Andrea Nardella

Theta-burst stimulation-induced plasticity over primary somatosensory cortex changes somatosensory temporal discrimination in healthy humans

Background The somatosensory temporal discrimination threshold (STDT) measures the ability to perceive two stimuli as being sequential. Precisely how the single cerebral structures contribute in controlling the STDT is partially known and no information is available about whether STDT can be modulated by plasticity-inducing protocols. Methodology/Principal Findings To investigate how the cortical and cerebellar areas contribute to the STDT we used transcranial magnetic stimulation and a neuronavigation system. We enrolled 18 healthy volunteers and 10 of these completed all the experimental sessions, including the control experiments. STDT was measured on the left hand before and after applying continuous theta-burst stimulation (cTBS) on the right primary somatosensory area (S1), pre-supplementary motor area (pre-SMA), right dorsolateral prefrontal cortex (DLPFC) and left cerebellar hemisphere. We then investigated whether intermittent theta-burst stimulation (iTBS) on the right S1 improved the STDT. After right S1 cTBS, STDT values increased whereas after iTBS to the same cortical site they decreased. cTBS over the DLPFC and left lateral cerebellum left the STDT statistically unchanged. cTBS over the pre-SMA also left the STDT statistically unchanged, but it increased the number of errors subjects made in distinguishing trials testing a single stimulus and those testing paired stimuli. Conclusions/Significance Our findings obtained by applying TBS to the cortical areas involved in processing sensory discrimination show that the STDT is encoded in S1, possibly depends on intrinsic S1 neural circuit properties, and can be modulated by plasticity-inducing TBS protocols delivered over S1. Our findings, giving further insight into mechanisms involved in somatosensory temporal discrimination, help interpret STDT abnormalities in movement disorders including dystonia and Parkinsons disease.

Theta-burst stimulation over primary motor cortex degrades early motor learning.

Theta‐burst stimulation (TBS) is currently used for inducing long‐lasting changes in primary motor cortex (M1) excitability. More information is needed on how M1 is involved in early motor learning (practice‐related improvement in motor performance, motor retention and motor consolidation). We investigated whether inhibitory continuous TBS (cTBS) is an effective experimental approach for modulating early motor learning of a simple finger movement in healthy humans. In a short task, 11 subjects practised 160 movements, and in a longer task also testing motor consolidation ten subjects practised 600 movements. During both experiments subjects randomly received real or sham cTBS over the left M1. Motor evoked potentials were tested at baseline and 7 min after cTBS. In the 160‐movement experiment to test motor retention, 20 movements were repeated 30 min after motor practice ended. In the 600‐movement experiment motor retention was assessed 15 and 30 min after motor practice ended, motor consolidation was tested by performing 20 movements 24 h after motor practice ended. Kinematic variables – movement amplitude, peak velocity and peak acceleration – were measured. cTBS significantly reduced the practice‐related improvement in motor performance of finger movements in the experiment involving 160 movements and in the first part of the experiment involving 600 movements. After cTBS, peak velocity and peak acceleration of the 20 movements testing motor retention decreased whereas those testing motor consolidation remained unchanged. cTBS over M1 degrades practice‐related improvement in motor performance and motor retention, but not motor consolidation of a voluntary finger movement.

Somatosensory temporal discrimination threshold may help to differentiate patients with multiple system atrophy from patients with Parkinson's disease.

Somatosensory temporal discrimination threshold (STDT) is defined as the threshold at which two tactile stimuli applied to the skin are perceived as clearly distinct.

Primary somatosensory cortical plasticity and tactile temporal discrimination in focal hand dystonia

OBJECTIVE To investigate whether theta burst stimulation (TBS) applied over primary somatosensory cortex (S1) modulates somatosensory temporal discrimination threshold (STDT) and writing performances in patients with focal hand dystonia (FHD). METHODS Twelve patients with FHD underwent STDT testing and writing tasks before and after intermittent, continuous, or sham TBS (iTBS, cTBS, sham TBS) over S1 contralateral to the affected hand. Twelve healthy subjects underwent iTBS and cTBS over S1 and STDT values were tested on the right hand before and after TBS. RESULTS Baseline STDT values were higher in patients than in healthy subjects on both the affected and unaffected hand. In patients and healthy subjects iTBS decreased, whereas cTBS increased STDT values and did so to a similar extent in both groups. In patients, although STDT values decreased after iTBS, they did not normalize. S1 modulation did not improve the writing performance. CONCLUSIONS In patients, S1 responds normally to protocols inducing homotopic synaptic plasticity. The inhibitory interneuron activity responsible for STDT is altered. SIGNIFICANCE The pathophysiological mechanisms underlying abnormal temporal discrimination differ from those responsible for motor symptoms in FHD.

Correlation between habituation of visual-evoked potentials and magnetophosphene thresholds in migraine: A case-control study

Introduction In migraine most studies report an interictal deficit of habituation of visual-evoked potentials (VEP-hab) and reduced thresholds for phosphene induction (PT) by transcranial magnetic stimulation (TMS). We searched for a possible correlation between VEP-hab and PT in migraine patients and healthy controls to test whether they reflect the same pathophysiological abnormality. Methods We assessed PT and VEP-hab measured as the percentage change of N1/P1 amplitude over six blocks of 100 responses in 15 healthy volunteers (HV) and in 13 episodic migraineurs without aura (MO) between attacks. Results were compared using Mann-Whitney U test. Interrelationships were examined using Spearmans correlation. Results In MO patients VEP-hab was reduced compared to HV (p = 0.001), while PT were not significantly different between HV and MO. There was no correlation between PT and VEP-hab in either group of participants. Conclusions We confirm that in interictal migraine VEP habituation is deficient, but magnetophosphene threshold normal. VEP-hab and PT were not correlated with each other in healthy controls or in migraineurs. This finding suggests that they index different facets of cortical excitability in migraine, i.e. a punctual normal measure of the cortical activation threshold for PT and a dynamic response pattern to repeated stimuli for VEP habituation.

Inferior parietal lobule encodes visual temporal resolution processes contributing to the critical flicker frequency threshold in humans

The measurement of the Critical Flicker Frequency threshold is used to study the visual temporal resolution in healthy subjects and in pathological conditions. To better understand the role played by different cortical areas in the Critical Flicker Frequency threshold perception we used continuous Theta Burst Stimulation (cTBS), an inhibitory plasticity-inducing protocol based on repetitive transcranial magnetic stimulation. The Critical Flicker Frequency threshold was measured in twelve healthy subjects before and after cTBS applied over different cortical areas in separate sessions. cTBS over the left inferior parietal lobule altered the Critical Flicker Frequency threshold, whereas cTBS over the left mediotemporal cortex, primary visual cortex and right inferior parietal lobule left the Critical Flicker Frequency threshold unchanged. No statistical difference was found when the red or blue lights were used. Our findings show that left inferior parietal lobule is causally involved in the conscious perception of Critical Flicker Frequency and that Critical Flicker Frequency threshold can be modulated by plasticity-inducing protocols.

Somatosensory temporal discrimination in Parkinson’s disease, dystonia and essential tremor: Pathophysiological and clinical implications

OBJECTIVE To investigate whether changes in the somatosensory temporal discrimination threshold (STDT) in Parkinsons disease (PD) and dystonia reflect the involvement of specific neural structures or mechanisms related to tremor, and whether the STDT can discriminate patients with PD, dystonia or essential tremor (ET). METHODS We tested STDT in 223 patients with PD, dystonia and ET and compared STDT values in patients with PD and dystonia with tremor with those of PD and CD without tremor. Data were compared with those of age-matched healthy subjects. RESULTS STDT values were high in patients with dystonia and PD but normal in ET. In PD, STDT values were similar in patients with resting or postural/action tremor and in those without tremor. In dystonia, STDT values were higher in patients with tremor than in those without tremor. The ROC curve showed that STDT discriminates tremor in dystonia from ET. CONCLUSIONS In PD, STDT changes likely reflect basal ganglia abnormalities and are unrelated to tremor mechanisms. In dystonia, the primary somatosensory cortex and cerebellum play an additional role. SIGNIFICANCE STDT provides information on the pathophysiological mechanisms of patients with movement disorders and may be used to differentiate patients with dystonia and tremor from those with tremor due to ET.

P 178. Reversal of motor learning-related effects in humans

The induction of long-term potentiation (LTP) like plasticity in the human primary motor cortex (M1) using repetitive Transcranial Magnetic Stimulation can be reversed (depotentiated) if another intervention, by itself ineffective in inducing plastic changes (for example a short form of continuous theta burst stimulation-cTBS150) is delivered immediately after an experimentally inducing plasticity protocol. We here investigated if it is also possible to depotentiate the LTP-like after-effects of motor learning in the M1 and the behavioural outcome of learning (i.e. motor learning retention) using the cTBS150 as a depotentiation protocol. We used a well-characterized motor training task in which behavioural improvement is known to be associated with LTP-like plasticity changes of M1, as measured by increased M1 excitability after motor training. Eleven healthy participants were given 15 learning blocks (15 movements each) to maximize the initial acceleration of ballistic finger movements. Participants improved their motor performance during the training task and, as expected, this behavioural improvement was associated with increased M1 excitability. We found that the motor learning-related LTP-like effects were reversed if cTBS150 was given immediately after the end of the training. A control experiment confirmed that cTBS150 alone did not modify the M1 excitability. The analysis of the behavioural data showed that cTBS150 did not modify the motor-learning related behavioural outcome, supporting the hypothesis that M1 is not involved in motor retention. The present study demonstrate that is possible to reverse, i.e. depotentiate, motor learning-related LTP-like effects in the human M1 but this effect does not have a behavioural counterpart. A similar approach could be adopted to investigate if it is also possible to reverse LTP-like effect of more complex forms of motor learning, or to reverse abnormal cortical excitability associated with inappropriate motor learning in pathological conditions.