Rocchi, Lorenzo; (2021) Sensorimotor integration in dystonia: pathophysiology and possible non-invasive approaches to therapy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Dystonia is a condition characterized by excessive and sustained muscle contractions causing abnormal postures and involuntary movements. The pathophysiology of dystonia includes loss of inhibition and abnormal plasticity in the somatosensory and motor systems; however, their contribution to the phenomenology of dystonia is still uncertain, and the possibility to target these abnormalities in an attempt to devise new treatments has not been thoroughly explored. This thesis describes how abnormal inhibition and plasticity in the somatosensory system of dystonic patients can be manipulated to ameliorate motor symptoms by means of peripheral stimulation. First, we characterized electrophysiological and behavioural markers of inhibition in the primary somatosensory cortex in a group of patients with idiopathic cervical dystonia (CD). Outcome measures included a) somatosensory temporal discrimination threshold (STDT); b) paired-pulse somatosensory evoked potentials (PP-SEP) tested with interstimulus intervals (ISIs) of 5, 20 and 40 ms; c) spatial somatosensory inhibition ratio (SIR) by measuring SEP interaction between simultaneous stimulation of the digital nerves in thumb and index finger; d) high-frequency oscillations (HFO) extracted from SEP obtained with stimulation of digital nerves of the index finger. This first investigation demonstrated that increased STDT in dystonia is related to reduced activity of inhibitory circuits within the primary somatosensory cortex, as reflected by reduced PP-SEP inhibition at ISI of 5 ms and reduced area of the late part of the HFO (l-HFO). In a second set of experiments, we applied high frequency repetitive somatosensory stimulation (HF-RSS), a patterned electric stimulation applied to the skin through surface electrodes, to the index finger in a sample of healthy subjects, with the aim to manipulate excitability and inhibition of the primary somatosensory (S1) and motor (M1) cortices. The former was assessed by the same methods used before (STDT, PP-SEP, HFO), with the addition of two psychophysical tasks designed to assess tactile spatial discrimination (grating orientation and bumps tests). Assessment of physiology of M1 was performed by means of short intracortical inhibition (SICI) assessed with TMS; this was performed with multiple conditioning stimulus (CS) intensities (70%, 80%, 90% of the active motor threshold) and with a insterstimulus interval (ISI) between conditioning and test stimulus of 3 ms. It was found that HF-RSS increased inhibition in S1 tested by PP-SEP and HFO; these changes were correlated with improvement in STDT. HF-RSS also enhanced bumps detection, while there was no change in grating orientation test. Finally, there was an increase in SICI, suggesting widespread changes in cortical sensorimotor interactions. Overall, these findings demonstrated that HF-RSS is able to modify the effectiveness of inhibitory circuitry in S1 and M1. The results obtained so far led us to hypothesize that HF-RSS could restore inhibition in dystonic patients, similar to what observed in healthy subjects. To test this, we applied HF-RSS on the index finger in a sample of patients with CD, and tested its effects with some of the outcome measures used before (STDT, PP-SEP, HFO, SIR, SICI). Unexpectedly, the results were opposite to what was predicted. Patients with CD showed a consistent, paradoxical response: after HF-RSS, they had reduced suppression of PP-SEP, as well as decreased HFO area and SICI, and increased SIR. STDT deteriorated after the stimulation protocol, and correlated with reduced measures of inhibition within S1 (PP-SEP at 5 ms ISI, l-HFO area). It was hypothesized that patients with CD have abnormal homeostatic inhibitory plasticity within the sensorimotor cortex and that this is responsible for their abnormal response to HF-RSS. Interestingly, this alteration in plasticity seems to be specific to idiopathic dystonia: when the same protocol was applied to patients with dystonia caused by lesions in the basal ganglia, the response was similar to healthy controls. This result suggests that reduced somatosensory inhibition and abnormal cortical plasticity are not strictly required for the clinical expression of dystonia, and that the abnormalities reported in idiopathic dystonia are not necessarily linked to basal ganglia damage. We then directed our attention to another form of peripheral electrical stimulation, delivered at low frequency (LF-RSS). Previous literature demonstrated that this pattern of stimulation had effects opposite to HF-RSS on tactile performance in healthy subjects; therefore, given the previous findings of abnormal response to HF-RSS in CD, we hypothesized that an inverse response might occur in these patients following LF-RSS as well. Our hypothesis was confirmed by the observation that LF-RSS, applied to the fingers in patients with CD, induced an increase in inhibition in the primary somatosensory and motor cortices. This was reflected by an improvement of STDT and an increase in PP-SEP suppression, HFO area and SICI. With this in mind, in the final project of the thesis, we tested the effects of HF-RSS and LF-RSS applied directly over two affected muscles in different groups of patients with focal hand dystonia (FHD), in an attempt to modulate involuntary muscle activity and, consequently, to ameliorate motor symptoms. Whereas HF-RSS was delivered synchronously over the two muscles, LF-RSS was given either synchronously or asynchronously. Outcome measures included a) PP-SEP obtained by direct stimulation of affected muscles, with ISIs of 5 and 30 ms; b) quantification of electromyographic (EMG) activity from tested muscles; c) SICI recorded from the affected muscles, with CS intensities ranging from 50% to 100% RMT and with an ISI of 3 ms; d) evaluation of hand function, assessed by the box and blocks test (BBT) and the nine-hole peg test (NHPT); e) SIR by measuring SEP interaction between simultaneous stimulation of the two muscles receiving repetitive stimulation. We confirmed the paradoxical response of dystonic patients to HF-RSS, which was reflected in decreased PP-SEP suppression and SICI and increased SIR. Importantly, this was paralleled by an increase in involuntary EMG activity and worse scores at the BBT and NHPT. This results were opposite when LF-RSS was delivered, either in its synchronous or asynchronous version, the latter being slightly more effective. Thus, LF-RSS was able to increase PP-SEP suppression and SICI, decrease SIR and reduce involuntary EMG activity, with consequent improvement in performance in the BBT and NHPT. Overall, our data provide novel insight into the neural mechanisms underlying loss of inhibition and deranged somatosensory plasticity in idiopathic dystonia and bring preliminary evidence that peripheral electrical stimulation can be used as a treatment in idiopathic focal hand dystonia.

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