Transcranial Magnetic Stimulation (TMS)Original ResearchTheta Burst Stimulation Modulates Cerebellar-Cortical Connectivity in Patients with Progressive Supranuclear Palsy
Introduction
Recent imaging studies revealed in PSP patients specific cerebellar abnormalities when measuring the volume of the cerebellum, superior cerebellar peduncles and midbrain. Shirota and colleagues [1] used TMS with a paired-pulse paradigm to investigate cerebellar functions in PSP patients. In this protocol a preceding TMS pulse over the cerebellum decreases the amplitude of motor evoked potentials (MEPs) elicited by TMS over the contralateral primary motor cortex (M1) when delivered at specific delays (interstimulus intervals-ISIs) around 5–7 ms. This inhibitory circuit is thought to be related to the activation of Purkinje cells that inhibit or dis-facilitate the dentato-thalamo-cortical pathway (cerebellar inhibition-CBI) [2]. The results showed that CBI was significantly reduced in PSP patients in comparison to PD patients, suggesting that Purkinje cells or the dentato-thalamo-cortical pathway is involved in PSP patients, although no clinical cerebellar sign was observed [1]. Here we aimed to investigate the plasticity of these cerebellar-cortical circuits in PSP patients. In healthy subjects rTMS can be used to induce long-lasting changes in the excitability of these circuits. Different TBS protocols are able to induce bi-directional and long-lasting changes in the excitability of the cerebello-thalamo-cortical circuits and therefore to activate different mechanisms of synaptic plasticity when applied over the lateral cerebellum [3], [4], [5]. We applied intermittent TBS (iTBS) over the lateral cerebellum bilaterally during 2 weeks to evaluate the hypothesis that the long-term potentiation of cerebello-cortical interactions could induce some favorable clinical and neurophysiological changes in patients with PSP. We used standard TMS methods to explore the functional connectivity between the cerebellar hemisphere and the contralateral motor cortex (CBI), and to measure the excitability of the contralateral primary motor cortex assessing intracortical inhibition (SICI) and intracortical facilitation (ICF) and short latency afferent inhibition (SLAI). Moreover we also performed resting state functional magnetic resonance (fMRI) to investigate changes in other remote interconnected areas. Finally PSP patients included in our study were submitted to a clinical evaluation by administering the PSP clinical rating scale [6] before and after the cerebellar iTBS sessions.
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Patients
Ten patients affected by PSP according with the clinical criteria of the National Institute of Neurologic Diseases and Stroke for PSP [7] were included in our study (4 M, 6 F; mean age: 59.3 ± 6.6; mean disease duration: 7 ± 1.2; mean UPDRS part III: 62.6 ± 9.4; mean H&Y: 4.1 ± 0.7; mean score MMSE: 25.7 ± 1.9) (see Table 1). Local ethical committee approved the project and written informed consents were obtained from all subjects before study initiation. All subjects were affected by the
TMS
The mean patients and healthy subjects RMT did not differ across groups (PSP = 45.9 ± 3.5%; PD: 49.9 ± 6.1%; HS = 47.2 ± 5.3% of Maximum of stimulator output (MSO)), as revealed by one-way ANOVA (F = 0.88; P = 0.71). When comparing baseline neurophysiological examinations in PSP patients, PD patients and HS repeated measures ANOVA performed on CBI measures revealed significant GROUP (F = 11.68; P = 0.0003) main effect but not ISI (F = 0.90; P = 0.41) nor GROUP × ISI (F = 0.58; P = 0.67)
Discussion
When compared to PD patients, our group of PSP patients was characterized by a pronounced loss of cortical inhibition as assessed by different neurophysiologic protocols exploring both intracortical inhibitory (SICI) as well as long-range inhibitory connectivity circuits (SLAI and CBI). The SICI findings are in agreement with previous investigations revealing that PSP patients have an important deficit of SICI [15], [16]. Patterns of reduced SICI have been related either to the loss of
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Conflict of interest: The authors declare no competing financial interests.
This work was supported by grant of the Italian Ministry of Health to GK (MR 08.7: “Markers of Pathological dysfunction in progressive supranuclear palsy”). The authors report no disclosures.