Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT03998787 |
| Other study ID # |
ALBE_01 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 1, 2020 |
| Est. completion date |
September 1, 2022 |
Study information
| Verified date |
February 2020 |
| Source |
Neuromed IRCCS |
| Contact |
Alfredo Berardelli |
| Phone |
+390649914700 |
| Email |
alfredo.berardelli[@]uniroma1.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
Parkinson's disease (PD) is characterized by bradykinesia, rigidity, and tremor. Several
scientific pieces of evidence, based on the use of kinematic techniques, have allowed
quantifying objectively the alterations of the voluntary movement in the different stages of
the disease. In recent years, several studies using transcranial magnetic stimulation (TMS)
techniques, have also shown abnormalities in neurophysiological parameters of the primary
motor cortex (M1) in patients with MP, in particular, a reduction in cortical excitability
and synaptic plasticity of M1. In addition to the central role played by a dopaminergic
deficit in MP, recent evidence suggests a possible involvement of the neurotransmitter
glutamatergic system. In the present monocentric observational study, the investigators
propose to assess possible correlations between polymorphisms of metabotropic glutamate type
3 receptors (mGlu3), clinical evaluation scales, alterations of kinematic motion parameters
and neurophysiological parameters of M1.
Description:
In recent years, numerous neurophysiological studies have characterized the alterations of
voluntary movement and the pathophysiological mechanisms of MP. Kinematic studies have shown
that in addition to bradykinesia, which literally means slowing of movement, voluntary
movements in PD are characterized by reduced amplitude (hypokinesia), altered rhythmicity
(dysrhythmia) and progressive decrease in amplitude and speed during the execution of
repetitive movements (sequence effect). Recent evidence also suggests that the
characteristics of voluntary movement can vary in the various stages of PD, it has been
observed, for example, that in early stages of disease, i.e. in newly diagnosed patients not
previously treated with dopaminergic drugs repetitive finger-tapping movements are
characterized by reduced amplitude and speed and the effect sequence, without significant
changes in the rhythm of movement. In the advanced stages of PD, movement is characterized by
a marked decrease in amplitude and velocity and by an altered rhythm of movement but not by
the sequence effect.
TMS is a neurophysiological technique that allows the non-invasive study of different
physiological mechanisms of M1 in humans. Stimulation, delivered in single stimuli, allows
for example to evaluate neurophysiological parameters such as motor thresholds, the amplitude
of motor evoked potentials (MEPs) and the so-called input-output recruitment curve of MEPs,
i.e. parameters that reflect the overall excitability of the corticospinal system. TMS
delivered in pairs of magnetic stimuli allows additional parameters to be evaluated, such as
intracortical inhibition at short intervals (SICI) and intracortical facilitation (ICF), i.e.
parameters that reflect the excitability of inhibitory and facilitator cortical interneurons.
In recent years, further protocols have been developed using the repetitive stimulation of M1
to induce lasting changes in the amplitude of MEPs that are thought to reflect the mechanisms
of synaptic plasticity, similar to similar phenomena observed in the experimental animal. In
particular, the technique of associative stimulation (PAS), is based on percutaneous
electrical stimulation of the peripheral nerve and concomitant stimulation of M1 by TMS at
certain inter-stimulation intervals (25ms or 10ms) to induce lasting changes, in a
facilitatory or inhibitory sense, in the amplitude of MEPs. Numerous TMS studies have been
performed in PD patients in recent years. Among the main results observed are altered
excitability of M1, especially a reduced SICI and reduced synaptic plasticity, tested with
the PAS technique or other methods. Recently, we have also observed that some alterations of
excitability and plasticity of M1 correlate with specific kinematic alterations of movement
in PD patients, suggesting therefore that neurophysiological changes of M1 contribute to the
pathophysiology of bradykinesia. In addition to the central role played by a dopaminergic
deficit in MP, recent evidence suggests a possible involvement of the neurotransmitter
glutamatergic system.
MAIN ASSUMPTIONS AND OBJECTIVES
Hypothesis:
Previous studies have observed relationships between the reduced cortical inhibition and
reduced synaptic plasticity of M1 and the overall severity of PD evaluated with standardized
clinical scales and kinematic motion analysis techniques. In the present study, we will
relate metabotropic type 3 glutamate receptor polymorphisms (mGlu3) to the severity of motor
and non-motor symptoms, cortical plasticity and other neurophysiological parameters in
patients with PD.
Preliminary data:
Previous observations obtained in our laboratory have shown that the kinematic study in PD is
a valid technique for objectively documenting various alterations of voluntary movement,
including bradykinesia, hypokinesia, altered rhythmicity, and sequence effect. These
characteristics may change at various stages of PD. For example, it has been observed that in
the early stages of illness, repetitive finger movements are characterized by reduced
amplitude and speed and by the sequence effect, without significant alterations in the rhythm
of the movement. In the advanced stages of PD, movement is characterized by a marked decrease
in amplitude and velocity and an altered rhythm of movement but not by the sequence effect.
Kinematic studies in patients with PD have also made it possible to objectively quantify the
effects of dopaminergic replacement therapy on the various alterations that characterize the
PD. The objective effects of dopaminergic therapy on the various alterations of voluntary
movement, quantified by kinematic studies, are variable. In particular, it has been
repeatedly observed that the sequencing effect in patients with PD does not improve
significantly following the administration of dopaminergic drugs. Previous observations
obtained in TMS studies have also demonstrated altered M1 excitability in patients with PD,
including for example reduced SICI and reduced synaptic plasticity, tested with the PAS
technique or other methods. In some cases, it has been observed that the administration of
dopaminergic drugs is able to normalize the alterations of neurophysiological parameters of
M1 in PD, the results are however variable. Recently, we have observed that some alterations
of excitability and plasticity of M1 correlate with specific kinematic alterations of
movement in PD patients, suggesting therefore that neurophysiological changes of M1
contribute to the pathophysiology of bradykinesia.
Objectives:
In the present monocentric observational study, the investigators propose to:
A) To carry out an accurate characterization of the alterations of the voluntary movement in
patients with PD through the use of standardized clinical scales and a computerized system
for the objective analysis of the voluntary movement and a detailed study of possible
neurophysiological alterations of M1 in patients with PD, through the use of TMS techniques.
B) Evaluate metabotropic type 3 glutamate receptor polymorphisms (mGlu3) in PD patients.
C) Investigate possible correlations between type 3 metabotropic glutamate receptor
polymorphisms (mGlu3), clinical evaluation scales, alterations of kinematic motion parameters
and neurophysiological parameters of M1.
METHODOLOGY AND EXPERIMENTAL DESIGN The study involves the recruitment of 20 PD patients,
diagnosed according to current clinical criteria and 20 healthy control subjects. Patients
with motor fluctuations and dyskinesia will be excluded. Recruitment of patients and control
subjects will be carried out at the IRCCS NEUROMED Institute, Pozzilli (IS). All PD patients
will undergo blood sampling to assess metabotropic glutamate type 3 (mGlu3) receptor
polymorphisms All study participants will give informed consent to the experimental
procedures, which will be approved by the local ethics committee and conducted in accordance
with the Helsinki Declaration.
Standardized clinical scales and a computerized system for objective analysis of voluntary
movement will be used to characterize alterations of voluntary movement in PD patients. With
this system, the movements of the upper limb will be examined, following the instructions
dictated by the scale most widely used today in the clinical environment, namely the new
version of the UPDRS, promoted by the Movement Disorder Society. The repetitive movements of
the fingers will be examined by inviting the patient to tap his index finger on his thumb.
For each test, the movements shall be made for 15 seconds in succession. Three recordings
will be made for each movement. Participants will be encouraged to make the movements as fast
and as wide as possible. The movements will be analyzed at the most affected side. The
computerized analysis system will allow to objectively extrapolate the parameters related to
speed, amplitude, the rhythm of the movement and effect-sequence.
The study of neurophysiological alterations of M1 will be carried out by means of the TMS
technique. Ejecting single magnetic stimuli, a measurement of parameters reflecting the
excitability of the corticospinal pathway will be carried out, i.e. the measurement of motor
thresholds and of the input-output recruitment curve. By delivering magnetic stimuli in
pairs, according to a condition-test paradigm, at inter-stimulus intervals fixed at 2-4-10
and 15ms parameters reflecting the excitability of intracortical circuits of inhibitory
(SICI) and facilitatory (ICF) type will be measured. Finally, the PAS technique will be used
to study the mechanisms of synaptic plasticity of M1. PAS uses joint peripheral nerve
stimulation (percutaneous electrical stimulation) and M1 (TMS) at an inter-stimulation
interval fixed at 25ms. During the PAS technique, 225 stimuli are delivered globally, at a
frequency of 0.4 Hz and for a total duration of 15 minutes of stimulation.
Patients with PD will be studied in a single experimental session, at least twelve hours
after the suspension of dopaminergic drugs (OFF session). Healthy control subjects will be
evaluated in a single experimental session.
MEANING AND INNOVATION The main innovative aspect of the study is the integrated approach
that involves the use of both techniques of kinematic analysis of movement, and techniques of
non-invasive brain stimulation. The present work could, therefore, allow to deepen the
current knowledge and to obtain advancement in terms of understanding the pathophysiological
mechanisms underlying the altered motor control in patients with PD.
EQUIPMENT AND RESOURCES The study will be carried out at the IRCCS NEUROMED Institute,
Pozzilli (IS). The institute has the material to conduct the study and in particular: the
optoelectronic system of infrared cameras (sampling rate, 120Hz), (SMART motion system, BTS
Engineering, Milan, Italy) for kinematic evaluation; the dedicated software for kinematic
data analysis (SMART Analyzer, BTS Engineering, Milan, ltaly); two Magstim magnetic
stimulators (Magstim Company, Withland, UK) for single and double stimulation magnetic
stimulation and one DS7 Digitimer electric simulator (Digitimer, UK) for PAS stimulation; one
D 360 Digitimer amplifier (Digitimer, UK) and one AD 1401 plus analogue-to-digital converter
(Cambridge Electronic Design, UK) for recording the electromyographic signal; one dedicated
software (Signal® version 4.00, Cambridge Electronic Design, UK) for off-line analysis of the
electromyographic signal.
TRANSLATIONAL RELEVANCE OF THE STUDY The results of the study could be useful for a better
understanding of the pathophysiological mechanisms, and in particular of the involvement of
M1, at the basis of the alterations of voluntary movement in MP. The results of the study
could also be useful in developing possible treatments, based on the use of subtype-selective
agonists and positive allosteric modulators of metabotropic glutamate type 3 receptors
(mGlu3).
