Early Neurophysiological Interventions in Acute Cerebral Lesions
Condition: Stroke; Acute Stroke
MeSH terms: Stroke
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): bihemispheric transcranial direct stimulation
Intervention type(s): Device
Intervention description(s): tDCS was applied with the anode placed over the M1 hand area of the ipsilesional motor cortex and the cathode over the same area of the contralesional motor cortex (C3/C4). For the active condition, patients received 5 consecutive daily sessions of 2 mA anodal tDCS over the AH and cathodal tDCS over the UH of 20 minutes each, with fade-in and fade-out periods of 1s. For the sham condition, the stimulation applied in the same sites and with the same parameters, was turned off after a fade-in period, 30 seconds of direct current stimulation and a fade-out period.
Repetitive peripheral nerve stimulation was performed by a peripheral nerve stimulator to the radial nerve and applied at the same time as tDCS. Radial nerve was chosen to improve wrist extension. Trains of 40 stimuli (ISI: 10 ms, duration: 1ms) were delivered every 6 seconds to the radial nerve through bipolar electrodes (5 cm diameter) at an intensity that could elicit a visible wrist extension (20-30 mA).
Other intervention name(s): repetitive peripheral stimulation
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 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 transcranial direct current stimulation (tDCS) over the affected hemisphere and cathodal over unaffected hemisphere combined with repetitive peripheral nerve stimulation (rPSN) and the other received sham tDCS associated to rPNS. Patients were examined before tDCS, 5 days and 3, 6 and 12 months after tDCS.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: transcranial direct current stimulation; stroke rehabilitation; neuromodulation; corticomotor excitability; repetitive peripheral nerve stimulation