Phd in CLINICAL EXPERIMENTAL NEUROSCIENCE AND PSYCHIATRY

Thesis title: Investigating human motor system physiology and Parkinson’s disease pathophysiology using combined transcranial magnetic stimulation and electroencephalography

The first part of the present thesis offers an introduction to the motor system organization, the pathophysiology of motor impairment in Parkinson’s disease, and the possibility to investigate the motor system through neuroimaging approaches such as electroencephalography (EEG) and transcranial magnetic stimulation (TMS). The second part is composed of the experimental studies that I conducted during my Ph.D. both at the Human Motor Control Section, National Institute of Health, Bethesda, USA and at the Department of Human Neuroscience at Sapienza University of Roma, Italy. The aim was to investigate motor control physiology and Parkinson’s disease (PD) pathophysiology using an integrated TMS-EEG approach. Study 1: Intracortical Inhibition and Surround Inhibition in the Motor Cortex Short-latency intracortical inhibition (SICI) and motor surround inhibition (mSI) are cortical phenomena that have been investigated with transcranial magnetic stimulation (TMS) over the primary motor cortex (M1). The mSI is believed to be necessary for the execution of fine finger movements, SICI may participate in mSI genesis, and however, the mechanisms underlying both mSI and SICI are not entirely clear. We explored the cortical physiology of SICI and mSI in healthy subjects by TMS-evoked cortical potentials (TEPs). Single (sp) and paired-pulse (pp) TMS were delivered on the ADM muscle cortical hotspot while recording EEG and EMG. Three conditions were tested: spTMS and ppTMS at rest, and spTMS at the onset of an index finger movement. SICI and mSI were calculated on the ADM motor evoked potential (MEP) and two groups were defined based on the presence of mSI. Average TEPs were calculated for each condition and five regions of interest. At movement onset, we observed a widespread reduction of the inhibitory late component N100 suggesting cortical facilitation associated with motor performance. At the M1 level, SICI and mSI are associated with similar modulation of TEPs consisting of a reduction of P30 and an increase of N45 amplitude. Our findings suggest that SICI and mSI modulate cortical excitability with shared inhibitory mechanisms. Study 2: Cortical Mechanisms underlying Variability in Intermittent Theta-Burst Stimulation-Induced Plasticity We tested the hypothesis that intermittent theta-burst stimulation (iTBS) variability depends on the ability to engage specific neurons in M1. In a sham-controlled interventional study on 31 healthy volunteers, we used concomitant transcranial magnetic stimulation (TMS) and electroencephalography (EEG). We compared baseline motor evoked potentials (MEPs), M1 iTBS-evoked EEG oscillations, and resting-state EEG (rsEEG) between subjects who did and did not show MEP facilitation following iTBS. We also investigated whether baseline MEP and iTBS-evoked EEG oscillations could explain inter and intraindividual variability in iTBS aftereffects. The facilitation group had smaller baseline MEPs than the no-facilitation group and showed more iTBS-evoked EEG oscillation synchronization in the alpha and beta frequency bands. Resting-state EEG power was similar between groups and iTBS had a similar non-significant effect on rsEEG in both groups. Baseline MEP amplitude and beta iTBS-evoked EEG oscillation power explained both inter and intraindividual variability in MEP modulation following iTBS. The results show that variability in iTBS-associated plasticity depends on the basal level of corticospinal excitability and on the ability of iTBS to engage M1 beta oscillations. These observations can be used to optimize iTBS investigational and therapeutic applications. Study 3: The role of the motor cortex in classic parkinsonian tremor We investigated the role of the M1 in the pathophysiology of parkinsonian tremor. We enrolled 10 PD patients with both re‐emergent and rest tremor. Tremor was assessed by spectral analysis, corticomuscular coherence and tremor‐resetting produced by transcranial magnetic stimulation over the primary motor cortex. We also recorded transcranial magnetic stimulation‐evoked potentials generated by motor cortex stimulation during rest tremor, tremor suppression during wrist extension, and re‐emergent tremor. Spectral analysis, corticomuscular coherence, and tremor resetting were compared between re‐emergent tremor and rest tremor. Both rest and re‐emergent tremor showed significant corticomuscular coherence and tremor resetting. The P60 component of transcranial magnetic stimulation‐evoked potentials reduced in amplitude during rest tremor suppression, recovered before re‐emergent tremor, was facilitated at re‐emergent tremor onset and returned to values similar to those of rest tremor during re‐emergent tremor. In conclusion, parkinsonian tremor is causally related to the activity of M1, which is likely a convergence node in the tremor generating cortico-subcortical network. Rest and re‐emergent tremor share common pathophysiological mechanisms in which the motor cortex plays a crucial role. Study 4: Cortical motor changes in Parkinson’s disease and the effect of dopaminergic medications Cortical motor changes are associated with PD, but their pathophysiological roles remain unknown. We investigated M1 and supplementary motor area (SMA) excitability in PD and the effect of dopaminergic medications using TMS-EEG. Fifteen PD patients and 12 healthy volunteers (HVs) participated in the study. We compared TEPs from M1 and SMA stimulation between PD patients and HVs, and in PD patients between OFF and ON medication conditions. We also recorded TEPs from the superior parietal lobule (SPL) and EEG responses evoked by sham stimulation as control conditions. We found that PD is associated with abnormalities in TEPs from all the stimulation sites, whereas EEG responses to sham stimulation were similar between PD and HVs. TEPs abnormalities in M1 and SMA were restored by dopaminergic therapy, whereas dopamine medication did not affect SPL TEPs. Finally, we found that abnormal TEPs from the most affected M1 showed inverse correlations with contralateral bradykinesia. In conclusion, our TMS-EEG study unveils specific cortical abnormalities in PD and their relation with dopaminergic degeneration. Also, we provided evidence suggesting that some cortical changes in PD may reflect compensatory mechanisms in response to an abnormal basal ganglia output.