Stroke Clinical Trial
Official title:
Early Neurophysiological Interventions in Acute Cerebral Lesions
Objective:
Transcranial direct current stimulation (tDCS) can change the excitability of the central
nervous system and contribute to motor recovery of stroke patients. The investigators
hypothesized that the benefit of tDCS may increase with interventions facilitating motor
responses, such as repetitive peripheral nerve stimulation (rPNS).
The aim of our study was to examine the short and long-term effects of real vs sham
bihemispheric tDCS on scales of motor function and neurophysiological tests in patients with
acute stroke and a moderate/severe motor impairment.
Methods:
The study was prospective, randomized, double-blind and placebo controlled. Twenty acute
stroke patients (ischemic and haemorrhagic) with Upper limb Fugl-Meyer (ULFM) score<19 were
randomized in two parallel groups: one group received 5 consecutive daily sessions of anodal
tDCS over the affected hemisphere (AH) and cathodal over unaffected hemisphere combined with
rPNS and the other received sham tDCS associated to rPNS. Pacients were examined before tDCS,
5 days and 3, 6 and 12 months after tDCS. The investigators evaluated ULFM and modified
Ashworth scales (MAS), resting motor threshold, motor and somatosensory evoked potentials
(MEPs and SEPs), silent periods and Hmax/Mmax ratio.
Transcranial direct current stimulation (tDCS) is a form of noninvasive brain stimulation
used to induce excitability changes in central nervous system circuits. The basis of tDCS
application in stroke patients follows the model of interhemispheric imbalance between the
damaged and intact hemispheres: anodal tDCS over affected hemisphere to induce long-lasting
increase in cortical excitability, cathodal tDCS over unaffected hemisphere to induce
long-lasting decrease in cortical excitability. Simultaneous effects on both hemispheres can
be obtained with bi-hemispheric tDCS. Minimum intensity and duration of tDCS is necessary to
induce long-lasting effects, which are referred as long-term potentiation and long-term
depression.
Most interventional tDCS studies have focused on chronic stroke patients, at a time in which
patients are supposed to have reached a plateau in their spontaneous recovery after the
lesion. Less research has evaluated the effects of an early tDCS intervention. tDCS protocols
differ in location of electrodes, session frequency and duration, dosage of electrical
charge, temporal window of tDCS delivery and other variables. The functional benefit of tDCS
may increase with the concomitant application of adjuvant therapeutic strategies such as
constraint-induced therapy, electrical stimulation or robot-mediated therapy. Sattler et al.
used radial nerve stimulation, together with tDCS, to facilitate motor output. It is possible
that repetitive peripheral nerve stimulation (rPNS) modulates corticospinal output at
somatotopically specific supraspinal sites through GABAergic interneurons. The patients that
improved in Sattler et al.'s study, as in other tDCS studies, had an initial mild to moderate
impairment of motor function. Improvement is more dubious in patients presenting with severe
motor deficit.
Our aim in this study was to examine the effectiveness of bihemispheric tDCS combined with
rPNS in acute stroke patients with pronounced motor impairment, the group of patients with
fewer options in therapeutic programs.
The benefit of applying tDCS early after stroke is still unclear. However, based on animal
models, the first month after stroke seems to be the optimal period to induce morphological
changes associated with increased plasticity, hence the therapeutic window was chosen between
5 and 20 days after the stroke event. The investigators reasoned that, if plastic changes
have been induced by tDCS, the clinical and neurophysiological benefit may manifest not just
immediately after treatment, but further ahead in the patient's natural evolution after the
stroke. For this reason, the investigators considered relevant to determine if the results of
tDCS treatment persisted in time and had a long-term effect, therefore extended our clinical
and neurophysiological follow-up to 12 months after treatment.
Methods:
Patients:
Twenty patients with a history of first acute stroke (ischemic and haemorrhagic) were
included, from April through December 2011, in a prospective, double-blind, randomized study.
Eleven patients were affected by an ischemic stroke: cortical and/or subcortical and 9 were
affected by a haemorrhagic stroke. Inclusion criteria were: first time single and unilateral
supratentorial stroke confirmed by CT or MRI, stroke interval between 5 and 20 days of study
onset, age 18 to 79 years, National Institutes of Health Stroke Scale (NIHSS) ≥6 and ≤21.
Exclusion criteria were preceding epileptic seizures, metallic implants within the brain or
pacemaker implants and coexistence of other neurological diseases.
Patients were included in the study when they were medically stable, between 5 and 17 days
after the stroke event. The study was conducted in according to the World Medical Association
Declaration of Helsinki and approved by the Clinical Research Ethics Committee (PR160/11).
Written, informed consent was obtained from all participants or their relatives before their
inclusion in the study.
Patients were randomized in two parallel groups: one group (11 patients) received 5
consecutive daily sessions of anodal tDCS over the affected hemisphere and cathodal over
unaffected hemisphere combined with repetitive peripheral nerve stimulation and the other (9
patients) received sham tDCS associated to repetitive peripheral nerve stimulation.
Patients were examined before tDCS, 5 days and 3, 6 and 12 months after tDCS.
Assessments Patients' condition was characterized using standardized clinical and
neurophysiological assessment tools on the day before onset of interventions.
Clinical assessment Neurological functioning was assessed using the NIHSS. Motor assessment
of the paretic upper limb and spasticity were evaluated using the upper limb Fugl-Meyer
(ULFM) and Modified Ashworth scales (MAS). MAS scale measures were taken for shoulder
abduction, elbow extension and wrist extension, which were used to calculate the mean value
of resistance during passive stretching, with higher scores reflecting greater resistance
(maximum 4).
Neurophysiological assessment
Transcranial magnetic stimulation:
Motor evoked potentials (MEPs) were recorded using a biphasic magnetic stimulator (Magstim
200; The Magstim Co. Ltd., UK) connected to a figure-of-eight magnetic stimulating coil
(70-mm outer diameter; The Magstim Co. Ltd., UK) placed over the cortical abductor digiti
minimi hotspot. A tight-fitting cloth cap marked with a 1cmx1cm grid was used for the mapping
of the target muscle cortical representation. The coil was positioned tangentially to the
scalp, with the handle pointing backwards at an angle of 45 degrees to midline and was moved
in 1-cm steps to localize the optimal scalp location in each hemisphere, from which the
largest MEPs in the abductor digiti minimi could be evoked. A Synergy electromyograph (Oxford
Instruments, Surrey, UK) was used to record MEPs from the abductor digiti minimi. Whenever
MEPs were not elicited in the affected upper limb at rest using maximal stimulator output,
patients were instructed to make an attempt to voluntarily activate the muscle. If no MEP
could be elicited using maximal stimulator output, MEPs amplitude was described as 0 mV.
Groppa S, Oliviero A, Eisen A et al. A practical guide to diagnostic transcranial magnetic
stimulation: report of an IFCN committee. Clin Neurophysiol 2012;123:858-882.
Resting motor threshold:
Resting motor threshold (rMT) was defined as the lowest stimulator output at the optimal
scalp site required to elicit a MEP of at least 50 μV in the relaxed abductor digiti minimi
in at least 5 of 10 trials.21 If no MEP could be elicited using maximal stimulator output,
then rMT was described as 100%.
Contralateral and ipsilateral silent period:
To elicit the silent period, transcranial magnetic stimulation was applied over the M1 area
of each hemisphere while patients sustained a steady maximum tonic contraction of the
abductor digiti minimi and a 500ms poststimulus period was analysed. Stimulation intensity
was 120% rMT. We essentially recorded simultaneously contralateral (cSP) and ipsilateral
silent period (iSP) to a unilateral stimulus. If patients were unable to maintain a stable
contraction with the paretic hand, the SP was considered unmeasurable. cSP duration was
measured from the onset of the MEP to the point of EMG resumption after a period of EMG
suppression and the mean of 10 trials was used to estimate the silent period duration. iSP
was quantified considering a period of relative suppression of EMG activity below the
background EMG activity.
Takechi U, Matsunaga K, Nakanishi R et al. Longitudinal changes of motor cortical
excitability and transcallosal inhibition after subcortical stroke. Clin Neurophysiol
2014;125: 2055-2069.
SEPs recording:
Somatosensory evoked potentials (SEPs) were elicited using electrical stimulation with the
same procedure described in detail in previous studies. Signals were recorded using Synergy
electromyograph (Oxford Instruments, Surrey, UK). SEPs data were compared between affected
and unaffected upper limbs.
Cruccu G, Aminoff MJ, Curio G et al. Recommendations for the clinical use of
somatosensory-evoked potentials. Clin Neurophysiol 2008;119:1705-19.
Mauguière F, Allison T, Babiloni C et al. Somatosensory evoked potentials. The International
Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl
1999;52:79-90.
H-reflex H-reflex responses were recorded from a 45-degree angle supinated arm and a slightly
contracted flexor carpi radialis muscle. When the flexor carpi radialis muscle couldn't be
contracted the paretic upper limb was positioned with the wrist in slight flexion. Recording
electrode was placed over the belly of the flexor carpi radialis and referred to an electrode
3 cm distal. Electrical stimuli delivered a square-wave pulse of 0.5 ms in duration and were
applied over the median nerve at the bicipital groove; above the cubital crease. Hmax/Mmax
responses were compared between the paretic and non-paretic sides.
Christie AD, Inglis JG, Boucher JP, Gabriel DA. Reliability of the FCR H-reflex. J Clin
Neurophysiol 2005;22:204-9.
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