threshold could be measured as a behavioral correlate.