Reversal of long term potentiation-like plasticity in primary motor cortex in patients with progressive supranuclear palsy

doi:10.1016/j.clinph.2017.06.032

Clinical Neurophysiology

Volume 128, Issue 9, September 2017, Pages 1547-1552

https://doi.org/10.1016/j.clinph.2017.06.032 Get rights and content

Highlights

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Intermittent theta-burst stimulation induced exaggerated LTP-like motor cortical plasticity in progressive supranuclear palsy (PSP) patients.
•
Despite enhanced plasticity, PSP patients had normal depotentiation in motor cortex.
•
Altered plasticity in PSP does not reflect abnormal depotentiation as a mechanism.

Abstract

Objective

Abnormal primary motor cortex plasticity might be involved in the pathophysiology of progressive supranuclear palsy. In the present study we aimed to investigate possible abnormalities of depotentiation, a mechanism involved in plasticity regulation, in this condition.

Methods

Primary motor cortex excitability, investigated with single and paired-pulse transcranial magnetic stimulation, as well as long-term potentiation-like plasticity and its reversibility, were studied using theta burst stimulation in 15 patients with progressive supranuclear palsy and 11 healthy controls. Participants underwent two sessions using (1) the intermittent theta-burst stimulation (potentiation protocol) and (2) intermittent theta-burst stimulation combined with a depotentiation protocol (a short continuous theta-burst stimulation).

Results

Patients with PSP had higher corticospinal excitability and lower intracortical inhibition than healthy controls. Intermittent theta-burst stimulation elicited an abnormally increased long term potentiation-like effect in patients in comparison to healthy subjects. However, the depotentiation protocol was able to reverse the effects intermittent theta-burst stimulation on motor cortex excitability both in patients and in healthy controls.

Conclusions

Altered primary motor cortex plasticity in patients with PSP does not reflect an abnormality of depotentiation.

Significance

This study provides information for a deeper understanding of the possible pathophysiological mechanisms underlying the altered M1 plasticity in PSP.

Introduction

Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder due to the deposition of tau-protein aggregates in several brain regions leading to parkinsonism, oculomotor abnormalities, early postural instability and falls. To date, the pathophysiological mechanisms of PSP are still poorly understood (Colosimo et al., 2014).

Neurophysiological studies using Transcranial Magnetic Stimulation (TMS) techniques in patients with PSP have disclosed a number of primary motor cortex (M1) abnormalities. PSP patients have enhanced MEP amplitudes at rest, i.e. increased steepness of the input–output (I/O) MEP curve and reduced short-interval intracortical inhibition (SICI), (Kühn et al., 2004, Conte et al., 2012, Brusa et al., 2014). These results overall indicate that enhanced corticospinal excitability and loss of intracortical inhibition of M1 are consistent pathophysiological abnormalities in PSP (Halliday et al., 2005). In addition to excitability changes, TMS techniques, namely the theta burst stimulation (TBS) protocols, have allowed investigation of M1 plasticity mechanisms in PSP (Conte et al., 2012). It has been observed that in intermittent TBS (iTBS) increases the MEP amplitude in PSP patients to a higher extent in comparison to healthy controls, thus suggesting altered LTP-like plasticity of M1 in this condition (Conte et al., 2012).

Previous studies in healthy subjects showed that TBS-related changes of M1 excitability can be reversed if an ineffective intervention, i.e. a short form of TBS, is given shortly afterward (Huang et al., 2010, Huang et al., 2011, Karabanov et al., 2015). Reversal of plasticity-like effects observed in human TMS studies are reminiscent of analogue phenomena observed in animal studies and termed depotentiation, (DePo), (Zhou and Poo, 2004). In physiological conditions, DePo regulates cortical plasticity by preventing acquisition of inappropriate learning and contributes to the developmental refinement of neural circuits (Zhou and Poo, 2004). Emerging evidence, however, suggests that DePo abnormalities underlie altered plasticity mechanisms in pathological conditions, like L-dopa induced dyskinesia and other hyperkinetic disorders (Huang et al., 2011, Calabresi et al., 2016). Whether abnormalities of DePo underlie the abnormally enhanced LTP-like plasticity of M1 in PSP is unknown. Clarifying this issue would contribute to a greater understanding of PSP pathophysiology.

In the present study, we aimed to investigate the mechanisms underlying altered M1 plasticity in PSP patients by specifically assessing possible abnormalities of DePo (Huang et al., 2010, Huang et al., 2011). For this purpose, in one session PSP patients underwent the iTBS protocol to test LTP-like mechanisms of M1. In another session patients underwent iTBS combined with a short continuous TBS (cTBS150) to assess the reversal (DePo) of plasticity-like effects of M1. Finally, we assessed possible relationships between neurophysiological parameters and demographic or clinical features in patients. Data collected in patients with PSP were been compared with those observed in a sample of healthy subjects.

Section snippets

Participants

Fifteen right-handed patients with PSP (5 women, mean age ± 1SD: 69.2 ± 6.2) and 11 right-handed healthy controls (HC), (4 women, mean age ± 1SD: 66.7 ± 6.6) participated in the study. Participants were recruited from the Department of Neurology and Psychiatry, Sapienza University, Rome, Italy and the Department of Neurosciences, Alfred Hospital, Melbourne, Australia.

The diagnosis of PSP was based on clinical criteria (Litvan et al., 1996). The clinical features were compatible with the Richardson’s

Results

All the study participants were able to complete the two main experimental sessions, no adverse effects were observed during the study. There was no difference in age (U = 61.0, P = 0.27) or gender ratio (P = 0.59) between patients with PSP and HC.

Discussion

In the present study, we observed that patients with PSP have an increased slope of the I/O MEP curve and reduced SICI in comparison to HC. Also, PSP patients had an abnormal increase in the MEP amplitude after iTBS of M1. These results are confirmatory of previous TMS investigations showing altered M1 excitability and plasticity in PSP (Kühn et al., 2004, Conte et al., 2012, Brusa et al., 2014). The original observation of the present study is that the DePo protocol (cTBS150), (Huang et al.,

Conclusions

This study provides information on the neurophysiological abnormalities in patients with PSP and a deeper understanding of the possible pathophysiological mechanisms underlying the altered M1 plasticity in this condition. The results support the hypothesis that altered cortical plasticity in PSP does not primarily reflect an intrinsic alteration of the regulatory mechanisms of plasticity per se, but it is possibly due to degeneration of intra-cortical inhibitory interneurons. Further studies in

Conflict of interest

None of the authors have potential conflicts of interest to be disclosed.

Funding sources

None.

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View full text

Reversal of long term potentiation-like plasticity in primary motor cortex in patients with progressive supranuclear palsy

Highlights

Abstract

Objective

Methods

Results

Conclusions

Significance

Introduction

Section snippets

Participants

Results

Discussion

Conclusions

Conflict of interest

Funding sources

Brain Stimul

Brain Stimul

Neuron

Brain Stimul

Clin Neurophysiol

Neurobiol Dis

Neurobiol Dis

Brain Stimul

Clin Neurol Neurosurg

Trends Neurosci

An inventory for measuring depression

Arch Gen Psychiatry

Hyperkinetic disorders and loss of synaptic downscaling

Nat Neurosci

Reversal of long-term potentiation-like plasticity processes after motor learning disrupts skill retention

J Neurosci

Depotentiation from potentiated synaptic strength in a tristable system of coupled phosphatase and kinase

Front Comput Neurosci

Fifty years of progressive supranuclear palsy

J Neurol Neurosurg Psychiatry

Abnormal cortical synaptic plasticity in primary motor area in progressive supranuclear palsy

Cereb Cortex