Dottorato in NEUROSCIENZE CLINICO-SPERIMENTALI E PSICHIATRIA

Titolo della tesi: Investigating the pathophysiology of idiopathic focal dystonia: evidence of motor and somatosensory cortex abnormalities from a TMS and an EEG study

The first part of the present thesis provides an introduction to focal idiopathic dystonia. Evidence available from neurophysiological studies are briefly reviewed, with particular focus on sensorimotor cortex abnormalities. The occurrence of somatosensory symptoms, as well as neurophysiological alteration in the somatosensory system, are also highlighted. In the final part of the introduction, previous pathophysiological hypotheses, and relative limitations due to unclear and controversial features of the evidenced abnormalities, are detailed. The second part of this thesis is composed of some of the experimental studies that I conducted during my Ph.D at the Department of Human Neuroscience at Sapienza University of Rome, Italy. The research questions were 1) to provide evidence of defective inhibitory activity and sensory motor integration abnormalities in different forms of focal dystonia, focusing on their possible topographical specificity 2) to investigate mechanisms of sensory trick (ST), a manoeuvre used by a large amount of patients with dystonia to transiently alleviate motor symptoms, by evaluating changes in cortical oscillations in the sensorimotor cortex induced by ST. Study 1 aimed to seek cortical abnormalities in a rare form of focal idiopathic dystonia, namely oromandibular dystonia (OMD). Only a few studies investigated cortical abnormalities in OMD, and only one neurophysiological study performed with transcranial magnetic stimulation (TMS) investigated face M1 and recorded from facial muscles. Whether OMD share cortical abnormalities with other forms of dystonia, and whether cortical abnormalities are present a topographical specificity is unknown. The presence of a direct relationship between the possible alterations at cortical level and dystonic motor symptoms may also shed light on a role of these abnormalities in determining clinical manifestations. To answer these questions we used TMS to investigate both face and hand M1 in a sample of patients with OMD, compared to healthy controls. Results showed that both abnormal intracortical inhibition, and sensory-motor integration are altered in OMD, only in the affected cortical area and muscle. The present finding suggests a topographic specificity of cortical abnormalities in OMD and offers possible speculations on mechanism underlain, as well as on their role. Study 2 aimed to investigate mechanisms underlying effects of ST in dystonia. Several hypotheses have been proposed, but the contribution of sensory and motor systems and their role in determining the effects of ST are unknown. In this study, we investigated whether ST modulates cortical oscillations. Possible changes in sensorimotor cortex oscillations during the execution of an effective ST have been sought in different experimental conditions, each designed to investigate the role of a specific components of sensory and motor systems on its effect. The presence of possible cortical changes related to the execution of an effective ST, and their occurrence in specific experimental conditions, may offer new information on whether and how sensorimotor cortex oscillations relate to the clinical effect of ST. Moreover this information would allow the role of different components of sensory and motor system in the effect of ST to be discussed. To this aim we used electroencephalogram (EEG) to record possible ST related modulation of cortical oscillations in the sensorimotor cortex before, during, and after ST execution in patients with cervical dystonia (CD) with effective ST, compared to patients without ST. Results showed an event related desynchronization (ERD) in the mu (8-13) band in sensorimotor cortical regions in patients performing an effective ST, that was present during its execution and that temporarily related to reduced electromyography (EMG) activity in the dystonic muscles. Moreover, we found that the ERD in the mu band occurs when ST is actively prepared and performed by the patients, but also, though to a lesser extent, when ST is passively executed, and even when this is performed without touching the skin. Overall, our findings suggest that oscillatory activity changes in the mu band over the sensorimotor cortex are involved in the pathophysiology of ST, and also that proprioceptive changes related to ST execution play a crucial role in determining the observed EEG changes in the sensory motor cortex. In the general discussion of this thesis, we formulated possible interpretation of results obtained, discussed in the light of previous evidence and hypotheses. We proposed a crucial role of proprioceptive information, as well as its abnormal processing, in determining cortical abnormalities in different forms of idiopathic focal dystonia. Moreover, we discussed the possible role of proprioceptive alterations in determining motor symptoms and peculiar features of different forms of idiopathic focal dystonia.